WO2013124740A2 - Dysfonctionnement de la protéine brca et signatures arnm utiles dans l'identification de patients atteints de tumeurs dues au dysfonctionnement de la protéine brca et prévision des bénéfices d'une thérapie anti-cancer sur des patients atteints de cancer - Google Patents

Dysfonctionnement de la protéine brca et signatures arnm utiles dans l'identification de patients atteints de tumeurs dues au dysfonctionnement de la protéine brca et prévision des bénéfices d'une thérapie anti-cancer sur des patients atteints de cancer Download PDF

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WO2013124740A2
WO2013124740A2 PCT/IB2013/000670 IB2013000670W WO2013124740A2 WO 2013124740 A2 WO2013124740 A2 WO 2013124740A2 IB 2013000670 W IB2013000670 W IB 2013000670W WO 2013124740 A2 WO2013124740 A2 WO 2013124740A2
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seq
brca
deficiency
deficiency signature
proteins
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PCT/IB2013/000670
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WO2013124740A3 (fr
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Cornelia Ramona Jimenez
Marc Omer WARMOES
Thang Viet PHAM
Sven ROTTENBERG
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Stichting Vu-Vumc
Stichting Het Nederlands Kanker Instituut
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Publication of WO2013124740A2 publication Critical patent/WO2013124740A2/fr
Publication of WO2013124740A3 publication Critical patent/WO2013124740A3/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57415—Specifically defined cancers of breast
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57484—Immunoassay; Biospecific binding assay; Materials therefor for cancer involving compounds serving as markers for tumor, cancer, neoplasia, e.g. cellular determinants, receptors, heat shock/stress proteins, A-protein, oligosaccharides, metabolites
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present disclosure relates to proteomes from BRCA 1 -deficient tumors and corresponding messenger RNA sequences useful in identifying patients with BRCA deficiency, identifying patients with BRCA pathway defects ("BRCAness"), identifying tumors with BRCA1 and/or BRCA2 defects, and in optimizing the therapeutic efficacy of anti-cancer therapy by detecting phenotypic genetic traits.
  • Classifiers comprising the proteomes, and/or subsets of proteins from the proteomes, and classifiers comprising the messenger RNA sequences, and/or subsets of the messenger RNA sequences, are also disclosed.
  • Breast cancer is the most frequently occurring cancer among women in the western world. It is a heterogeneous cancer disease, consisting of several subtypes.
  • a disadvantage to the use of (neo)adjuvant systemic therapy is the lack of predictive tests to individualize the choice of certain combinations of drugs for an individual breast cancer patient to ensure maximal benefit with minimal toxicity.
  • highly toxic adjuvant treatment regimens such as high dose alkylating chemotherapy with hematopoietic stem-cell rescue
  • the survival benefit when compared with standard chemotherapy is approximately 10% for patients with 10 or more positive axillary lymph nodes. It would thus be advantageous to be able to target those 10% of patients who would benefit from high dose alkylating chemotherapy.
  • few predictive tests presently exist. Because of the relatively high toxicity and the low level of efficacy in unselected breast cancer patients, alkylating agents are not commonly used in the treatment of breast cancer, with the exception of cyclophosphamide.
  • Alkylating chemotherapy and platinating agents work by causing interstrand
  • BRCAl A major function of BRCAl is its role in homology-directed double-strand break (DSB) repair, a DNA repair mechanism that uses the sister chromatid as a template, and therefore repairs double-strand breaks in an error- free manner. Deficiencies in homology-directed DNA repair cause high levels of genomic instability that increase the risk of tumorigenesis.
  • Breast cancer associated with BRCAl mutations accounts for only 1-2% of breast cancer cases in the Western world.
  • BRCAl hereditary breast cancer falls into the molecular sub-type of basal-like breast cancer that has a poor prognosis. Sporadic basal-like breast tumors represent approximately 10-15% of all breast carcinomas and comprise many tumors that share key features of BRCAl - associated tumors.
  • PARP inhibitors novel poly(ADP-ribose) polymerase inhibitors
  • Mutations of the BRCA2 gene can cause the BRCA2 protein to be abnormal and defective. Defective BRCA2 protein is unable to function normally and thus cannot repair breaks in DNA. As a result, mutations build up that can cause uncontrolled cell growth, leading to cancers. In addition to breast cancer in men and women, mutations in the BRCA2 gene can lead to an increased risk of ovarian, fallopian, prostate, and pancreatic cancers, as well as malignant melanoma. Several other types of cancer have also been seen in certain families carrying BRCA2 gene mutations. Identification of a mutation in the BRCA2 gene in a patient can assist a health care provider in determining the proper course of treatment for the patient. Additionally, mutation identification allows for pre-symptomatic mutation screening in family members.
  • methods of optimizing the therapeutic efficacy of anti-cancer therapies by identifying patients who would benefit from one or more anti-cancer therapies, including, without limitation, DNA double strand break-inducing regimens such as high dose alkylating chemotherapy, by reliably determining homologous recombination deficiency in tumor biopsies, and by identifying patients with cancers harboring a defective BRCAl - deficient DNA repair system or BRCA2-deficient repair system, or both (cancer deficient in homology-directed DNA repair), are useful.
  • the present disclosure is based on the discovery that certain differentially expressed proteins associated with BRCAl -deficient tumors can be used to identify cancer patients with BRCAl -deficient tumors and/or BRCA2-deficient tumors and to predict whether such patients will benefit from anti-cancer therapy.
  • the present disclosure is also based on the discovery that the analysis of tumor proteins is useful in identifying patients with BRCAl -like and/or BRCA2-like cancer and selecting patients that will benefit from tailored anti-cancer therapies.
  • the present disclosure is based on the discovery that certain proteins are significantly differentially regulated between BRCAl-deficient tumors and BRCAl proficient tumors and that differential regulation can be used as a means of identifying cancer patients with BRCAl -deficient tumors and/or BRCA2-deficient tumors and predicting whether such patients will benefit from anti-cancer therapy.
  • the present disclosure is based on the discovery that certain up-regulated proteins seen in BRCAl -deficient tumors can be used to identify cancer patients with BRCAl -deficient tumors and to predict whether such patients will benefit from anticancer therapy.
  • the present disclosure is based on the discovery that certain up-regulated proteins seen in BRCAl -deficient tumors can be used to identify cancer patients with BRCA2-deficient tumors and to predict whether such patients will benefit from anti- cancer therapy.
  • the present disclosure is based on the discovery that certain up-regulated proteins seen in BRCAl -deficient tumors that exhibit DNA-repair, chromatin remodeling and associated functions can be used to identify cancer patients with BRCA1- deficient tumors and/or BRCA2-deficient tumors (cancer deficient in homology-directed DNA repair) and to predict whether such patients will benefit from anti-cancer therapy.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 417 significantly differentially regulated proteins with DNA repair(-associated) functions set forth in Fig. 1 that can enrich for homology-directed DNA repair deficient tumors.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 417 significantly differentially regulated proteins with DNA repair(-associated) functions set forth in Fig. 1 that can identify cancer patients having a BRCAl deficiency.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 417 significantly differentially regulated proteins with DNA repair- associated) functions set forth in Fig. 1 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCAl deficiency.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 417 significantly differentially regulated proteins with DNA repair(-associated) functions set forth in Fig. 1 that can identify cancer patients having a BRCA2 deficiency.
  • BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 417 significantly differentially regulated proteins with DNA repair(-associated) functions set forth in Fig. 1 that can identify cancer patients having a BRCA2 deficiency.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 417 significantly differentially regulated proteins with DNA repair(-associated) functions set forth in Fig. 1 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCA2 deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 417 significantly differentially regulated proteins with DNA repair(- associated) functions set forth in Fig. 1 that can enrich for homology-directed DNA repair deficient tumors.
  • the present disclosure provides a BRCA- deficiency signature comprising the 417 significantly differentially regulated proteins with DNA repair(-associated) functions set forth in Fig. 1 that can identify cancer patients having a BRCA1 deficiency.
  • the present disclosure provides a BRCA- deficiency signature comprising the 417 significantly differentially regulated proteins with DNA repair(-associated) functions set forth in Fig. 1 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCA1 deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 417 significantly differentially regulated proteins with DNA repair(- associated) functions set forth in Fig. 1 that can identify cancer patients having a BRCA2 deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 417 significantly differentially regulated proteins with DNA repair(- associated) functions set forth in Fig. 1 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCA2 deficiency.
  • the BRCA-deficiency signatures may comprise a set of at least 5 proteins selected from the 417 significantly differentially regulated proteins with DNA repair(-associated) functions set forth in Fig. 1.
  • the BRCA-deficiency signatures may comprise a set of at least 6 proteins selected from the 417 significantly differentially regulated proteins with DNA repair(-associated) functions set forth in Fig. 1.
  • the BRCA-deficiency signatures may comprise a set of at least 7 proteins selected from the 417 significantly differentially regulated proteins with DNA repair(-associated) functions set forth in Fig. 1.
  • the BRCA-deficiency signatures may comprise a set of at least 8 proteins selected from the 417 significantly differentially regulated proteins with DNA repair(-associated) functions set forth in Fig. 1.
  • the BRCA-deficiency signatures may comprise a set of at least 9 proteins selected from the 417 significantly differentially regulated proteins with DNA repair(-associated) functions set forth in Fig. 1.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 45 up- regulated proteins with DNA repair(-associated) functions set forth in Fig. 2 that can enrich for homology-directed DNA repair deficient tumors.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig. 2 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCA1 deficiency.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 45 up- regulated proteins with DNA repair(-associated) functions set forth in Fig. 2 that can identify cancer patients having a BRCA2 deficiency.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig. 2 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCA2 deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig. 2 that can enrich for homology-directed DNA repair deficient tumors.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig. 2 that can identify cancer patients having a BRCA1 deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig. 2 that can enrich for homology- directed DNA repair deficient tumors and identify cancer patients having a BRCA1 deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig. 2 that can identify cancer patients having a BRCA2 deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig. 2 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCA2 deficiency.
  • the BRCA-deficiency signatures may comprise a set of at least 5 proteins selected from the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig. 2.
  • the BRCA-deficiency signatures may comprise a set of at least 6 proteins selected from the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig. 2.
  • the BRCA-deficiency signatures may comprise a set of at least 7 proteins selected from the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig. 2.
  • the BRCA-deficiency signatures may comprise a set of at least 8 proteins selected from the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig. 2.
  • the BRCA-deficiency signatures may comprise a set of at least 9 proteins selected from the 45 up-regulated proteins with DNA repair(-associated) functions set forth in Fig. 2.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45 that can enrich for homology-directed DNA repair deficient tumors.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45 that can identify cancer patients having a BRCA1 deficiency.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCA1 deficiency.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45 that can identify cancer patients having a BRCA2 deficiency.
  • the present disclosure provides BRCA- deficiency signatures comprising at least one, and in some embodiments a plurality, of the amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCA2 deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45 that can enrich for homology-directed DNA repair deficient tumors.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45 that can identify cancer patients having a BRCA1 deficiency.
  • the present disclosure provides a BRCA- deficiency signature comprising the 45 amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCA1 deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45 that can identify cancer patients having a BRCA2 deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCA2 deficiency.
  • the BRCA-deficiency signatures may comprise a set of at least 5 amino acid sequences selected from the 45 amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45.
  • the BRCA-deficiency signatures may comprise a set of at least 6 amino acid sequences selected from the 45 amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45.
  • the BRCA-deficiency signatures may comprise a set of at least 7 amino acid sequences selected from the 45 amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45.
  • the BRCA-deficiency signatures may comprise a set of at least 8 amino acid sequences selected from the 45 amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45.
  • the BRCA-deficiency signatures may comprise a set of at least 9 amino acid sequences selected from the 45 amino acid sequences of SEQ ID NO: 1 through SEQ ID NO: 45.
  • the present disclosure provides methods of using the protein and amino acid sequence-based BRCA-deficiency signatures disclosed herein to identify cancer having a BRCA1 deficiency.
  • the present disclosure provides methods of using the protein and amino acid sequence-based BRCA-deficiency signatures disclosed herein to identify cancer having a BRCA2 deficiency.
  • the present disclosure provides methods of using the protein and amino acid sequence-based BRCA-deficiency signatures to predict whether a patient having cancer with a BRCA1 deficiency will benefit from anti-cancer therapy.
  • the present disclosure provides methods of using the protein and amino acid sequence-based BRCA-deficiency signatures to predict whether a patient having cancer with a BRCA2 deficiency will benefit from anti-cancer therapy.
  • the present disclosure is based on the discovery that certain nucleic acid sequences that code for differentially expressed proteins associated with BRCA1 -deficient tumors can be used to identify cancer patients with BRCA1 -deficient tumors and/or BRCA2-deficient tumors and to predict whether such patients will benefit from anti-cancer therapy.
  • the present disclosure is also based on the discovery that the analysis of nucleic acid sequences coding for tumor proteins is useful in identifying patients with BRCAl-like cancer and/or BRCA2-like cancer and selecting patients that will benefit from tailored anti-cancer therapies.
  • the present disclosure is based on the discovery that certain nucleic acid sequences code for proteins that are significantly differentially regulated between BRCA 1 -deficient tumors and BRCA1 proficient tumors and that differential regulation can be used as a means of identifying cancer patients with BRCA1 -deficient tumors and/or BRCA2-deficient tumors and predicting whether such patients will benefit from anti-cancer therapy.
  • the present disclosure is based on the discovery that certain nucleic acid sequences that code for up-regulated proteins seen in BRCAl-deficient tumors can be used to identify cancer patients with BRCAl-deficient tumors and to predict whether such patients will benefit from anti-cancer therapy.
  • the present disclosure is based on the discovery that certain nucleic acid sequences that code for up-regulated proteins seen in BRCAl-deficient tumors can be used to identify cancer patients with BRCA2-deficient tumors and to predict whether such patients will benefit from anti-cancer therapy.
  • the present disclosure is based on the discovery that certain nucleic acid sequences that code for up-regulated proteins seen in BRCAl-deficient tumors that exhibit DNA-repair, chromatin remodeling and associated functions can be used to identify cancer patients with BRCAl-deficient tumors and/or BRCA2-deficient tumors and to predict whether such patients will benefit from anti-cancer therapy.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90 that can enrich for homology- directed DNA repair deficient tumors.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90 that can identify cancer patients having a BRCAl deficiency.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCAl deficiency.
  • the present disclosure provides BRCA-deficiency signatures comprising at least one, and in some embodiments a plurality, of the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90 that can identify cancer patients having a BRCA2 deficiency.
  • the present disclosure provides BRCA- deficiency signatures comprising at least one, and in some embodiments a plurality, of the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCA2 deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90 that can enrich for homology-directed DNA repair deficient tumors.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90 that can identify cancer patients having a BRCAl deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCAl deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90 that can identify cancer patients having a BRCA2 deficiency.
  • the present disclosure provides a BRCA-deficiency signature comprising the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90 that can enrich for homology-directed DNA repair deficient tumors and identify cancer patients having a BRCA2 deficiency.
  • the BRCA-deficiency signatures may comprise a set of at least 5 nucleic acid sequences selected from the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90.
  • the BRCA-deficiency signatures may comprise a set of at least 6 nucleic acid sequences selected from the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90.
  • the BRCA-deficiency signatures may comprise a set of at least 7 nucleic acid sequences selected from the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90.
  • the BRCA-deficiency signatures may comprise a set of at least 8 nucleic acid sequences selected from the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90.
  • the BRCA-deficiency signatures may comprise a set of at least 9 nucleic acid sequences selected from the 45 nucleic acid sequences of SEQ ID NO: 46 through SEQ ID NO: 90.
  • the present disclosure provides methods of using the nucleic acid-based BRCA-deficiency signatures disclosed herein to identify cancer having a BRCA1 deficiency.
  • the present disclosure provides methods of using the nucleic acid-based BRCA-deficiency signatures disclosed herein to identify cancer having a BRCA2 deficiency.
  • the present disclosure provides methods of using the nucleic acid-based BRCA-deficiency signatures to predict whether a patient having cancer with a BRCA1 deficiency will benefit from anti-cancer therapy.
  • the present disclosure provides methods of using the nucleic acid-based BRCA-deficiency signatures to predict whether a patient having cancer with a BRCA2 deficiency will benefit from anti-cancer therapy.
  • Figure 1 provides a list of 417 proteins that are significantly differentially regulated in BRCA1 -deficient mammalian breast tumor tissue lysates, as compared to BRCA1 -proficient mammalian tumor tissue lysates.
  • Figure 2 provides a list of 45 proteins that are up-regulated in BRCA1- deficient mammalian breast tumor tissue lysates, as compared to BRCA1 -proficient mammalian tumor tissue lysates.
  • Anti-cancer therapy means any one, or a plurality, of therapies and/or drugs used to treat cancer, or any combinations thereof, including a) homologous recombination deficiency-targeted drugs and/or treatments; and b) drugs or treatments that directly or indirectly cause double strand DNA breaks.
  • This definition includes, without limitation, high dose platinum-based alkylating chemotherapy, platinum compounds, thiotepa,
  • cyclophosphamide iphosphamide, nitrosureas, nitrogen mustard derivatives, mitomycins, epipodophyllotoxins, camptothecins, anthracyclines, poly(ADP-ribose) polymerase (PARP) inhibitors, ionizing radiation, ABT-888, olaparib (AZT-2281), gemcitabine, CEP-9722, AG014699, AG014699 with Temozolomide, and BSI-201.
  • PARP poly(ADP-ribose) polymerase
  • Array refers to an arrangement, on a substrate surface, of multiple nucleic acid probes (as defined herein) of predetermined identity.
  • sequences of the multiple nucleic acid probes are known.
  • an array comprises a plurality of target elements, each target element comprising one or more nucleic acid probes immobilized on one or more solid surfaces, to which sample nucleic acids can be hybridized.
  • each individual probe is immobilized to a designated, discrete location (i.e., a defined location or assigned position) on the substrate surface.
  • each nucleic acid probe is immobilized to a discrete location on an array and each has a sequence that is either specific to, or characteristic of, a particular nucleic acid sequence coding for a protein that is significantly up-regulated in BRCA1 -deficient tumors.
  • a nucleic acid probe is specific to, or characteristic of, a particular nucleic acid sequence because it contains a nucleic acid sequence that is unique to that nucleic acid sequence. Such a probe preferentially hybridizes to a single nucleic acid molecule, relative to other nucleic acid molecules isolated from the same tissue.
  • the nucleic acid probes can contain sequence(s) corresponding to specific genes or proteins.
  • nucleic acid probes contain sequences specific to, or characteristic of, any one or more of the proteins recited in Fig. 1. In various embodiments, at least some of the nucleic acid probes contain sequences specific to, or characteristic of, any one or more of the proteins recited in Fig. 2.
  • the probes may be arranged on the substrate in a single density, or in varying densities.
  • the density of each of the probes can be varied to accommodate certain factors such as, for example, the nature of the test sample, the nature of a label used during hybridization, the type of substrate used, and the like.
  • Each probe may comprise a mixture of nucleic acids of varying lengths and, thus, varying sequences.
  • a single probe may contain more than one copy of a cloned nucleic acid, and each copy may be broken into fragments of different lengths. Each length will thus have a different sequence.
  • the length, sequence and complexity of the nucleic acid probes may be varied. In various embodiments, the length, sequence and complexity are varied to provide optimum hybridization and signal production for a given hybridization procedure, and to provide the required resolution among different genes or genomic locations.
  • BRC A 1 -deficiency means cancer, as defined herein, having cells containing a mutation of the BRCA1 locus or a deficiency in the homologous recombination-dependent double strand break DNA repair pathway that alters BRCA1 activity or function, either directly or indirectly.
  • BRCA2-deficiencv means cancer, as defined herein, having cells containing a mutation of the BRCA2 locus or a deficiency in the homologous recombination-dependent double strand break DNA repair pathway that alters BRCA2 activity or function, either directly or indirectly.
  • Cancer means a malignant neoplasm involving unregulated cell growth, where cells divide and grow uncontrollably forming malignant tumors.
  • the unregulated cell growth can be caused by a deficiency in the BRCA1 gene, the BRCA2 gene, or both.
  • cancer is intended to mean unregulated cell growth arising from a BRCA1 and/or BRCA2 deficiency.
  • the definition of cancer includes breast cancer, cancer of mammary tissue, lung cancer, ovarian cancer, colon cancer, gastric cancer and all other types of cancer that are presently known, or may hereafter be discovered, to be caused by BRCA1 and/or BRCA2 deficiency (cancer deficient in homology-directed DNA repair).
  • Hybridization refers to the binding of two single stranded nucleic acids via complementary base pairing. Extensive guides to the hybridization of nucleic acids can be found in: Tijssen, Laboratory Techniques in Biochemistry and Molecular Biology- Hybridization with Nucleic Acid Probes Part I, Ch. 2, “Overview of principles of hybridization and the strategy of nucleic acid probe assays” (1993), Elsevier, N.Y.; and Sambrook et ah, Molecular Cloning: A Laboratory Manual (3rd ed.) Vol. 1-3 (2001), Cold Spring Harbor Laboratory, Cold Spring Harbor Press, N.Y.
  • hybridizing specifically to refers to the preferential binding, duplexing, or hybridizing of a nucleic acid molecule to a particular probe under stringent conditions.
  • stringent conditions refers to hybridization conditions under which a probe will hybridize preferentially to its target subsequence, and to a lesser extent, or not at all, to other sequences in a mixed population (e.g., a nucleic acid extraction from a tissue biopsy).
  • Stringent hybridization and stringent hybridization wash conditions are sequence-dependent and are different under different environmental parameters.
  • highly stringent hybridization and wash conditions are selected to be about 5° C lower than the thermal melting point (Tm) for a specific sequence at a defined ionic strength and pH.
  • Tm is the temperature at which 50% of the target sequence hybridizes to a perfectly matched probe.
  • Very stringent conditions are selected to be equal to the Tm for a particular probe.
  • a high stringency wash is preceded by a low stringency wash to remove background probe signal.
  • An example of stringent hybridization conditions for hybridization of complementary nucleic acids which have more than 100 complementary residues on an array is 42° C using standard hybridization solutions, with the hybridization being carried out overnight.
  • An example of highly stringent wash conditions is a 0.15 M NaCl wash at 72° C for 15 minutes.
  • An example of stringent wash conditions is a wash in
  • 0.2X Standard Saline Citrate (SSC) buffer at 65° C for 15 minutes.
  • Nucleic acid refers to a deoxyribonucleotide or ribonucleotide in either single- or double-stranded form and includes all nucleic acids comprising naturally occurring nucleotide bases as well as nucleic acids containing any and/or all analogues of natural nucleotides. This term also includes nucleic acid analogues that are metabolized in a manner similar to naturally occurring nucleotides, but at rates that are improved for the purposes desired. This term also encompasses nucleic-acid-like structures with synthetic backbone analogues including, without limitation, phosphodiester, phosphorothioate,
  • PNAs peptide nucleic acids
  • PNAs contain non-ionic backbones, such as N-(2- aminoethyl) glycine units. Phosphorothioate linkages are described in: WO 97/03211 ; WO 96/39154; and Mata (1997) Toxicol. Appl. Pharmacol. 144: 189-197.
  • Probe or “nucleic acid probe” refer to one or more nucleic acid fragments whose specific hybridization to a sample can be detected.
  • probes are arranged on a substrate surface in an array. The probe may be unlabelled, or it may contain one or more labels so that its binding to a nucleic acid can be detected.
  • a probe can be produced from any source of nucleic acids from one or more particular, pre-selected portions of a chromosome including, without limitation, one or more clones, an isolated whole chromosome, an isolated chromosome fragment, or a collection of polymerase chain reaction (PCR) amplification products.
  • PCR polymerase chain reaction
  • the probe may be a member of an array of nucleic acids as described in WO 96/17958.
  • Techniques capable of producing high density arrays can also be used for this purpose (see, e.g. , Fodor (1991) Science 767-773; Johnston (1998) Curr. Biol. 8: Rl 71 -Rl 74; Schummer (1997) Biotechniques 23: 1087-1092; Kern (1997)
  • the sequence of the probes can be varied.
  • the probe sequence can be varied to produce probes that are substantially identical to the probes disclosed hereinbelow, but that retain the ability to hybridize specifically to the same targets or samples as the probe from which they were derived.
  • Reference sample refers to BRCA-deficient protein signatures, disclosed herein, or BRCA-deficiency nucleic acid signatures, disclosed herein, whose expression levels and/or sequence identity are known. Such protein signatures or nucleic acid signatures serve as a reference to which one or more test samples are compared.
  • Test sample refers to a proteome or a full complement of nucleic acid molecules isolated from a tumor obtained from a subject whose BRCAl status and/or BRCA2 status (deficient or proficient) is unknown.
  • the present disclosure is directed to the detection of the expression level of certain differentially regulated proteins and/or nucleic acid molecules of one or more test samples.
  • the present inventors have confirmed that a large proportion (20%) of the proteome of mammalian mammary tumor tissue is significantly differentially regulated (either up-regulated or down-regulated) in BRCAl -deficient tumors as compared to BRCA1- proficient tumors.
  • the differentially regulated proteins seen in BRCAl -deficient tumors are almost exclusively related to BRCAl status and only partially to cell type, making them ideally suited as predictive measures of BRCA-deficiency status in cancer.
  • the data presented in this disclosure shows an extensive up-regulation of a broad range of DNA repair/chromatin remodeling pathways and protein complexes in BRCAl -deficient tumors.
  • the present disclosure is based on the discovery that certain up-regulated proteins seen in BRCAl -deficient tumors can be used to identify cancer patients with BRCAl -deficient tumors and/or to predict whether such patients will benefit from anticancer therapy. In various aspects, the present disclosure is based on the discovery that certain up-regulated proteins seen in BRCAl -deficient tumors can be used to identify cancer patients with BRCA2-deficient tumors and/or to predict whether such patients will benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising one or more proteins that are up-regulated in BRCAl -deficient tumors are disclosed.
  • the BRCA-deficiency signatures can be used to identify cancer patients with BRCAl -deficient tumors.
  • the BRCA-deficiency signatures can be used to identify cancer patients with BRCA2-deficient tumors.
  • the BRCA-deficiency signatures can be used to predict whether such patients will benefit from anti-cancer therapy.
  • the present inventors have identified 417 proteins that are significantly differentially regulated in BRCA1 -deficient tumors, which are useful in the methods and signatures disclosed herein.
  • the 417 proteins are shown in Fig. 1.
  • BRCA-deficiency signatures comprising one or more of the significantly differentially regulated proteins shown in Fig. 1 are disclosed. These BRCA-deficiency signatures can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer. These BRCA-deficiency signatures can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer. These BRCA-deficiency signatures can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient. These BRCA-deficiency signatures can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 5 proteins selected from the following 417 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: Tacstdl, Lamal, 2610018G03Rik, Thumpdl, Mfge8, Serpine2, 1110067D22Rik, Nipsnapl, Fxyd3, Beam, Hlfx, Myhl4, Mafg, Cul5, Aldhlal, Pnptl, 1600014C10Rik, Rifl, Fl lr, Heatr2, Add3, Slc25a35, Trim33, Chd8, Gtf3cl, F12, Aqp5, Trim29, Ladl, Ppfial, Rsfl, Mrps25, Pdcd4, Otud6b, Pdzdl l, Dock9, Zfr, Kifl l, Agrn, Zfand6, Cdk
  • the BRCA-deficiency signatures comprising a set of at least 5 proteins selected from the foregoing 417 proteins can be used as diagnostic tools to detect patients who are carrying a BRCAl-mutation and/or have B RC A 1 -deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 5 proteins selected from the foregoing 417 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 5 proteins selected from the foregoing 417 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 5 proteins selected from the foregoing 417 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anticancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 6 proteins selected from the following 417 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: Tacstdl, Lamal, 2610018G03Rik, Thumpdl, Mfge8, Serpine2, 1110067D22Rik, Nipsnapl, Fxyd3, Beam, Hlfx, Myhl4, Mafg, Cul5, Aldhlal, Pnptl, 1600014C10Rik, Rifl, Fl lr, Heatr2, Add3, Slc25a35, Trim33, Chd8, Gtf3cl, F12, Aqp5, Trim29, Ladl, Ppfial, Rsfl, Mrps25, Pdcd4, Otud6b, Pdzdl l, Dock9, Zfr, Kifl 1, Agrn, Zfand6, Cdk9,
  • the BRCA-deficiency signatures comprising a set of at least 6 proteins selected from the foregoing 417 proteins can be used as diagnostic tools to detect patients who are carrying a BRCAl-mutation and/or have B RC A 1 -deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 6 proteins selected from the foregoing 417 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 6 proteins selected from the foregoing 417 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 6 proteins selected from the foregoing 417 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti- cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 7 proteins selected from the following 417 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: Tacstdl, Lamal, 2610018G03Rik, Thumpdl, Mfge8, Serpine2, 1110067D22Rik, Nipsnapl, Fxyd3, Beam, Hlfx, Myhl4, Mafg, Cul5, Aldhlal, Pnptl, 1600014C10Rik, Rifl, Fl lr, Heatr2, Add3, Slc25a35, Trim33, Chd8, Gtf3cl, F12, Aqp5, Trim29, Ladl, Ppfial, Rsfl, Mrps25, Pdcd4, Otud6b, Pdzdl l, Dock9, Zfr, Kifl l, Agrn, Zfand6, Cdk
  • the BRCA-deficiency signatures comprising a set of at least 7 proteins selected from the foregoing 417 proteins can be used as diagnostic tools to detect patients who are carrying a BRCAl-mutation and/or have B RC A 1 -deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 7 proteins selected from the foregoing 417 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 7 proteins selected from the foregoing 417 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 7 proteins selected from the foregoing 417 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anticancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 8 proteins selected from the following 417 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: Tacstdl, Lamal, 2610018G03Rik, Thumpdl, Mfge8, Serpine2, 1110067D22Rik, Nipsnapl, Fxyd3, Beam, Hlfx, Myhl4, Mafg, Cul5, Aldhlal, Pnptl, 1600014C10Rik, Rifl, Fl lr, Heatr2, Add3, Slc25a35, Trim33, Chd8, Gtf3cl, F12, Aqp5, Trim29, Ladl, Ppfial, Rsfl, Mrps25, Pdcd4, Otud6b, Pdzdl l, Dock9, Zfr, Kifl 1, Agrn, Zfand6, Cdk9,
  • the BRCA-deficiency signatures comprising a set of at least 8 proteins selected from the foregoing 417 proteins can be used as diagnostic tools to detect patients who are carrying a BRCAl-mutation and/or have B RC A 1 -deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 8 proteins selected from the foregoing 417 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 8 proteins selected from the foregoing 417 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 8 proteins selected from the foregoing 417 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti- cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 9 proteins selected from the following 417 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: Tacstdl, Lamal, 2610018G03Rik, Thumpdl, Mfge8, Serpine2, 1110067D22Rik, Nipsnapl, Fxyd3, Beam, Hlfx, Myhl4, Mafg, Cul5, Aldhlal, Pnptl, 1600014C10Rik, Rifl, Fl lr, Heatr2, Add3, Slc25a35, Trim33, Chd8, Gtf3cl, F12, Aqp5, Trim29, Ladl, Ppfial, Rsfl, Mrps25, Pdcd4, Otud6b, Pdzdl l, Dock9, Zfr, Kifl l, Agrn, Zfand6, Cdk
  • the BRCA-deficiency signatures comprising a set of at least 9 proteins selected from the foregoing 417 proteins can be used as diagnostic tools to detect patients who are carrying a BRCAl-mutation and/or have B RC A 1 -deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 9 proteins selected from the foregoing 417 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 9 proteins selected from the foregoing 417 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 9 proteins selected from the foregoing 417 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anticancer therapy.
  • a BRCA-deficiency signature comprising the following 417 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: Tacstdl, Lamal, 2610018G03Rik, Thumpdl, Mfge8, Serpine2, 1110067D22Rik, Nipsnapl, Fxyd3, Beam, Hlfx, Myhl4, Mafg, Cul5, Aldhlal, Pnptl, 1600014C10Rik, Rifl, Fl lr, Heatr2, Add3, Slc25a35, Trim33, Chd8, Gtf3cl, F12, Aqp5, Trim29, Ladl, Ppfial, Rsfl, Mrps25, Pdcd4, Otud6b, Pdzdl l, Dock9, Zfr, Kifl l, Agrn, Zfand6, Cd
  • the 417 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 417 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 417 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 5 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: CDH3, OGT, KIF4A, COL14A1 and ITGB4.
  • the foregoing 5 -protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 5 -protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 5 -protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 5 -protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 6 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: CDH3, OGT, KIF4A, COL14A1, ITGB4 and CUL5.
  • the foregoing 6-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 6-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 6-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 6-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: CDH3, OGT, KIF4A, COL14A1, ITGB4, CUL5 and NDRG1.
  • the foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 8 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: CDH3, OGT, KIF4A, COL14A1, ITGB4, CUL5, NDRG1 and BYSL.
  • the foregoing 8-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1- deficient cancer.
  • the foregoing 8-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the foregoing 8-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 8-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 9 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: CDH3, OGT, KIF4A, COL14A1, ITGB4, CUL5, NDRG1 , BYSL and COL4A1.
  • the foregoing 9-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCAl-mutation and/or have B RCA 1 -deficient cancer.
  • the foregoing 9-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 9-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 9-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCAl -deficient tumors: TBL2, UQCRC1, CUL5, ITGB4, FBL, VPS13A and TJP2.
  • the foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCAl -mutation and/or have BRCAl -deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCAl -deficient tumors: PSPCl, CDK9, KIF4A, FUR, PECR, SMARCA4 and UBAP2.
  • the foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCAl -mutation and/or have BRCAl -deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCAl -deficient tumors: BZW2, NUP210, SCRIB, RSFl, OTUD6B, DHRS7B and CDH3.
  • the foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCAl -mutation and/or have BRCAl -deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCAl -deficient tumors: CCDC6, TRIP12, CUL5, AKAP8, NUP214, UXT and COL4A1.
  • the foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCAl -mutation and/or have BRCAl -deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCAl -deficient tumors: SERPINDl, SART3, CUL5, LIN7C, ADD3, DDT and PDS5A.
  • SERPINDl SERPINDl
  • SART3, CUL5, LIN7C, ADD3, DDT and PDS5A The foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCAl -mutation and/or have BRCAl -deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCAl -deficient tumors: SMARCA5, NUP210, TRIP12, CUL5, OGT, POLD1 and NF1.
  • SMARCA5 The foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: SMARCA5, DHX9, CSTF1, TRIP12, BYSL, CUL5 and JUP.
  • the foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: TP53BP1, DRG1, COL14A1, FRYL, HNRNPF, ROMOl and DOCK1.
  • the foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1- deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: CDK9, CUL5, CSTF3, ADD3, DHX30, DDT and EIF3G.
  • the foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: NUP210, SERPIND1, BAX, CUL5, BIRC6, KRT78 and PDS5A.
  • the foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 56 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: TOP2A, TOPI, SUPT16H, SSRP1, SMC3, SMC1A, SRSF3, SRSF1, PRPF8, DHX9, AGRN, AGRN, AP1M2, BZW2, CBX3, CDH1, CDH3, CKAP5, CLNS1A, COL18A1, CPOX, CRIP2, CTNNA1, CTNNB1, DAK, DEK, DNMT1, FUR, FXYD3, GPC4, ILF3, ITGB4, LAMA4, LAMA5, LAMB 2, LAMC1, LGALS7, MACF1, NCL, NOLC1, NPM3, PKP3, PLTP, PTN, PURB, SART3, SLC3A2, SLC7A5, SSB, THUMPD1 , USP39, WDR5, TINAGL1
  • the foregoing 56-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 56-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 56-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 56-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: BZW2, NUP210, GRHPR, CUL5, HMCN1, BDH1 and RAE1.
  • the foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: CDH3, OGT, KIF4, ITGB4, COL14A1, BYSL and CUL5.
  • the foregoing 7-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 15 proteins that are significantly differentially regulated in BRCA1 -deficient tumors: CDH3, OGT, KIF4, COL14A1, ITGB4, NUP210, EIF4A3, BYSL, CUL5, COL4A1, APOD, NDRG1, LAMB2, HMCN1 and PBRM1.
  • the foregoing 15-protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 15-protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 15-protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 15-protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • the present inventors have identified 45 proteins that are up-regulated in
  • BRCA1 -deficient tumors which are useful in the methods and signatures disclosed herein.
  • the 45 proteins are shown in Fig. 2.
  • BRCA-deficiency signatures comprising one or more of the 45 up-regulated proteins shown in Fig. 2 are disclosed. These BRCA- deficiency signatures can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer. These BRCA-deficiency signatures can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer. These BRCA-deficiency signatures can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient. These BRCA-deficiency signatures can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 5 proteins selected from the following 45 proteins that are up-regulated in BRCAl-deficient tumors: TRRAP, BAZ1B, SMC3, NCAPD2, RPA1, SIN3A, POLD1, SNRNP200, SMC1A, TOP2A, SMARCC1, TOP2B, HCFC1, PCNA, RSF1, CSNK2A1, CDC5L, TOPI, OGT, EP400, MSH6, TRIM28, SFRS1, SRCAP, PARP1, SMARCA4, CREBBP, ATM, RAD21, PRPF8, C20ORF20, CSTF1, MTA1, DDX21, HNRNPF, NCBP1, SMARCA5, MSH2, SFRS3, DHX9, SUPT16H, CSTF3, SSRP1, SMC4, and ARID 1 A.
  • the BRCA-deficiency signatures comprising a set of at least 5 proteins selected from the foregoing 45 proteins can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 5 proteins selected from the foregoing 45 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 5 proteins selected from the foregoing 45 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 5 proteins selected from the foregoing 45 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 6 proteins selected from the following 45 proteins that are up-regulated in BRCA1 -deficient tumors: TRRAP, BAZ1B, SMC3, NCAPD2, RPA1, SIN3A, POLD1, SNRNP200, SMC1A, TOP2A, SMARCC1, TOP2B, HCFC1, PCNA, RSF1, CSNK2A1, CDC5L, TOPI, OGT, EP400, MSH6, TRIM28, SFRS1, SRCAP, PARP1, SMARCA4, CREBBP, ATM, RAD21, PRPF8, C20ORF20, CSTFl, MTAl, DDX21, HNRNPF, NCBPl, SMARCA5, MSH2, SFRS3, DHX9, SUPT16H, CSTF3, SSRPl, SMC4, and ARIDIA.
  • the BRCA-deficiency signatures comprising a set of at least 6 proteins selected from the foregoing 45 proteins can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 6 proteins selected from the foregoing 45 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 6 proteins selected from the foregoing 45 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 6 proteins selected from the foregoing 45 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 7 proteins selected from the following 45 proteins that are up-regulated in BRCAl-deficient tumors: TRRAP, BAZ1B, SMC3, NCAPD2, RPA1, SIN3A, POLD1, SNRNP200, SMC1A, TOP2A, SMARCC1, TOP2B, HCFC1, PCNA, RSF1, CSNK2A1, CDC5L, TOPI, OGT, EP400, MSH6, TRIM28, SFRS1, SRCAP, PARP1, SMARCA4, CREBBP, ATM, RAD21, PRPF8, C20ORF20, CSTFl, MTAl, DDX21, HNRNPF, NCBPl, SMARCA5, MSH2, SFRS3, DHX9, SUPT16H, CSTF3, SSRPl, SMC4, and ARIDIA.
  • the BRCA-deficiency signatures comprising a set of at least 7 proteins selected from the foregoing 45 proteins can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 7 proteins selected from the foregoing 45 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 7 proteins selected from the foregoing 45 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 7 proteins selected from the foregoing 45 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 8 proteins selected from the following 45 proteins that are up-regulated in BRCA1 -deficient tumors: TRRAP, BAZ1B, SMC3, NCAPD2, RPA1, SIN3A, POLD1, SNRNP200, SMC1A, TOP2A, SMARCC1, TOP2B, HCFC1, PCNA, RSF1, CSNK2A1, CDC5L, TOPI, OGT, EP400, MSH6, TRIM28, SFRS1, SRCAP, PARP1, SMARCA4, CREBBP, ATM, RAD21, PRPF8, C20ORF20, CSTFl, MTAl, DDX21, HNRNPF, NCBPl, SMARCA5, MSH2, SFRS3, DHX9, SUPT16H, CSTF3, SSRPl, SMC4, and ARIDIA.
  • the BRCA-deficiency signatures comprising a set of at least 8 proteins selected from the foregoing 45 proteins can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 8 proteins selected from the foregoing 45 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 8 proteins selected from the foregoing 45 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 8 proteins selected from the foregoing 45 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 9 proteins selected from the following 45 proteins that are up-regulated in BRCAl-deficient tumors: TRRAP, BAZ1B, SMC3, NCAPD2, RPA1, SIN3A, POLD1, SNRNP200, SMC1A, TOP2A, SMARCC1, TOP2B, HCFC1, PCNA, RSF1, CSNK2A1, CDC5L, TOPI, OGT, EP400, MSH6, TRIM28, SFRS1, SRCAP, PARP1, SMARCA4, CREBBP, ATM, RAD21, PRPF8, C20ORF20, CSTFl, MTAl, DDX21, HNRNPF, NCBPl, SMARCA5, MSH2, SFRS3, DHX9, SUPT16H, CSTF3, SSRPl, SMC4, and ARIDIA.
  • the BRCA-deficiency signatures comprising a set of at least 9 proteins selected from the foregoing 45 proteins can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 9 proteins selected from the foregoing 45 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 9 proteins selected from the foregoing 45 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 9 proteins selected from the foregoing 45 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 45 proteins that are up-regulated in BRCAl- deficient tumors: TRRAP, BAZ1B, SMC3, NCAPD2, RPA1, SIN3A, POLD1, SNRNP200, SMC1A, TOP2A, SMARCC1, TOP2B, HCFC1, PCNA, RSF1, CSNK2A1, CDC5L, TOPI, OGT, EP400, MSH6, TRIM28, SFRS1, SRCAP, PARP1, SMARCA4, CREBBP, ATM, RAD21, PRPF8, C20ORF20, CSTF1, MTA1, DDX21, HNRNPF, NCBP1, SMARCA5, MSH2, SFRS3, DHX9, SUPT16H, CSTF3, SSRP1, SMC4, and ARID 1 A.
  • the foregoing 45 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the foregoing 45 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 45 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 45 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures are provided, the BRCA- deficiency signatures comprising the following 3 proteins that are up-regulated in BRCAl- deficient tumors: OGT, PRPF8 and POLD1.
  • the BRCA-deficiency signatures comprising these 3 proteins can be used as diagnostic tools to detect patients who are carrying a BRCA1- mutation and/or have BRCAl-deficient cancer.
  • the BRCA-deficiency signatures comprising these 3 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising these 3 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising these 3 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anticancer therapy.
  • BRCA-deficiency signatures are provided, the BRCA- deficiency signatures comprising the following 4 proteins that are up-regulated in BRCA1- deficient tumors: OGT, PRPF8, POLD1 and MSH2.
  • the BRCA-deficiency signatures comprising these 4 proteins can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have B RCA 1 -deficient cancer.
  • the BRCA-deficiency signatures comprising these 4 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA- deficiency signatures comprising these 4 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising these 4 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures are provided, the BRCA- deficiency signatures comprising the following 5 proteins that are up-regulated in BRCA1- deficient tumors: OGT, PRPF8, POLD1, MSH2 and HNRNPF.
  • the BRCA-deficiency signatures comprising these 5 proteins can be used as diagnostic tools to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the BRCA- deficiency signatures comprising these 5 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising these 5 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising these 5 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures are provided, the BRCA- deficiency signatures comprising the following 6 proteins that are up-regulated in BRCA1- deficient tumors: OGT, PRPF8, POLD1, MSH2, HNRNPF and RPA1.
  • the BRCA- deficiency signatures comprising these 6 proteins can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the BRCA-deficiency signatures comprising these 6 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising these 6 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising these 6 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures are provided, the BRCA- deficiency signatures comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: OGT, PRPF8, POLD1, MSH2, HNRNPF, RPA1 and TOP2B.
  • the BRCA- deficiency signatures comprising these 7 proteins can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • BRCA-deficiency signatures comprising these 7 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising these 7 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising these 7 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures are provided, the BRCA- deficiency signatures comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: OGT, PRPF8, POLD1, MSH2, RPA1, TOP2B and NCBP1.
  • the BRCA- deficiency signatures comprising these 7 proteins can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the BRCA-deficiency signatures comprising these 7 proteins can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising these 7 proteins can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising these 7 proteins can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 5 proteins that are up-regulated in BRCA1- deficient tumors: OGT, PRPF8, POLD1, MSH2 and NCBP1.
  • the foregoing 5 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have B RCA 1 -deficient cancer.
  • the foregoing 5 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 5 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 5 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 6 proteins that are up-regulated in BRCA1- deficient tumors: OGT, PRPF8, POLDl, MSH2, NCBPl and RPAl.
  • the foregoing 6 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have B RCA 1 -deficient cancer.
  • the foregoing 6 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 6 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 6 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: OGT, PRPF8, POLDl, MSH2, NCBPl, RPAl and SSRP1.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 8 proteins that are up-regulated in BRCA1- deficient tumors: OGT, PRPF8, POLDl, MSH2, NCBPl, RPAl, SSRP1 and TOP2B.
  • the foregoing 8 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 8 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 8 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 8 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 9 proteins that are up-regulated in BRCA1- deficient tumors: OGT, PRPF8, POLD1, MSH2, NCBP1, RPA1, SSRP1, TOP2B and MTA1.
  • the foregoing 9 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 9 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 9 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 9 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: MTA1, MSH6, TOP2B, RPA1, PRPF8, POLD1 and NCBP1.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: MSH2, SRCAP, RPA1, SMC4, PRPF8, POLD1 and NCBP1.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: MSH2, RPA1, PRPF8, DDX21, POLD1, SIN3A and NCBP1.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: ARID 1 A, TRIM28, RPA1, CSTF3, PRPF8, POLD1 and SIN3A.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature is provided, the BRCA- deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: SMARCA5, MTA1, TOP2B, RPAl, DDX21, POLDl and TOP2A.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: MSH2, TOP2B, RPAl, ATM, PRPF8, POLDl and TRRAP.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: MSH2, DHX9, TOP2B, RPAl, PRPF8, TRRAP and NCBP1.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: MSH2, TRIM28, MTAl, TOP2B, RPAl, ATM and PRPF8.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: MSH2, CREBBP, RPAl, SMC4, PRPF8, POLD1 and NCBP1.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: TRIM28, TOP2B, RPAl, PRPF8, POLD1, TRRAP and HNRNPF.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 36 proteins that are up-regulated in BRCA1- deficient tumors: TOP2A, TRIM28,MSH2, DHX9, SMC4, RPA1, MSH6, POLD1, TRRAP, CREBBP, PCNA, ATM, MTA1, PARP1, TOPI, DDX21, SMC1A, SFRS1, C20ORF20, RAD21, CSTF1, OGT, TOP2B, ARID 1 A, RSF1, CSNK2A1, SMARCA4, SMARCC1, SUPT16H, SMC3, SFRS3, SSRP1, PRPF8, HCFC1, NCAPD2 and CDC5L.
  • the foregoing 36 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 36 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 36 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 36 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 21 proteins that are up-regulated in BRCA1- deficient tumors: TOP2A, TRIM28, MSH2, DHX9, SMC4, RPA1, MSH6, POLD1, TRRAP, CREBBP, PCNA, ATM, MTA1, PARP1, TOPI, DDX21, SMC1A, SFRS1, C20ORF20, RAD21 and CSTF1.
  • the foregoing 21 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1- deficient cancer.
  • the foregoing 21 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the foregoing 21 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 21 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 9 proteins that are up-regulated in BRCA1- deficient tumors: TOP2A, TRIM28, MSH2, DHX9, SMC4, RPA1, MSH6, POLD1 and TRRAP.
  • the foregoing 9 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 9 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 9 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 9 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: DHX9, SMC4, TRRAP, RAD21, CSTF1, NCAPD2 and CDC5L.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 20 proteins that are up-regulated in BRCA1- deficient tumors: DHX9, SMC4, RAD21, TOP2A, TRIM28, MSH2, RPA1, MSH6, POLD1, CREBBP, PCNA, ATM, MTA1, PARP1, TOPI, DDX21, OGT, TOP2B, ARID 1 A and RSF1.
  • the foregoing 20 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 20 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 20 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 20 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 10 proteins that are up-regulated in BRCA1- deficient tumors: DHX9, TOP2A, TOPI, SMC1A, SFRS1, SUPT16H, SMC3, SFRS3,
  • the foregoing 10 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1- deficient cancer.
  • the foregoing 10 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the foregoing 10 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 10 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 10 proteins that are up-regulated in BRCA1- deficient tumors: TOP2A, TOPI, SUPT16H, SSRP1, SMC3, SMC1A, SFRS3, SFRS1, PRPF8 and DHX9.
  • the foregoing 10 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1- deficient cancer.
  • the foregoing 10 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the foregoing 10 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 10 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 9 proteins that are up-regulated in BRCA1- deficient tumors: TRRAP, BAZ1B, SMC1A, TOP2A, MSH6, PARP1, ATM, MSH2 and SMC4.
  • the foregoing 9 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 9 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 9 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 9 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: TRRAP, NCAPD2, CDC5L, RAD21, DHX9, CSTF3 and SMC4.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 8 proteins that are up-regulated in BRCA1- deficient tumors: TRRAP, NCAPD2, TOP2A, CDC5L, RAD21, DHX9, CSTF3 and SMC4.
  • the foregoing 8 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 8 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 8 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 8 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 33 proteins that are up-regulated in BRCA1- deficient tumors: TRRAP, BAZ1B, SMC3, NCAPD2, SIN3A, POLD1, SNRNP200, SMCIA, TOP2A, SMARCCl, TOP2B, PCNA, RSFl, CSNK2A1, CDC5L, MSH6, TRIM28, SRCAP, PARP1, SMARCA4, CREBBP, ATM, RAD21, DDX21, HNRNPF, SMARCA5, MSH2, DHX9, SUPT16H, CSTF3, SSRP1, SMC4 and ARID 1 A.
  • the foregoing 33 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCAl -mutation and/or have BRCAl -deficient cancer.
  • the foregoing 33 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 33 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 33 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 37 proteins that are up-regulated in BRCA1- deficient tumors: TRRAP, BAZ1B, SMC3, NCAPD2, SIN3A, POLD1, SNRNP200, SMC1A, TOP2A, SMARCC1, TOP2B, PCNA, RSFl, CSNK2A1, CDC5L, EP400, MSH6, TRIM28, SRCAP, PARP1, SMARCA4, CREBBP, ATM, RAD21, C20ORF20, CSTF1, DDX21, HNRNPF, NCBP1, SMARCA5, MSH2, DHX9, SUPT16H, CSTF3, SSRP1, SMC4 and ARID1A.
  • the foregoing 37 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCAl -mutation and/or have BRCAl - deficient cancer.
  • the foregoing 37 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the foregoing 37 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 37 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 36 proteins that are up-regulated in BRCAl - deficient tumors: TRRAP, SMC3, NCAPD2, RPA1, POLD1, SMC1A, TOP2A, SMARCC1, TOP2B, HCFCl, PCNA, RSFl, CSNK2A1, CDC5L, TOPI, OGT, MSH6, TRIM28, SFRSl, PARP1, SMARCA4, CREBBP, ATM, RAD21, PRPF8, C20ORF20, CSTF1, MTA1, DDX21, MSH2, SFRS3, DHX9, SUPT16H, SSRP1, SMC4 and ARID 1 A.
  • the foregoing 36 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCAl -mutation and/or have BRCAl -deficient cancer.
  • the foregoing 36 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 36 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 36 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 21 proteins that are up-regulated in BRCA1- deficient tumors: TRRAP, RPA1, POLD1, SMC1A, TOP2A, PCNA, TOPI, MSH6, TRIM28, SFRS1, PARP1, CREBBP, ATM, RAD21, C20ORF20, CSTF1, MTA1, DDX21, MSH2, DHX9 and SMC4.
  • the foregoing 21 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 21 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 21 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 21 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 9 proteins that are up-regulated in BRCA1- deficient tumors: TRRAP, RPA1, POLD1, TOP2A, MSH6, TRIM28, MSH2, DHX9 and SMC4.
  • the foregoing 9 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 9 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 9 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 9 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: TRRAP, NCAPD2, CDC5L, RAD21, CSTF1, DHX9 and SMC4.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 20 proteins that are up-regulated in BRCA1- deficient tumors: RPA1, POLD1, TOP2A, TOP2B, PCNA, RSF1, TOPI, OGT, MSH6, TRIM28, PARP1, CREBBP, ATM, RAD21, MTA1, DDX21, MSH2, DHX9, SMC4 and ARID 1 A.
  • the foregoing 20 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 20 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the foregoing 20 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 20 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 10 proteins that are up-regulated in BRCA1- deficient tumors: SMC3, SMC1A, TOP2A, TOPI, SFRS1, PRPF8, SFRS3, DHX9,
  • the foregoing 10 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCAl-mutation and/or have BRCA1- deficient cancer.
  • the foregoing 10 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the foregoing 10 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 10 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 16 proteins that are up-regulated in BRCA1- deficient tumors: SIN3A, POLD1, TOP2A, TOP2B, OGT, TRIM28, SFRS1, CREBBP, ATM, C20ORF20, HNRNPF, NCBP1, MSH2, SSRP1, SMC4 and ARID 1 A.
  • the foregoing 16 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 16 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 16 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 16 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: TRRAP, RPAl, POLDl, TOP2B, ATM, PRPF8 and MSH2.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 proteins that are up-regulated in BRCA1- deficient tumors: RPAl, POLDl, TOP2B, OGT, PRPF8, NCBP1 and MSH2.
  • the foregoing 7 protein BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the foregoing 7 protein BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the foregoing 7 protein BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 5 amino acid sequences selected from the following 45 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO:
  • the BRCA-deficiency signatures comprising a set of at least 5 amino acid sequences selected from the foregoing 45 amino acid sequences can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 5 amino acid sequences selected from the foregoing 45 amino acid sequences can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 5 amino acid sequences selected from the foregoing 45 amino acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 5 amino acid sequences selected from the foregoing 45 amino acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 6 amino acid sequences selected from the following 45 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO:
  • the BRCA-deficiency signatures comprising a set of at least 6 amino acid sequences selected from the foregoing 45 amino acid sequences can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 6 amino acid sequences selected from the foregoing 45 amino acid sequences can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 6 amino acid sequences selected from the foregoing 45 amino acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 6 amino acid sequences selected from the foregoing 45 amino acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 7 amino acid sequences selected from the following 45 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO:
  • the BRCA-deficiency signatures comprising a set of at least 7 amino acid sequences selected from the foregoing 45 amino acid sequences can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 7 amino acid sequences selected from the foregoing 45 amino acid sequences can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 7 amino acid sequences selected from the foregoing 45 amino acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 7 amino acid sequences selected from the foregoing 45 amino acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 8 amino acid sequences selected from the following 45 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO:
  • the BRCA-deficiency signatures comprising a set of at least 8 amino acid sequences selected from the foregoing 45 amino acid sequences can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 8 amino acid sequences selected from the foregoing 45 amino acid sequences can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 8 amino acid sequences selected from the foregoing 45 amino acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 8 amino acid sequences selected from the foregoing 45 amino acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 9 amino acid sequences selected from the following 45 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO:
  • the BRCA-deficiency signatures comprising a set of at least 9 amino acid sequences selected from the foregoing 45 amino acid sequences can be used as diagnostic tools to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 9 amino acid sequences selected from the foregoing 45 amino acid sequences can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 9 amino acid sequences selected from the foregoing 45 amino acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 9 amino acid sequences selected from the foregoing 45 amino acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 45 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 35,
  • the 45 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1- deficient cancer.
  • the 45 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 45 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 45 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 5 amino acid sequences: SEQ ID NO: 19, SEQ ID NO: 30, SEQ ID NO: 7, SEQ ID NO: 38 and SEQ ID NO: 36.
  • the 5 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have B RCA 1 -deficient cancer.
  • the 5 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 5 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 5 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 6 amino acid sequences: SEQ ID NO: 19, SEQ ID NO: 30, SEQ ID NO: 7, SEQ ID NO: 38, SEQ ID NO: 36 and SEQ ID NO: 5.
  • the 6 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the 6 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 6 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 6 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 19, SEQ ID NO: 30, SEQ ID NO: 7, SEQ ID NO: 38, SEQ ID NO: 36, SEQ ID NO: 5 and SEQ ID NO: 43.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 8 amino acid sequences: SEQ ID NO: 19, SEQ ID NO: 30, SEQ ID NO: 7, SEQ ID NO: 38, SEQ ID NO: 36, SEQ ID NO: 5, SEQ ID NO: 43 and SEQ ID NO: 12.
  • the 8 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the 8 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 8 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 8 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 9 amino acid sequences: SEQ ID NO: 19, SEQ ID NO: 30, SEQ ID NO: 7, SEQ ID NO: 38, SEQ ID NO: 36, SEQ ID NO: 5, SEQ ID NO: 43, SEQ ID NO: 12 and SEQ ID NO: 33.
  • the 9 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1- mutation and/or have BRCAl-deficient cancer.
  • the 9 amino acid sequence BRCA- deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 9 amino acid sequence BRCA- deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 9 amino acid sequence BRCA- deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 33, SEQ ID NO: 21, SEQ ID NO: 12, SEQ ID NO: 5, SEQ ID NO: 30, SEQ ID NO: 7 and SEQ ID NO: 36.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 38, SEQ ID NO: 24, SEQ ID NO: 5, SEQ ID NO: 44, SEQ ID NO: 30, SEQ ID NO: 7 and SEQ ID NO: 36.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 38, SEQ ID NO: 5, SEQ ID NO: 30, SEQ ID NO: 34, SEQ ID NO: 7, SEQ ID NO: 6 and SEQ ID NO: 36.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 45, SEQ ID NO: 22, SEQ ID NO: 5, SEQ ID NO: 42, SEQ ID NO: 30, SEQ ID NO: 7 and SEQ ID NO: 6.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 37, SEQ ID NO: 33, SEQ ID NO: 12, SEQ ID NO: 5, SEQ ID NO: 34, SEQ ID NO: 7 and SEQ ID NO: 10.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 38, SEQ ID NO: 12, SEQ ID NO: 5, SEQ ID NO: 28, SEQ ID NO: 30, SEQ ID NO: 7 and SEQ ID NO: 1.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 12, SEQ ID NO: 5, SEQ ID NO: 30, SEQ ID NO: 1 and SEQ ID NO: 36.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 38, SEQ ID NO: 22, SEQ ID NO: 33, SEQ ID NO: 12, SEQ ID NO: 5, SEQ ID NO: 28 and SEQ ID NO: 30.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 38, SEQ ID NO: 27, SEQ ID NO: 5, SEQ ID NO: 44, SEQ ID NO: 30, SEQ ID NO: 7 and SEQ ID NO: 36.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 22, SEQ ID NO: 12, SEQ ID NO: 5, SEQ ID NO: 30, SEQ ID NO: 7, SEQ ID NO: 1 and SEQ ID NO: 35.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 36 amino acid sequences: SEQ ID NO: 10, SEQ ID NO: 22, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 5, SEQ ID NO: 21, SEQ ID NO: 7, SEQ ID NO: 1, SEQ ID NO: 27, SEQ ID NO: 14, SEQ ID NO: 28, SEQ ID NO: 33, SEQ ID NO: 25, SEQ ID NO: 18, SEQ ID NO: 34, SEQ ID NO: 9, SEQ ID NO: 23, SEQ ID NO: 31, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 19, SEQ ID NO: 12, SEQ ID NO: 45, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 26, SEQ ID NO: 11, SEQ ID NO: 41, SEQ ID NO: 3, SEQ ID NO: 39, SEQ ID NO: 43, SEQ ID NO: 30, SEQ ID NO: 13,
  • the 36 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1- mutation and/or have BRCAl-deficient cancer.
  • the 36 amino acid sequence BRCA- deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 36 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 36 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anticancer therapy.
  • a BRCA-deficiency signature comprising the following 21 amino acid sequences: SEQ ID NO: 10,
  • the 21 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have B RCA 1 -deficient cancer.
  • the 21 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 21 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 21 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 9 amino acid sequences: SEQ ID NO: 10, SEQ ID NO: 22, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 5, SEQ ID NO: 21, SEQ ID NO: 7 and SEQ ID NO: 1.
  • the 9 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1- mutation and/or have BRCAl-deficient cancer.
  • the 9 amino acid sequence BRCA- deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 9 amino acid sequence BRCA- deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 9 amino acid sequence BRCA- deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 1, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 4 and SEQ ID NO: 17.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 20 amino acid sequences: SEQ ID NO: 40, SEQ ID NO: 44, SEQ ID NO: 29, SEQ ID NO: 10, SEQ ID NO: 22, SEQ ID NO: 38, SEQ ID NO: 5, SEQ ID NO: 21, SEQ ID NO: 7, SEQ ID NO: 27, SEQ ID NO: 14, SEQ ID NO: 28, SEQ ID NO: 33, SEQ ID NO: 25, SEQ ID NO: 18, SEQ ID NO: 34, SEQ ID NO: 19, SEQ ID NO: 12, SEQ ID NO: 45 and SEQ ID NO: 15.
  • the 20 amino acid sequence BRCA- deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the 20 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 20 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 20 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti- cancer therapy.
  • a BRCA-deficiency signature comprising the following 10 amino acid sequences: SEQ ID NO: 40, SEQ ID NO: 10, SEQ ID NO: 18, SEQ ID NO: 9, SEQ ID NO: 23, SEQ ID NO: 41, SEQ ID NO: 3, SEQ ID NO: 39, SEQ ID NO: 43 and SEQ ID NO: 30.
  • the 10 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the 10 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 10 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 10 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 10 amino acid sequences: SEQ ID NO: 10, SEQ ID NO: 18, SEQ ID NO: 41, SEQ ID NO: 43, SEQ ID NO: 3, SEQ ID NO: 9, SEQ ID NO: 39, SEQ ID NO: 23, SEQ ID NO: 30 and SEQ ID NO: 40.
  • the 10 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the 10 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 10 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 10 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 9 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 21, SEQ ID NO: 25, SEQ ID NO: 28, SEQ ID NO: 38, and SEQ ID NO: 44.
  • the 9 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1- mutation and/or have BRCAl-deficient cancer.
  • the 9 amino acid sequence BRCA- deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 9 amino acid sequence BRCA- deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 9 amino acid sequence BRCA- deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 17, SEQ ID NO: 29, SEQ ID NO: 40, SEQ ID NO: 42, and SEQ ID NO: 44.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 8 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 10, SEQ ID NO: 17, SEQ ID NO: 29, SEQ ID NO: 40, SEQ ID NO: 42, and SEQ ID NO: 44.
  • the 8 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the 8 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 8 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 8 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 33 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO: 43, SEQ ID NO: 44, and SEQ ID NO: 45.
  • the 33 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the 33 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 33 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 33 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 37 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 20, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 24, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 34, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 37, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO: 42, SEQ ID NO:
  • the 37 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have B RCA 1 -deficient cancer.
  • the 37 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 37 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 37 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 36 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 26, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 30, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, SEQ ID NO:
  • the 36 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1- mutation and/or have BRCAl-deficient cancer.
  • the 36 amino acid sequence BRCA- deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 36 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 36 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anticancer therapy.
  • a BRCA-deficiency signature comprising the following 21 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 14, SEQ ID NO: 18, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 31, SEQ ID NO: 32, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 40, and SEQ ID NO: 44.
  • the 21 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have B RCA 1 -deficient cancer.
  • the 21 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 21 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 21 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 9 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 38, SEQ ID NO: 40, and SEQ ID NO: 44.
  • the 9 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1- mutation and/or have BRCAl-deficient cancer.
  • the 9 amino acid sequence BRCA- deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 9 amino acid sequence BRCA- deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 9 amino acid sequence BRCA- deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 4, SEQ ID NO: 17, SEQ ID NO: 29, SEQ ID NO: 32, SEQ ID NO: 40, and SEQ ID NO: 44.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 20 amino acid sequences: SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 21, SEQ ID NO: 22, SEQ ID NO: 25, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 29, SEQ ID NO: 33, SEQ ID NO: 34, SEQ ID NO: 38, SEQ ID NO: 40, SEQ ID NO: 44, and SEQ ID NO: 45.
  • the 20 amino acid sequence BRCA- deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the 20 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 20 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 20 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti- cancer therapy.
  • a BRCA-deficiency signature comprising the following 10 amino acid sequences: SEQ ID NO: 3, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 18, SEQ ID NO: 23, SEQ ID NO: 30, SEQ ID NO: 39, SEQ ID NO: 40, SEQ ID NO: 41, and SEQ ID NO: 43.
  • the 10 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the 10 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 10 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 10 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 16 amino acid sequences: SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 10, SEQ ID NO: 12, SEQ ID NO: 19, SEQ ID NO: 22, SEQ ID NO: 23, SEQ ID NO: 27, SEQ ID NO: 28, SEQ ID NO: 31, SEQ ID NO: 35, SEQ ID NO: 36, SEQ ID NO: 38, SEQ ID NO: 43, SEQ ID NO: 44, and SEQ ID NO: 45.
  • the 16 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the 16 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the 16 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 16 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 1, SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 12, SEQ ID NO: 28, SEQ ID NO: 30, and SEQ ID NO: 38.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 amino acid sequences: SEQ ID NO: 5, SEQ ID NO: 7, SEQ ID NO: 12, SEQ ID NO: 19, SEQ ID NO: 30, SEQ ID NO: 36, and SEQ ID NO: 38.
  • the 7 amino acid sequence BRCA-deficiency signature can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the 7 amino acid sequence BRCA-deficiency signature can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the 7 amino acid sequence BRCA-deficiency signature can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • the BRCA-deficiency protein signatures disclosed herein can be used as diagnostic tools, to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1- deficient cancer and to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer. Therefore, in various aspects, the BRCA-deficiency protein signatures provided in this disclosure are capable of determining whether an individual cancer patient has BRCA1 -deficient cancer and/or BRCA2-deficient cancer.
  • BRCA1 pathway dysfunction and/or BRCA2 pathway dysfunction provides an opportunity for therapeutic intervention. Emerging preclinical evidence shows that cancers with a defective DNA repair system, such as a mutation in the BRCAlgene and/or the BRCA2 gene, may be extremely sensitive to DNA damaging agents, such as platinum compounds and bifunctional alkylating agents. Therefore, patients with cancers harboring a defective BRCA1 -deficient and/or BRCA2-deficient DNA repair system may specifically benefit from high dose alkylating chemotherapy, a DNA double strand break (DSB)-inducing regimen.
  • DSB DNA double strand break
  • Tumors with homologous recombination deficiency have been shown to be particularly sensitive to DNA double strand break (DSB)-inducing agents, such as alkylators and platinum drugs or platinating agents. Both classes of drugs are employed in metastatic breast cancer.
  • DSB DNA double strand break
  • PARP inhibitors novel poly(ADP-ribose) polymerase inhibitors
  • BRCA1 -deficient and BRCA2- deficient cancers are susceptible to treatment with anti-cancer therapy (as defined herein) and patients having BRCAl-deficient and/or BRCA2-deficient cancers will benefit from receipt of anti-cancer therapy.
  • the BRCA-deficiency protein signatures provided in this disclosure are therefore capable of predicting benefit of anti-cancer therapy in an individual patient and can also be used as predictive tests to identify cancer patients likely to benefit from anti-cancer therapy.
  • the present disclosure provides methods of using the BRCA-deficiency protein signatures disclosed herein to determine whether a patient has cancer caused by a BRCA1 deficiency. In various aspects, the present disclosure provides methods of using the BRCA-deficiency protein signatures disclosed herein to determine whether a patient has cancer caused by a BRCA2 deficiency.
  • the methods comprise generating a test sample comprising the proteome of a cancer isolated from a patient; measuring the expression level of the proteins of the test sample; comparing the expression level of the proteins of the test sample to at least one of the BRCA-deficiency protein signatures provided by the present disclosure; and identifying the cancer as BRCA1- deficient or B RC A 1 -proficient and/or BRCA2-deficient or BRCA2-proficient; wherein when the expression level of the proteins of the test sample is similar to the expression level of the corresponding proteins in the at least one of the BRCA-deficiency protein signatures, the tumor is classified as BRCA1- and/or BRCA2-deficient.
  • the methods comprise generating a test sample comprising the proteome of a cancer isolated from a patient; measuring the expression level of the proteins of the test sample; comparing the expression level of the proteins of the test sample to at least one of the BRCA-deficiency protein signatures provided by the present disclosure; and identifying the tumor as B RC A 1 -deficient or BRCA1 -proficient and/or BRCA2-deficient or BRCA2-proficient; wherein when the expression level of the proteins of the test sample is the same (within acceptable levels of experimental error) as the expression level of the corresponding proteins in the at least one of the BRCA-deficiency protein signatures, the cancer is classified as BRCA1- and/or BRCA2-deficient.
  • the methods comprise generating a test sample comprising the proteome of a cancer isolated from a blood sample obtained from a patient; measuring the expression level of the proteins of the test sample; comparing the expression level of the proteins of the test sample to at least one of the BRCA-deficiency protein signatures provided by the present disclosure; and identifying the tumor as BRCA1 -deficient or BRCA1 -proficient and/or BRCA2-deficient or BRCA2-proficient; wherein when the expression level of the proteins of the test sample is the same (within acceptable levels of experimental error) as the expression level of the corresponding proteins in the at least one of the BRCA-deficiency protein signatures, the cancer is classified as BRCA1- and/or BRCA2- deficient.
  • the present disclosure provides methods of using the BRCA-deficiency protein signatures disclosed herein to optimize anti-cancer therapy.
  • the methods comprise generating a test sample comprising the proteome of a cancer isolated from a patient; measuring the expression level of the proteins of the test sample; comparing the expression level of the proteins of the test sample to at least one of the BRCA-deficiency protein signatures provided by the present disclosure; and administering anti-cancer therapy to the patient when the expression level of the proteins of the test sample is similar to the expression level of the corresponding proteins in the at least one of the BRCA-deficiency protein signatures.
  • the methods comprise generating a test sample comprising the proteome of a cancer isolated from a patient; measuring the expression level of the proteins of the test sample; comparing the expression level of the proteins of the test sample to at least one of the BRCA-deficiency protein signatures provided by the present disclosure; and administering anti-cancer therapy to the patient when the expression level of the proteins of the test sample is the same (within acceptable levels of experimental error) as the expression level of the corresponding proteins in the at least one of the BRCA-deficiency protein signatures.
  • the methods comprise generating a test sample comprising the proteome of a cancer isolated from a blood sample obtained from a patient; measuring the expression level of the proteins of the test sample; comparing the expression level of the proteins of the test sample to at least one of the BRCA-deficiency signatures provided by the present disclosure; and administering anti-cancer therapy to the patient when the expression level of the proteins of the test sample is the same (within acceptable levels of experimental error) as the expression level of the corresponding proteins in the at least one of the BRCA-deficiency signatures.
  • the BRCA-deficiency protein signatures provided by the present disclosure are capable of determining whether or not a tumor is BRCAl-deficient. Using the methods described above, in various aspects, the BRCA-deficiency protein signatures provided by the present disclosure are capable of determining whether or not a tumor is BRCA2-deficient.
  • the BRCA-deficiency protein signatures provided by the present disclosure can be used to predict an individual subject's benefit of anti-cancer therapy.
  • the expression levels of the up-regulated proteins comprising the protein signatures of the present disclosure are known and/or may be readily determined ⁇ see, e.g. , Example 1). In that regard, the protein signatures of the present disclosure can serve as reference samples (as defined herein).
  • the expression levels of the up-regulated proteins comprising the protein signatures of the present disclosure are known and/or may be readily determined ⁇ see, e.g. , Example 1). In that regard, the protein signatures of the present disclosure can serve as reference samples (as defined herein).
  • the expression levels of the up-regulated proteins comprising the protein signatures of the present disclosure are known and/or may be readily determined ⁇ see, e.g. , Example 1). In that regard, the protein signatures of the present disclosure can serve as reference samples (as defined herein).
  • the expression levels of the up-regulated proteins comprising the protein signatures of the present disclosure are known and/or may be readily determined ⁇ see, e.g. , Example 1). In that regard, the protein signatures
  • proteins/reference samples may be compared to the expression levels of a test sample of cancer proteins obtained from a patient. Therefore, the expression levels of the proteins comprising any of the protein signatures disclosed herein (reference samples) can be compared to the expression level of the same proteins obtained from a cancer in a patient (test sample).
  • similarity between the expression level of a test sample of cancer proteins obtained from a patient and the expression levels of any one or more of the reference sample protein signatures disclosed herein identifies the cancer as BRCA1 - deficient. In some embodiments, similarity between the expression level of a test sample of cancer proteins obtained from a patient and the expression levels of any one or more of the reference sample protein signatures disclosed herein identifies the cancer as BRCA2- deficient.
  • substantial similarity between the expression level of a test sample of cancer proteins obtained from a patient and the expression levels of any one or more of the reference sample protein signatures disclosed herein identifies the cancer as B RCA 1 -deficient. In some embodiments, substantial similarity between the expression level of a test sample of cancer proteins obtained from a patient and the expression levels of any one or more of the reference sample protein signatures disclosed herein identifies the cancer as BRCA2-deficient. In each case, identity (or "identical”) can be established when the protein expression levels between the test and reference samples provide output readings that are the same within acceptable levels of experimental error.
  • the degree of similarity between the level of expression of the proteins comprising a test sample and the level of expression of the proteins comprising a reference sample is determined based on signal intensity, such as that derived from an assay (e.g. , ELISA, see below).
  • signal intensity such as that derived from an assay (e.g. , ELISA, see below).
  • the ratio of the signal intensity of the proteins comprising a test sample, as compared to the signal intensity of the proteins comprising a reference sample is calculated. This calculation quantifies the differential level of expression of the proteins of the test sample, as compared to the reference sample, if any. In some embodiments, this calculation is carried out quantitatively or semi- quantitatively.
  • the reference sample comprises proteins taken from a tumor, or collection of tumors, known to be BRCA-deficient.
  • the signal intensity produced by any given reference sample is representative of BRCA-deficiency and detection of a statistically significant deviation (increase or decrease) in the signal intensity produced by the proteins of the test sample, as compared to the signal produced by the proteins of the reference sample, is sufficient.
  • the quantification of the expression levels of proteins of a test sample comprises an estimation of the level of expression, as a semiquantitative or relative measure, that is sufficient to predict the presence or absence of BRCA-deficiency (as compared to a reference sample) and thus prospectively direct the determination of therapy for a subject.
  • determination of a level of protein expression in a test sample that is the same, or greater, than that produced by the reference sample is indicative of BRCA deficiency in the tumor from which the test sample was derived. Therefore, in certain embodiments detection of signal intensity from a test sample that is the same, within experimentally acceptable margins of error, as the signal intensity produced by the reference sample is sufficient to classify the tumor from which the test sample was produced as BRCA- deficient. In certain embodiments, detection of signal intensity from a test sample that is greater, within experimentally acceptable margins of error, than the signal intensity produced by the reference sample is sufficient to classify the tumor from which the test sample was produced as BRCA-deficient.
  • detection of signal intensity from a test sample that is less, within experimentally acceptable margins of error, than the signal intensity produced by the reference sample is sufficient to classify the tumor from which the test sample was produced as BRCA-proficient.
  • the deviation of signal intensity of the test sample from the reference sample is measured as a percent difference.
  • a reference sample is deemed to have produced a signal that is less than the reference sample if the signal intensity of the test sample measures at the level selected from: the signal intensity of the reference sample less 5%; the signal intensity of the reference sample less 10%; the signal intensity of the reference sample less 15%; the signal intensity of the reference sample less 20%; the signal intensity of the reference sample less 25%; the signal intensity of the reference sample less 30%; the signal intensity of the reference sample less 35%; the signal intensity of the reference sample less 40%; the signal intensity of the reference sample less 45%; the signal intensity of the reference sample less 50%; the signal intensity of the reference sample less 55%; the signal intensity of the reference sample less 60%; the signal intensity of the reference sample less 65%; the signal intensity of the reference sample less 70%; the signal intensity of the reference sample less 75%; the signal intensity of the reference sample less 80%; the signal intensity of the reference sample less 85%; the signal intensity of the reference sample less 90%; the signal intensity of the reference sample less 95%; and the signal intensity of the reference sample less 100% (or no signal produced
  • the deviation of signal intensity of the test sample from the reference sample is measured as a -fold difference, or a difference based upon unit signal production.
  • a reference sample is deemed to have produced a signal that is less than the reference sample if the signal intensity of the test sample is selected from: two-fold less than the signal intensity of the reference sample; three-fold less than the signal intensity of the reference sample; four-fold less than the signal intensity of the reference sample; five-fold less than the signal intensity of the reference sample; six-fold less than the signal intensity of the reference sample; seven-fold less than the signal intensity of the reference sample; eight-fold less than the signal intensity of the reference sample; nine- fold less than the signal intensity of the reference sample; ten-fold less than the signal intensity of the reference sample; and greater than ten-fold less than the signal intensity of the reference sample.
  • complete identity between the expression level of a test sample of cancer proteins obtained from a patient and the expression levels of any one or more of the reference sample protein signatures disclosed herein identifies the tumor as
  • BRCAl -deficient complete identity between the expression level of a test sample of cancer proteins obtained from a patient and the expression levels of any one or more of the reference sample protein signatures disclosed herein identifies the tumor as BRCA2-deficient.
  • Tumors with homologous recombination deficiency have been shown to be particularly sensitive to anti-cancer therapy which can include, without limitation, DNA double strand break (DSB)-inducing agents, such as alkylators and platinum drugs or platinating agents.
  • DSB DNA double strand break
  • BRCAl- and BRCA2-deficient tumors are therefore sensitive to anticancer therapy (as defined herein).
  • identification of a tumor as BRCAl -deficient, using any one or more of the protein signatures disclosed herein identifies the patient as one who will benefit from anti-cancer therapy.
  • identification of a tumor as BRCA2-deficient, using any one or more of the protein signatures disclosed herein identifies the patient as one who will benefit from anti-cancer therapy.
  • the expression level of any one or more of the up-regulated proteins comprising the BRCA-deficiency protein signatures disclosed herein, and/or the expression levels of any one or more proteins isolated from a test sample (i.e., from a cancer obtained from a patient), can be determined using any one or more of a number of techniques.
  • the expression levels can be determined using routine assays such as, for example, antibody-based methods such as immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), of which the latter allows for non-invasive testing.
  • the expression levels can be determined using targeted multiplex mass spectrometry as a means of quantifying protein signatures in tumor tissues or blood taken from a subject.
  • the expression levels can be determined using mass- spectrometry based proteomics technologies (see, e.g. , Example 1), which have matured to the extent that they can now identify and quantify thousands of proteins.
  • protein expression levels can be determined via immunohistochemistry, which is a process capable of detecting proteins directly in the cells of a section of isolated and fixed tissue via the use of antibodies that bind specifically to the proteins of interest.
  • Immunohistochemistry is a widely used technique to visualize the distribution and localization of differentially expressed proteins between two tissues.
  • a tissue sample is taken from a subject and properly fixed (e.g. , by heat fixation, perfusion, immersion or chemical fixation) to make the epitopes of the proteins of interest available for binding by the antibodies.
  • the tissue sample may be taken from cancer in a subject known to have a BRCAl -deficient tumor to create a reference sample.
  • the tissue sample may be taken from cancer in a subject known to have a BRCA2-deficient tumor to create a reference sample.
  • the tissue sample may be taken from a tumor in subject whose BRCAl and/or BRCA2 status (deficient or proficient) is unknown, to create a test sample.
  • the tissue samples are taken from corresponding tissues and corresponding regions within the tissues in order to create similar testing parameters between the reference and test samples. The proteins in the reference sample and the test sample can be analyzed in parallel or individually.
  • Detecting the protein(s) of interest in a reference sample or a test sample can be accomplished by contact with an antibody that is specifically directed to the protein(s) of interest.
  • an antibody that is specifically directed to the protein(s) of interest.
  • One or more antibodies may be used, depending on the number of proteins to be tested in a single reference or test sample. Detection via contact with an antibody may be done directly, whereby the antibody itself is coupled with a label that will allow for visualization of binding to the protein, or indirectly, where a second antibody that specifically binds to the first antibody is used, the second antibody having the label to allow for visualization.
  • Visualizing an antibody-protein interaction can be accomplished in a number of ways. In the direct detection method, the antibody itself is conjugated to an agent that allows for visualization such as an enzyme (e.g.
  • a peroxidase that can catalyze a color- producing reaction
  • a fluorophore e.g. , fluorescein or rhodamine
  • a second antibody is used that is conjugated to an agent that allows for visualization, such as an enzyme or a fluorophore.
  • the level of differential expression of a protein between a reference sample and a test sample may be determined by measuring the difference in intensity of the visualization means employed. In that regard, in some embodiments the same means of visualization is utilized in both samples. If the signal produced by the reference sample is different from the signal produced in the test sample, then the protein of interest is present in different quantities in the samples, indicating differential expression.
  • the means of visualizing the signal in each sample is linked to an antibody and each antibody will bind to a limited number of proteins in the sample. Therefore, the number of antibodies binding to proteins of a sample is directly proportional to the total number of proteins present in the sample and the strength of the signal produced by the antibody-protein interaction in a sample is directly proportional to the amount of protein present in the sample.
  • the ratio of the signal intensity of the test sample to that of the reference sample is then calculated, to measure the protein expression levels between the test sample and the reference sample. The difference in the signal ratio determines whether the total level of protein expression of each protein in the test sample is increased or decreased, as compared to the reference sample. If the signal produced by the reference sample is the same (within acceptable levels of experimental error) as the signal produced in the test sample, then the protein of interest is present in
  • protein expression levels can be determined via enzyme-linked immunosorbent assay (ELISA), which is an analytic assay that utilizes a solid-phase enzyme immunoassay to detect the presence of a protein in an isolated sample.
  • ELISA enzyme-linked immunosorbent assay
  • an unknown amount of a sample is affixed to a substrate surface and an antibody is placed into contact with the substrate surface such that the antibody is also placed into contact with the sample.
  • the antibody will bind to the sample provided that an antigen capable of being bound by the antibody is present in the sample.
  • the antibody is typically linked to some means of visualizing binding, which in some embodiments is an enzyme, so that binding of the antibody to the sample can be detected.
  • a substance that contains the enzyme's substrate is placed into contact with the surface, and thus the antibody, such that the subsequent enzymatic reaction produces a detectable signal.
  • the signal may be a color change in the substrate or a fluorescent emission.
  • a protein sample isolated from a cancer known to be BRCA1 -deficient is affixed to a substrate surface to create a reference sample.
  • a protein sample isolated from a cancer known to be BRCA2-deficient is affixed to a substrate surface to create a reference sample.
  • a protein sample isolated from a tumor in a subject whose BRCA1 and/or BRCA2 status (deficient or proficient) is unknown is affixed to a substrate surface to create a test sample.
  • the proteins in each sample are the same (the reference sample protein is the same as the test sample protein); by way of example, the reference sample can contain TOP2A isolated from a BRCAl-deficient breast tumor and the test sample can contain TOP2A isolated from a breast tumor whose BRCA status is not known.
  • the substrate surface may contain more than one isolated area (e.g. , wells) such that the reference sample protein and the test sample protein are each affixed in their own isolated area and also so that the same substrate surface may accommodate multiple proteins from the reference sample and the test sample.
  • the substrate surface is a microtiter plate.
  • At least one antibody having specificity for the protein in the reference and test samples is placed in contact with the protein in the reference and test samples so that it may bind to the protein.
  • the proteins in the reference sample and the test sample can be analyzed in parallel or individually.
  • the antibody can be covalently linked to an enzyme, or can itself be detected by a secondary antibody that is linked to an enzyme.
  • the substrate of the enzyme is then placed in contact with each of the reference sample and the test sample to produce a visible signal, which indicates the quantity of protein in each sample. If the signal produced in the reference sample is different from the signal produced in the test sample, then the protein is present in different quantities in the samples, indicating differential expression.
  • the means of visualizing the signal in each sample is linked to an antibody and each antibody will bind to a limited number of proteins in the sample. Therefore, the number of antibodies binding to proteins of a sample is directly proportional to the total number of proteins present in the sample and the strength of the signal produced by the antibody-protein interaction in a sample is directly proportional to the amount of protein present in the sample.
  • the ratio of the signal intensity of the test sample to that of the reference sample is then calculated, to measure the protein expression levels between the test sample and the reference sample. The difference in the signal ratio determines whether the total level of protein expression of each protein in the test sample is increased or decreased, as compared to the reference sample. If the signal in the reference sample is the same (within acceptable levels of experimental error) as the signal produced in the test sample, then the protein of interest is present in
  • protein expression levels can be determined via targeted multiplex mass spectrometry.
  • LC-MS/MS can be used to determine the expression level of proteins isolated from a BRCA1- and/or BRCA2-deficient cancer, and thus create a reference sample.
  • LC-MS/MS can be used to determine the expression level of proteins isolated from a cancer whose BRCAl/2 status is not known to create a test sample. The levels of protein expression can then be compared between the two samples.
  • matrix-assisted laser desorption/ionization time-of-flight mass spectrometry can be used to image histological sections taken from BRCA1- and/or BRCA2-deficient tumors (reference samples) and histological sections taken from tumor samples whose BRCAl/2 status are not known (test samples).
  • MALDI-MS can be used to image naturally occurring molecules, such as proteins, within a reference sample and within a test sample such that the presence and the levels of expression of the proteins can be compared between the two samples.
  • the protein based BRCA-deficiency signatures disclosed herein are advantageous in comparison to transcript-based and genomic markers, as the expression level of the disclosed proteins comprising the deficiency signatures can be measured using routine assays such as, for example, antibody-based methods such as immunohistochemistry and ELISA, of which the latter allows for non-invasive testing.
  • protein profiles of BRCA1- and/or BRCA2-deficient mouse cancers can be generated using high-resolution tandem mass spectrometry-based proteomics.
  • proteomics can be employed based on ID gel electrophoresis in combination with nano-LC-MS/MS and spectral counting to compare the protein profile of a BRCA1- and/or BRCA2-deficient cancer and the protein profile of a BRCA1- and/or BRCA2 -proficient cancer.
  • the two protein profiles can then be compared in order to determine which proteins are differentially regulated between the two cancer types.
  • Pathway and protein complex analysis can then be used to identify the functions of the proteins that are differentially regulated between the two cancer types.
  • one or more proteins that are significantly up-regulated in B RCA 1 -deficient tumors and that have DNA repair and related functions can be utilized in one or more of the protein signatures disclosed herein.
  • mass spectrometry based proteomics can be used to identify proteins associated with BRCA1- and/or BRCA2-deficient cancers.
  • inbred mouse models of human BRCAl-deficient breast cancer that display a minimal amount of genetic variability can be used. Such models can harbor conditional tissue-specific mutations in the BRCA1 and p53 genes. The majority of the tumors manifested by the mouse models are highly similar to their human counterparts with respect to histological and molecular characteristics and show a high level of genomic instability.
  • proteomics can be employed based on ID gel electrophoresis in combination with nano-LC-MS/MS and spectral counting to compare the protein profile of tumors isolated from inbred mouse models of human BRCA1 -deficient breast cancer and the protein profile of tumors isolated from inbred mouse models of human BRCA1 -proficient breast cancer.
  • Differentially expressed proteins including but not limited to up-regulated proteins, can be determined using such techniques.
  • Isolation of proteins from tissue samples can be accomplished via any number of techniques. For example, in certain embodiments, a tissue sample from a BRCA1- deficient cancer may be taken and homogenized. Similarly, a tissue sample from a BRCA1- proficient cancer may be taken and separately homogenized. As will be evident to a person of ordinary skill in the art, each sample is processed separately to avoid cross-contamination and to ensure that the comparison between the two samples is scientifically sound. For purposes of brevity, the following description relates to the sample taken from a BRCA1- deficient cancer, however the same processing can be performed on the BRCA1 -proficient cancer.
  • the proteins in the cancer tissue sample are solubilized in an appropriate buffer (e.g. , a buffer containing an anionic surfactant such as sodium dodecyl sulfate), and then heat denatured.
  • the proteins can then be fractionated according to their electrophoretic mobility using any number of gel electrophoresis techniques such as, for example, one-dimensional sodium dodecyl sulfate -polyacrylamide gel electrophoresis.
  • the gel can be fixed and stained to reveal the bands of fractionated proteins isolated from the BRCA1 -deficient cancer. Data relating to electrophoretic mobility and band color intensity can be obtained.
  • each of the individual gel lanes can be cut into a plurality of bands and each band can be processed separately to remove the proteins therefrom, thereby creating a library of individual pools of proteins isolated from the B RCA 1 -deficient cancer.
  • each gel band can be processes for in-gel digestion by reducing any cysteine bonds that may be present in the proteins in each band (e.g. , by treatment with dithiotreitol) and then incubating each band with an appropriate protease (e.g. , trypsin). The resulting peptides can then be extracted from each gel band and stored prior to LC-MS analysis.
  • the peptides in each pool can then be separated by LC-MS/MS.
  • the MS/MS spectra obtained from each pool can then be analyzed (e.g. , by use of one or more algorithms and comparison to known databases) to determine the intact protein and peptide fragment composition.
  • the MS/MS spectra of the proteins contained in each gel band pool can be searched against the human IPI database, and the results imported into one or more software programs that can organize the gel-band data, validate peptide identifications and generate a list of identified proteins for the gel band pool (see, e.g., Example 1).
  • MS/MS analysis can also serve to quantify the amount of each protein and peptide present in each gel band pool.
  • proteins that are significantly differentially expressed in a BRCAl -deficient cancer are suitable for use in the protein signatures disclosed herein.
  • proteins that are significantly differentially expressed in a BRCAl -deficient cancer, as compared to a BRCAl -proficient cancer are suitable for use in the protein signatures disclosed herein.
  • proteins that are significantly up-regulated in a BRCAl -deficient cancer, as compared to a BRCAl -proficient cancer are suitable for use in the protein signatures disclosed herein.
  • proteins that are significantly up-regulated in a BRCAl -deficient cancer and exhibit DNA-repair, chromatin remodeling and associated functions, as compared to a BRCAl -proficient cancer are suitable for use in the protein signatures disclosed herein.
  • kits for use in the methods described above can comprise one or more of the BRCA-deficiency protein signatures as well as any one or more of the reagents required to perform the methods described herein.
  • the kits comprise instructions for using the BRCA- deficiency protein classifiers to perform the methods provided by the present disclosure.
  • Such kits may include any or all of the following: assay reagents, buffers, one or more of the BRCA-deficiency protein signatures, one or more substrates for immobilization of the proteins of the BRCA-deficiency protein signatures and the proteins of a test sample, and optionally enzyme conjugated antibodies and substrate solutions.
  • kits may include instructional materials containing directions (i.e. , protocols) for the practice of the methods of this invention.
  • instructional materials typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention.
  • Such media include, but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like.
  • Such media may include addresses to internet sites that provide such instructional materials.
  • the present inventors have confirmed that a large proportion (20%) of the proteome of mammalian mammary tumor tissue is significantly differentially regulated (either up-regulated or down-regulated) in BRCA1 -deficient tumors as compared to BRCA1- proficient tumors.
  • the differentially regulated proteins seen in BRCA 1 -deficient tumors are almost exclusively related to BRCA1 status and only partially to cell type, making them and their corresponding nucleic acid sequences, ideally suited as predictive measures of BRCA- deficiency status in cancer.
  • the data presented in this disclosure shows an extensive up- regulation of a broad range of DNA repair/chromatin remodeling pathways and protein complexes in BRCA1 -deficient tumors.
  • the present disclosure is based on the discovery that certain up-regulated proteins seen in BRCA1 -deficient cancer, and the nucleic acid sequences that code for those up-regulated proteins, can be used to identify cancer patients with BRCA1- deficient cancer and/or to predict whether such patients will benefit from anti-cancer therapy.
  • the present disclosure is based on the discovery that certain up-regulated proteins seen in BRCA1 -deficient cancer, and the nucleic acid sequences that code for those up-regulated proteins, can be used to identify cancer patients with BRCA2-deficient cancer and/or to predict whether such patients will benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising one or more nucleic acid sequences of proteins that are up-regulated in BRCA1 -deficient tumors are disclosed.
  • the BRCA-deficiency signatures can be used to identify cancer patients with BRCA1 -deficient tumors.
  • the BRCA- deficiency signatures can be used to identify cancer patients with BRCA2-deficient tumors.
  • the BRCA-deficiency signatures can be used to predict whether such patients will benefit from anti-cancer therapy.
  • the present inventors have identified 45 proteins that are up-regulated in BRCA1 -deficient tumors and have elucidated the corresponding nucleic acid sequences of each of the 45 up-regulated proteins, which are useful in the methods and signatures disclosed herein.
  • the 45 proteins are shown in Fig. 2 and their corresponding nucleic acid sequences are disclosed as SEQ ID NOS: 46 - 90. Therefore, in various embodiments,
  • BRCA-deficiency signatures comprising one or more of SEQ ID NOS: 46 - 90 are disclosed.
  • the BRCA-deficiency signatures comprise at least one of SEQ ID NOS: 46-90. These BRCA-deficiency signatures can be used as diagnostic tools to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer. These BRCA-deficiency signatures can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer. These BRCA- deficiency signatures can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient. These BRCA-deficiency signatures can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 5 nucleic acid sequences selected from the following 45 nucleic acid sequences that code for proteins that are up-regulated in BRCA1 -deficient tumors: SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO:
  • the BRCA-deficiency signatures comprising a set of at least 5 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can be used as diagnostic tools to detect patients who are carrying a BRCAl-mutation and/or have BRCA1- deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 5 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 5 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 5 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 6 nucleic acid sequences selected from the following 45 nucleic acid sequences that code for proteins that are up-regulated in BRCA1 -deficient tumors: SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO:
  • the BRCA-deficiency signatures comprising a set of at least 6 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can be used as diagnostic tools to detect patients who are carrying a BRCAl-mutation and/or have BRCA1- deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 6 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 6 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 6 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 7 nucleic acid sequences selected from the following 45 nucleic acid sequences that code for proteins that are up-regulated in BRCA1 -deficient tumors: SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO:
  • the BRCA-deficiency signatures comprising a set of at least 7 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can be used as diagnostic tools to detect patients who are carrying a BRCAl-mutation and/or have BRCA1- deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 7 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 7 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 7 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 8 nucleic acid sequences selected from the following 45 nucleic acid sequences that code for proteins that are up-regulated in BRCA1 -deficient tumors: SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO:
  • the BRCA-deficiency signatures comprising a set of at least 8 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can be used as diagnostic tools to detect patients who are carrying a BRCAl-mutation and/or have BRCA1- deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 8 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 8 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 8 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • BRCA-deficiency signatures comprising a set of at least 9 nucleic acid sequences selected from the following 45 nucleic acid sequences that code for proteins that are up-regulated in BRCA1 -deficient tumors: SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO:
  • the BRCA-deficiency signatures comprising a set of at least 9 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can be used as diagnostic tools to detect patients who are carrying a BRCAl-mutation and/or have BRCA1- deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 9 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can also be used as diagnostic tools to detect patients who are carrying a BRCA2-mutation and/or have BRCA2- deficient cancer.
  • the BRCA-deficiency signatures comprising a set of at least 9 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signatures comprising a set of at least 9 nucleic acid sequences selected from the foregoing 45 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 45 nucleic acid sequences that code for proteins that are up-regulated in BRCA1 -deficient tumors: SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 46, SEQ ID NO: 47
  • the BRCA- deficiency signature comprising the foregoing 45 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1- deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 45 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2- mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 45 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA- deficiency signature comprising the foregoing 45 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 16 nucleic acid sequences that code for proteins that are up-regulated in BRCA1 -deficient tumors: SEQ ID NO: 55, SEQ ID NO: 68, SEQ ID NO: 89, SEQ ID NO: 67, SEQ ID NO: 83, SEQ ID NO: 52, SEQ ID NO: 76, SEQ ID NO: 88, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 64, SEQ ID NO: 57, SEQ ID NO: 90, SEQ ID NO: 80, SEQ ID NO: 51 and SEQ ID NO: 81.
  • the BRCA-deficiency signature comprising the foregoing 16 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have B RCA 1 -deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 16 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 16 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signature comprising the foregoing 16 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 9 nucleic acid sequences that code for proteins that are up-regulated in BRCAl - deficient tumors: SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 66, SEQ ID NO: 70, SEQ ID NO: 73, SEQ ID NO: 83 and SEQ ID NO: 89.
  • the BRCA-deficiency signature comprising the foregoing 9 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCAl-mutation and/or have BRCA1- deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 9 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2- mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 9 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA- deficiency signature comprising the foregoing 9 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 nucleic acid sequences that code for proteins that are up-regulated in BRCAl - deficient tumors: SEQ ID NO: 46, SEQ ID NO: 49, SEQ ID NO: 62, SEQ ID NO: 74, SEQ ID NO: 85, SEQ ID NO: 87 and SEQ ID NO: 89.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCAl-mutation and/or have BRCAl -deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 8 nucleic acid sequences that code for proteins that are up-regulated in BRCAl - deficient tumors: SEQ ID NO: 46, SEQ ID NO: 49, SEQ ID NO: 55, SEQ ID NO: 62, SEQ ID NO: 74, SEQ ID NO: 85, SEQ ID NO: 87 and SEQ ID NO: 89.
  • the BRCA-deficiency signature comprising the foregoing 8 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 8 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 8 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signature comprising the foregoing 8 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 33 nucleic acid sequences that code for proteins that are up-regulated in BRCA1 -deficient tumors: SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 79, SEQ ID NO: 80, SEQ ID NO: 82, SEQ ID NO: 83, SEQ ID NO: 46, SEQ ID NO
  • the BRCA-deficiency signature comprising the foregoing 33 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCA1 -deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 33 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 33 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signature comprising the foregoing 33 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 37 nucleic acid sequences that code for proteins that are up-regulated in BRCA1 -deficient tumors: SEQ ID NO: 46, SEQ ID NO: 47, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 53, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 69, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 79, SEQ ID NO: 46, SEQ ID NO
  • the BRCA-deficiency signature comprising the foregoing 37 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 37 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 37 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signature comprising the foregoing 37 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 36 nucleic acid sequences that code for proteins that are up-regulated in BRCAl-deficient tumors: SEQ ID NO: 46, SEQ ID NO: 48, SEQ ID NO: 49, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 56, SEQ ID NO: 57, SEQ ID NO: 58, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 71, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 46, SEQ ID NO
  • the BRCA-deficiency signature comprising the foregoing 36 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCA1- mutation and/or have BRCAl-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 36 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 36 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • a BRCA-deficiency signature comprising the foregoing 36 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature is provided comprising the following 21 nucleic acid sequences that code for proteins that are up-regulated in BRCA1 -deficient tumors: SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 59, SEQ ID NO: 63, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 76, SEQ ID NO: 77, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 83, SEQ ID NO: 46, S
  • the BRCA-deficiency signature comprising the foregoing 21 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCA1 -mutation and/or have BRCAl-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 21 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 21 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signature comprising the foregoing 21 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 9 nucleic acid sequences that code for proteins that are up-regulated in BRCAl- deficient tumors: SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 55, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 83, SEQ ID NO: 85 and SEQ ID NO: 89.
  • BRCA-deficiency signature comprising the foregoing 9 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCAl-mutation and/or have BRCAl- deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 9 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2- mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 9 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA- deficiency signature comprising the foregoing 9 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 nucleic acid sequences that code for proteins that are up-regulated in BRCAl- deficient tumors: SEQ ID NO: 46, SEQ ID NO: 49, SEQ ID NO: 62, SEQ ID NO: 74, SEQ ID NO: 77, SEQ ID NO: 85 and SEQ ID NO: 89.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a B RC A 1 -mutation and/or have BRCA1 -deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 20 nucleic acid sequences that code for proteins that are up-regulated in BRCA1 -deficient tumors: SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 59, SEQ ID NO: 60, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 70, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 83, SEQ ID NO: 85, SEQ ID NO: 89 and SEQ ID NO: 90.
  • the BRCA-deficiency signature comprising the foregoing 20 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCA1- mutation and/or have BRCAl-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 20 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 20 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signature comprising the foregoing 20 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 10 nucleic acid sequences that code for proteins that are up-regulated in BRCAl-deficient tumors: SEQ ID NO: 48, SEQ ID NO: 54, SEQ ID NO: 55, SEQ ID NO: 63, SEQ ID NO: 68, SEQ ID NO: 75, SEQ ID NO: 84, SEQ ID NO: 85, SEQ ID NO: 86 and SEQ ID NO: 88.
  • the BRCA-deficiency signature comprising the foregoing 10 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCA1- mutation and/or have BRCAl-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 10 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 10 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signature comprising the foregoing 10 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 16 nucleic acid sequences that code for proteins that are up-regulated in BRCAl -deficient tumors: SEQ ID NO: 51, SEQ ID NO: 52, SEQ ID NO: 55, SEQ ID NO: 57, SEQ ID NO: 64, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 72, SEQ ID NO: 73, SEQ ID NO: 76, SEQ ID NO: 80, SEQ ID NO: 81, SEQ ID NO: 83, SEQ ID NO: 88, SEQ ID NO: 89 and SEQ ID NO: 90.
  • the BRCA-deficiency signature comprising the foregoing 16 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCAl -mutation and/or have BRCAl -deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 16 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 16 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signature comprising the foregoing 16 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 nucleic acid sequences that code for proteins that are up-regulated in BRCAl - deficient tumors: SEQ ID NO: 46, SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 57, SEQ ID NO: 73, SEQ ID NO: 75 and SEQ ID NO: 83.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCAl -mutation and/or have BRCAl -deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • a BRCA-deficiency signature comprising the following 7 nucleic acid sequences that code for proteins that are up-regulated in BRCAl - deficient tumors: SEQ ID NO: 50, SEQ ID NO: 52, SEQ ID NO: 57, SEQ ID NO: 64, SEQ ID NO: 75, SEQ ID NO: 81 and SEQ ID NO: 83.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can be used as a diagnostic tool to detect patients who are carrying a BRCAl -mutation and/or have BRCAl -deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can also be used as a diagnostic tool to detect patients who are carrying a BRCA2-mutation and/or have BRCA2-deficient cancer.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can be used in one or more of the methods disclosed herein to predict the benefit of anti-cancer therapy in an individual patient.
  • the BRCA-deficiency signature comprising the foregoing 7 nucleic acid sequences can also be used in one or more of the methods disclosed herein as a predictive test to identify cancer patients likely to benefit from anti-cancer therapy.
  • the BRCA-deficiency signatures comprising nucleic acid sequences coding for proteins that are up-regulated in BRCAl -deficient tumors disclosed herein can be used as diagnostic tools, to detect patients who are carrying a BRCAl -mutation and/or have a
  • the BRCA-deficiency nucleic acid signatures provided in this disclosure are capable of determining whether an individual cancer patient has a BRCAl -deficient tumor. Additionally, in various aspects, the BRCA- deficiency nucleic acid signatures provided in this disclosure are capable of determining whether an individual cancer patient has a BRCA2-deficient tumor.
  • Tumors with homologous recombination deficiency have been shown to be particularly sensitive to DNA double strand break (DSB)-inducing agents, such as alkylators and platinum drugs or platinating agents. Both classes of drugs are employed in metastatic breast cancer.
  • DSB DNA double strand break
  • PARP inhibitors The novel poly(ADP-ribose) polymerase inhibitors (PARP inhibitors) are specifically effective in homologous recombination deficient tumors as well, and have shown spectacular activity in clinical studies recently. Therefore, BRCAl- and BRCA2-deficient cancers are susceptible to treatment with anti-cancer therapy (as defined herein) and patients having BRCAl - and BRCA2-deficient cancers will benefit from receipt of anti-cancer therapy.
  • the BRCA-deficiency nucleic acid signatures provided in this disclosure are therefore capable of predicting benefit of anti-cancer therapy in an individual patient and can also be used as predictive tests to identify cancer patients likely to benefit from anti-cancer therapy.
  • the present disclosure provides methods of using the BRCA-deficiency nucleic acid signatures disclosed herein to determine whether a tumor has a BRCAl and/or BRCA2 deficiency.
  • the methods comprise generating a test sample comprising nucleic acid sequences isolated from a cancer from a patient; measuring the expression level of the nucleic acid sequences of the test sample; comparing the expression level of the nucleic acid sequences of the test sample to at least one of the BRCA-deficiency nucleic acid signatures provided by the present disclosure; and identifying the cancer as BRCAl -deficient or BRCAl -proficient and/or BRCA2-deficient or BRCA2 -proficient; wherein when the expression level of the nucleic acid sequences of the test sample is similar to the expression level of the corresponding nucleic acid sequences in the at least one of the BRCA-deficiency nucleic acid signatures, the cancer is classified as BRCAl - and/or BRCA2-
  • the methods comprise generating a test sample comprising nucleic acid sequences isolated from a cancer form a patient; measuring the expression level of the nucleic acid sequences of the test sample; comparing the expression level of the nucleic acid sequences of the test sample to at least one of the BRCA-deficiency nucleic acid signatures provided by the present disclosure; and identifying the cancer as BRCAl -deficient or BRCAl -proficient and/or BRCA2-deficient or BRCA2-proficient; wherein when the expression level of the nucleic acid sequences of the test sample is the same as the expression level of the corresponding nucleic acid sequences in the at least one of the BRCA-deficiency nucleic acid signatures, the cancer is classified as BRCAl -deficient.
  • the present disclosure provides methods of using the BRCA-deficiency nucleic acid signatures disclosed herein to optimize anti-cancer therapy.
  • the methods comprise generating a test sample comprising nucleic acid sequences isolated from a cancer from a patient; measuring the expression level of the nucleic acid sequences of the test sample; comparing the expression level of the nucleic acid sequences of the test sample to at least one of the BRCA-deficiency nucleic acid signatures provided by the present disclosure; and administering anti-cancer therapy to the patient when the expression level of the nucleic acid sequences of the test sample is similar to the expression level of the corresponding nucleic acid sequences in the at least one of the BRCA-deficiency nucleic acid signatures.
  • the methods comprise generating a test sample comprising nucleic acid sequences isolated from a cancer from a patient; measuring the expression level of the nucleic acid sequences of the test sample; comparing the expression level of the nucleic acid sequences of the test sample to at least one of the BRCA-deficiency nucleic acid signatures provided by the present disclosure; and administering anti-cancer therapy to the patient when the expression level of the nucleic acid sequences of the test sample is the same (within acceptable levels of experimental error) as the expression level of the corresponding nucleic acid sequences in the at least one of the BRCA-deficiency nucleic acid signatures.
  • the BRCA-deficiency nucleic acid signatures provided by the present disclosure are capable of determining whether or not a cancer is BRCA1 -deficient.
  • the BRCA-deficiency nucleic acid signatures provided by the present disclosure are capable of determining whether or not a cancer is BRCA2-deficient.
  • the BRCA-deficiency nucleic acid signatures provided by the present disclosure can be used to predict an individual subject's benefit of anti-cancer therapy.
  • the expression levels of the up-regulated nucleic acid sequences comprising the nucleic acid signatures of the present disclosure are known and/or may be readily determined.
  • the nucleic acid signatures of the present disclosure can serve as reference samples (as defined herein).
  • the expression levels of the up-regulated nucleic acid sequences/reference samples may be compared to the expression levels of a test sample of nucleic acid sequences isolated from a cancer tissue sample obtained from a patient.
  • the expression levels of the nucleic acid sequences comprising any of the nucleic acid signatures disclosed herein can be compared to the expression level of the corresponding nucleic acid sequences obtained from a cancer in a patient (test sample).
  • similarity between the expression level of a test sample of nucleic acid isolated from a cancer obtained from a patient and the expression levels of any one or more of the reference sample nucleic acid signatures disclosed herein identifies the tumor as BRCAl-deficient. In some embodiments, similarity between the expression level of a test sample of nucleic acid isolated from a cancer obtained from a patient and the expression levels of any one or more of the reference sample nucleic acid signatures disclosed herein identifies the tumor as BRCA2-deficient.
  • substantial similarity between the expression level of a test sample of nucleic acid sequences isolated from a cancer obtained from a patient and the expression levels of any one or more of the reference sample nucleic acid signatures disclosed herein identifies the tumor as BRCAl -deficient. In some embodiments, substantial similarity between the expression level of a test sample of nucleic acid sequences isolated from a cancer obtained from a patient and the expression levels of any one or more of the reference sample nucleic acid signatures disclosed herein identifies the tumor as BRCA2- deficient. In some embodiments, substantial similarity means that the expression level of at least one nucleic acid sequence of the test sample is 50-90% identical to the expression level of the corresponding nucleic acid sequence(s) in the reference sample. In some
  • substantial similarity means that the expression level of a plurality of nucleic acid sequences of the test sample is 50-90% identical to the expression level of the corresponding nucleic acid sequences in the reference sample. In some embodiments, substantial similarity means that the expression level of all of the nucleic acid sequences of the test sample is 50-90% identical to the expression level of the corresponding nucleic acid sequences in the reference sample. In each case, identity (or “identical”) can be established when the protein expression levels between the test and reference samples provide output readings that are the same within acceptable levels of experimental error.
  • the degree of similarity between the level of expression of the nucleic acid sequences comprising a test sample and the level of expression of the nucleic acid sequences comprising a reference sample is determined based on signal intensity, such as that derived from an assay (e.g. , aCGH, see below).
  • signal intensity such as that derived from an assay (e.g. , aCGH, see below).
  • the ratio of the signal intensity of the nucleic acid sequences comprising a test sample, as compared to the signal intensity of the nucleic acid sequences comprising a reference sample is calculated. This calculation quantifies the differential level of expression of the nucleic acid sequences of the test sample, as compared to the reference sample, if any. In some embodiments, this calculation is carried out quantitatively or semi-quantitatively.
  • the reference sample comprises nucleic acid sequences taken from a tumor, or collection of tumors, known to be BRCA-deficient.
  • the signal intensity produced by any given reference sample is representative of BRCA-deficiency and detection of a statistically significant deviation (increase or decrease) in the signal intensity produced by the nucleic acid sequences of the test sample, as compared to the signal produced by the nucleic acid sequences of the reference sample, is sufficient.
  • the quantification of the expression levels of nucleic acid sequences of a test sample comprises an estimation of the level of expression, as a semi-quantitative or relative measure, that is sufficient to predict the presence or absence of BRCA-deficiency (as compared to a reference sample) and thus prospectively direct the determination of therapy for a subject.
  • determination of a level of expression of the nucleic acid sequences in a test sample that is the same, or greater, than that produced by the reference sample is indicative of BRCA deficiency in the tumor from which the test sample was derived. Therefore, in certain embodiments detection of signal intensity from a test sample that is the same, within experimentally acceptable margins of error, as the signal intensity produced by the reference sample is sufficient to classify the tumor from which the test sample was produced as BRCA-deficient. In certain embodiments, detection of signal intensity from a test sample that is greater, within experimentally acceptable margins of error, than the signal intensity produced by the reference sample is sufficient to classify the tumor from which the test sample was produced as BRCA-deficient.
  • detection of signal intensity from a test sample that is less, within experimentally acceptable margins of error, than the signal intensity produced by the reference sample is sufficient to classify the tumor from which the test sample was produced as BRCA-proficient.
  • the deviation of signal intensity of the test sample from the reference sample is measured as a percent difference.
  • a reference sample is deemed to have produced a signal that is less than the reference sample if the signal intensity of the test sample measures at a level selected from: the signal intensity of the reference sample less 5%; the signal intensity of the reference sample less 10%; the signal intensity of the reference sample less 15%; the signal intensity of the reference sample less 20%; the signal intensity of the reference sample less 25%; the signal intensity of the reference sample less 30%; the signal intensity of the reference sample less 35%; the signal intensity of the reference sample less 40%; the signal intensity of the reference sample less 45%; the signal intensity of the reference sample less 50%; the signal intensity of the reference sample less 55%; the signal intensity of the reference sample less 60%; the signal intensity of the reference sample less 65%; the signal intensity of the reference sample less 70%; the signal intensity of the reference sample less 75%; the signal intensity of the reference sample less 80%; the signal intensity of the reference sample less 85%; the signal intensity of the reference sample less 90%; the signal intensity of the reference sample less 95%; and the signal intensity of the reference sample less 100% (or no signal
  • the deviation of signal intensity of the test sample from the reference sample is measured as a -fold difference, or a difference based upon unit signal production.
  • a reference sample is deemed to have produced a signal that is less than the reference sample if the signal intensity of the test sample is selected from: two-fold less than the signal intensity of the reference sample; three-fold less than the signal intensity of the reference sample; four-fold less than the signal intensity of the reference sample; five-fold less than the signal intensity of the reference sample; six-fold less than the signal intensity of the reference sample; seven-fold less than the signal intensity of the reference sample; eight-fold less than the signal intensity of the reference sample; ninefold less than the signal intensity of the reference sample; ten-fold less than the signal intensity of the reference sample; and greater than ten-fold less than the signal intensity of the reference sample.
  • complete identity between the expression level of a test sample of nucleic acid sequences isolated from a cancer obtained from a patient and the expression levels of any one or more of the reference sample nucleic acid signatures disclosed herein identifies the tumor as BRCA1 -deficient. In some embodiments, complete identity between the expression level of a test sample of nucleic acid sequences isolated from a cancer obtained from a patient and the expression levels of any one or more of the reference sample nucleic acid signatures disclosed herein identifies the tumor as BRCA2-deficient.
  • Tumors with homologous recombination deficiency have been shown to be particularly sensitive to anti-cancer therapy which can include, without limitation, DNA double strand break (DSB)-inducing agents, such as alkylators and platinum drugs or platinating agents.
  • DSB DNA double strand break
  • BRCA1- and BRCA2-deficient tumors are therefore sensitive to anticancer therapy (as defined herein).
  • identification of a tumor as BRCA1- and/or BRCA2-deficient using any one or more of the nucleic acid signatures disclosed herein, identifies the patient as one who will benefit from anti-cancer therapy.
  • the expression level of any one or more of the up-regulated nucleic acid sequences comprising the BRCA-deficiency nucleic acid signatures disclosed herein, and/or the expression levels of any one or more nucleic acid sequences isolated from a test sample (i.e. , from a cancer obtained from a patient), can be determined using any one or more of a number of techniques.
  • the expression level of the nucleic acid sequences of a test sample and/or the expression level of the nucleic acid sequences of a reference sample may be measured via array-based comparative genomic hybridization.
  • Array comparative genomic hybridization is a technique that is used to detect copy number variations of nucleic acids at a higher level of resolution than chromosome-based comparative genomic hybridization.
  • nucleic acids from a test sample and nucleic acids from a reference sample are labelled differentially.
  • the test sample and the reference sample are then hybridized to an array comprising a plurality of probes, which are derived from sequences of interest.
  • the differential labelling is then used to visualize the hybridized nucleic acids from the test and reference samples.
  • the ratio of the signal intensity of the test sample to that of the reference sample is then calculated, to measure the copy number changes between the test sample and the reference sample.
  • the difference in the signal ratio determines whether the total copy numbers of the nucleic acids in the test sample are increased or decreased, as compared to the reference sample.
  • the test sample and the reference sample may be hybridized to the array separately or they may be mixed together and hybridized
  • Samples that are labelled differentially are labelled such that one of the two samples is labelled with a first detectable agent and the other of the two samples is labelled with a second detectable agent, wherein the first detectable agent and the second detectable agent produce distinguishable signals.
  • Detectable agents that produce distinguishable signals can include, for example, matched pairs of fluorescent dyes.
  • the methods of the present disclosure comprise analyzing at least one test sample of nucleic acid molecules isolated from a cancer obtained from a patient by array-based comparative genomic hybridization to obtain information relating to the level of expression of the nucleic acid molecules(s), if any, and comparing the level of expression to corresponding nucleic acid molecules comprising one or more of the BRCA-deficiency nucleic acid signatures disclosed herein. Based on the information obtained, the tumor may be classified as BRCAl -deficient or BRCAl -proficient and/or BRCA2-deficient or BRCA2-proficient.
  • Information relating to the expression level of the nucleic acid sequences present in a sample can include, for example, an increase in expression level in one or more nucleic acid molecules, a decrease in expression level in one or more nucleic acid molecules, and/or no change in the expression level of one or more nucleic acid molecules.
  • This information is obtained by analyzing the difference in signal intensity between the test sample and a reference sample at one or more corresponding locations on the array representing one or more nucleic acid sequences of interest. The analysis can be performed using any of a variety of methods, means and variations thereof for carrying out array-based comparative genomic hybridization.
  • the reference samples are any one or more of the
  • BRCA-deficiency nucleic acid signatures provided by the present disclosure, which represent nucleic acid isolated from a known BRCAl -deficient cancer that code for proteins that are significantly differentially up-regulated as compared to BRCAl -proficient cancers.
  • the reference samples are derived from cancers that are known to be BRCAl -deficient.
  • the reference samples are derived from a pool of subjects.
  • the reference samples comprise pooled nucleic acid isolated from BRCAl - deficient cancers from a plurality (e.g. at least 4-10) of female subjects.
  • the reference samples comprise pooled nucleic acid isolated from BRCA2- deficient cancers from a plurality (e.g. at least 4-10) of female subjects.
  • a plurality e.g. at least 4-10 of female subjects.
  • the reference samples are derived from inbred genetic mouse models of
  • the reference samples comprise an average of the expression levels of nucleic acid coding for proteins that are significantly differentially up- regulated in BRCA-deficient cancers.
  • the nucleic acid expression levels are known and are obtainable from one or more publicly available data sets.
  • the reference samples comprise an average of the expression levels of nucleic acid coding for proteins that are significantly differentially up-regulated in BRCA1 -deficient cancers set forth in the Johnsen data set (see, e.g. , Example 1).
  • the reference samples comprise an average of the expression levels of nucleic acid coding for proteins that are significantly differentially up-regulated in BRCA2-deficient cancers set forth in the Johnsen data set (see, e.g. , Example 1). In some embodiments, the reference samples comprise an average of the expression levels of nucleic acid coding for proteins that are significantly differentially up-regulated in sporadically arising cancers set forth in the Johnson data set (see, e.g. , Example 1).
  • the nucleic acid molecules comprising the test samples and the reference samples may be obtained by any suitable method of nucleic acid isolation and/or extraction.
  • the test sample and the reference sample are mRNA.
  • Methods of mRNA extraction are well known in the art and several kits for the extraction and purification of mRNA from tissue samples are commercially available from, e.g. , Clontech (Mountain View, CA), Qiagen (Valencia, CA) and Life Technologies/Invitrogen (Carlsbad, CA), among others.
  • test samples and the reference samples may be differentially labelled with any detectable agents or moieties.
  • the detectable agents or moieties are selected such that they generate signals that can be readily measured and such that the intensity of the signals is proportional to the amount of labelled nucleic acids present in the sample.
  • the detectable agents or moieties are selected such that they generate localized signals, thereby allowing resolution of the signals from each spot on an array.
  • Standard nucleic acid labeling methods include: incorporation of radioactive agents, direct attachment of fluorescent dyes or of enzymes, chemical modification of nucleic acids to make them detectable immunochemically or by other affinity reactions, and enzyme-mediated labeling methods including, without limitation, random priming, nick translation, PCR and tailing with terminal transferase.
  • Other suitable labeling methods include psoralen-biotin, photoreactive azido derivatives, and DNA alkylating agents.
  • test sample and reference sample nucleic acids are labelled by Universal Linkage System, which is based on the reaction of monoreactive cisplatin derivatives with the N7 position of guanine moieties in DNA (see, e.g. , Heetebrij et al., Cytogenet. Cell. Genet. (1999), 87: 47-52).
  • detectable agents or moieties can be used to label test and/or reference samples. Suitable detectable agents or moieties include, but are not limited
  • radionuclides such as, for example, P, S, H, C, I, I, and others
  • fluorescent dyes chemiluminescent agents such as, for example, acridinium esters, stabilized dioxetanes, and others
  • microparticles such as, for example, quantum dots, nanocrystals, phosphors and others
  • enzymes such as, for example, those used in an ELISA, horseradish peroxidase, beta-galactosidase, lucif erase, alkaline phosphatase and others
  • colorimetric labels such as, for example, dyes, colloidal gold and others
  • magnetic labels such as, for example, DynabeadsTM; and biotin, dioxigenin or other haptens and proteins for which antisera or monoclonal antibodies are available.
  • the test samples and the reference samples are labelled with fluorescent dyes.
  • Suitable fluorescent dyes include, without limitation, Cy-3, Cy-5, Texas red, FITC, Spectrum Red, Spectrum Green, phycoerythrin, rhodamine, and fluorescein, as well as equivalents, analogues and/or derivatives thereof.
  • the fluorescent dyes selected display a high molar absorption coefficient, high fluorescence quantum yield, and photostability.
  • the fluorescent dyes exhibit absorption and emission wavelengths in the visible spectrum (i.e., between 400nm and 750nm) rather than in the ultraviolet range of the spectrum (i.e., lower than 400nm).
  • the fluorescent dyes are Cy-3 (3-N,N'-diethyltetramethylindo-dicarbocyanine) and Cy-5 (5-N,N'-diethyltetramethylindo-dicarbocyanine). Cy-3 and Cy-5 form a matched pair of fluorescent labels that are compatible with most fluorescence detection systems for array-based instruments.
  • the fluorescent dyes are Spectrum Red and Spectrum Green.
  • a key component of aCGH is the hybridization of a test sample and a reference sample to an array.
  • Exemplary hybridization and wash protocols are described, for example, in Sambrook et al. (2001), supra; Tijssen (1993), supra; and Anderson (Ed.), "Nucleic Acid Hybridization” (1999), Springer Verlag: New York, N.Y. In some
  • the hybridization protocols used for aCGH are those of Pinkel et al., Nature Genetics (1998), 20:207-211. In some embodiments, the hybridization protocols used for aCGH are those of Kallioniemi, Proc. Natl. Acad. Sci. USA (1992), 89:5321-5325.
  • the array may be contacted simultaneously with differentially labelled nucleic acid sequences of the test sample and the reference sample. This may be done by, for example, mixing the labelled test sample and the labelled reference sample together to form a hybridization mixture, and contacting the array with the mixture.
  • repetitive sequences e.g. , Alu sequences, LI sequences, satellite sequences, MRE sequences, simple homo-nucleotide tracts, and/or simple oligonucleotide tracts
  • repetitive sequences e.g. , Alu sequences, LI sequences, satellite sequences, MRE sequences, simple homo-nucleotide tracts, and/or simple oligonucleotide tracts
  • Removing repetitive sequences or disabling their hybridization capacity can be accomplished using any of a variety of well-known methods.
  • These methods include, but are not limited to, removing repetitive sequences by hybridization to specific nucleic acid sequences immobilized to a solid support (see, e.g., Brison et ah, Mol. Cell. Biol. (1982), 2: 578- 587); suppressing the production of repetitive sequences by PCR amplification using adequately designed PCR primers; inhibiting the hybridization capacity of highly repeated sequences by self-reassociation (see, e.g. , Britten et al , Methods of Enzymology (1974), 29: 363-418); or removing repetitive sequences using hydroxyapatite which is commercially available from a number of sources including, for example, Bio-Rad Laboratories, Richmond, VA.
  • the hybridization capacity of highly repeated sequences in a test sample and/or in a reference sample is competitively inhibited by including, in the hybridization mixture, unlabelled blocking nucleic acids.
  • the unlabelled blocking nucleic acids are therefore mixed with the hybridization mixture, and thus with a test sample and a reference sample, before the mixture is contacted with an array.
  • the unlabelled blocking nucleic acids act as a competitor for the highly repeated sequences and bind to them before the hybridization mixture is contacted with an array. Therefore, the unlabelled blocking nucleic acids prevent labelled repetitive sequences from binding to any highly repetitive sequences of the nucleic acid probes, thus decreasing the amount of background signal present in a given hybridization.
  • the unlabelled blocking nucleic acids are Human Cot- 1 DNA. Human Cot- 1 DNA is commercially available from a number of sources including, for example, Gibco/BRL Life Technologies (Gaithersburg, MD).
  • the ratio of the signal intensity of the test sample as compared to the signal intensity of the reference sample is calculated. This calculation quantifies the differential level of expression of the nucleic acid molecules of the test sample, as compared to the reference sample, if any. In some embodiments, this calculation is carried out quantitatively or semi-quantitatively. In certain embodiments, it is not necessary to determine the exact number associated with differential expression of the nucleic acid molecules comprising the test sample and the reference sample, as detection of a significant increase or decrease in expression level from the expression level in the reference sample is sufficient.
  • the quantification of the expression levels of the nucleic acid molecules of a test sample comprises an estimation of the level of expression, as a semi-quantitative or relative measure usually suffices to predict the presence or absence of BRCA-deficiency and thus prospectively direct the determination of therapy for a subject.
  • Quantitative techniques may be used to determine the expression level of the nucleic acid molecules present in a test sample and/or in a reference sample.
  • quantitative and semi-quantitative techniques to determine expression levels exist including, for example, semi-quantitative PCR analysis or quantitative real-time PCR.
  • the Polymerase Chain Reaction (PCR) per se is not a quantitative technique, however PCR-based methods have been developed that are quantitative or semi-quantitative in that they give a reasonable estimate of original copy numbers of nucleic acids present in a tissue sample ⁇ i.e., expression level of nucleic acid), within certain limits.
  • PCR techniques include, for example, quantitative PCR and quantitative real-time PCR (also known as RT-PCR, RQ- PCR, QRT-PCR or RTQ-PCR).
  • quantitative PCR and quantitative real-time PCR also known as RT-PCR, RQ- PCR, QRT-PCR or RTQ-PCR.
  • RT-PCR quantitative real-time PCR
  • RQ-PCR quantitative real-time PCR
  • QRT-PCR QRT-PCR
  • RTQ-PCR quantitative real-time PCR
  • Fluorescence in situ hybridization permits the analysis of the expression level of individual nucleic acid molecules and can be used to study the expression level of individual nucleic acid molecules across tissue samples obtained from different donor sources (see, e.g. , Pinkel et al., Proc. Natl. Acad. Sci. U.S.A. (1988), 85, 9138-42). Comparative genomic hybridization can also be used to probe for nucleic acid expression levels (see, e.g. , Kallioniemi et al, Science (1992), 258: 818-21 ; and Houldsworth et al, Am. J. Pathol.
  • the expression level of nucleic acid molecules of interest may also be determined using quantitative PCR techniques such as real-time PCR (see, e.g. , Suzuki et al, Cancer Res. (2000), 60:5405-9).
  • quantitative microsatellite analysis can be performed for rapid measurement of relative nucleic acid sequence copy numbers.
  • the copy numbers of a test sample relative to a reference sample is assessed using quantitative, real-time PCR amplification of loci carrying simple sequence repeats. Simple sequence repeats are used because of the large numbers that have been precisely mapped in numerous organisms.
  • Exemplary protocols for quantitative PCR are provided in Innis et al., PCR Protocols, A Guide to Methods and Applications (1990), Academic Press, Inc. N.Y.
  • Semi -quantitative techniques that may be used to determine specific copy numbers include, for example, multiplex ligation-dependent probe
  • kits for use in the methods described above.
  • the kits can comprise one or more of the BRCA-deficiency nucleic acid signatures as well as any one or more of the reagents required to perform the methods described herein.
  • the kits comprise instructions for using the BRCA- deficiency nucleic acid signatures to perform the methods provided by the present disclosure.
  • Such kits may include any or all of the following: assay reagents, buffers, one or more of the BRCA-deficiency nucleic acid signatures, and pre-made arrays comprising probes corresponding to sequences of interest.
  • the kits may include instructional materials containing directions ⁇ i.e. , protocols) for the practice of the methods of this invention.
  • instructional materials typically comprise written or printed materials they are not limited to such. Any medium capable of storing such instructions and communicating them to an end user is contemplated by this invention. Such media include, but are not limited to electronic storage media (e.g., magnetic discs, tapes, cartridges, chips), optical media (e.g., CD ROM), and the like. Such media may include addresses to internet sites that provide such instructional materials.
  • electronic storage media e.g., magnetic discs, tapes, cartridges, chips
  • optical media e.g., CD ROM
  • Such media may include addresses to internet sites that provide such instructional materials.
  • Proteomics of mouse BRCAl-deficient mammary tumors identifies DNA repair proteins with diagnostic and prognostic value in human breast cancer [0311]
  • BRCAl hereditary breast cancer a type of cancer with defects in the homology-directed DNA repair pathway, would benefit from the identification of proteins for diagnosis which might also be of potential use as screening, prognostic or predictive markers.
  • Sporadic breast cancers with defects in the BRCAl pathway might also be diagnosed.
  • proteomics were employed based on ID gel electrophoresis in combination with nano- LC-MS/MS and spectral counting to compare the protein profiles of mammary tumor tissues of genetic mouse models.
  • the protein profiles of BRCAl -deficient mouse models were compared to the protein profiles of BRCAl -proficient mouse models.
  • a total of 3,545 proteins were identified, of which 801 were significantly differentially regulated between the BRCAl -deficient and proficient breast tumors.
  • Pathway and protein complex analysis identified DNA repair and related functions as the major processes associated with the up-regulated proteins in the BRCAl -deficient tumors.
  • a BRCAl -deficiency signature of 45 proteins was identified that enriches for homology-directed DNA repair deficiency in human gene expression breast cancer datasets. This signature also exhibits prognostic power across multiple datasets, with optimal performance in a dataset enriched in tumors deficient in homology-directed DNA repair.
  • mouse proteomes from BRCAl -proficient and deficient mammary tumors several markers associated with BRCAl -deficiency and a prognostic signature for human breast cancer deficient in homology-directed DNA repair were identified.
  • conditional tissue-specific mutations in BRCA1 and p53 were analyzed .
  • the majority of these tumors are highly similar to their human counterpart with respect to histological and molecular characteristics and show a high level of genomic instability.
  • two BRCA1 -proficient reference tumor models that are genomically stable were analyzed 25 .
  • a BRCA1 -deficiency signature was elucidated based on 45 proteins with DNA repair- associated) functions that can enrich for homology-directed DNA repair deficient tumors and identify breast cancer patients with a poor prognosis in various publicly available breast cancer gene expression datasets.
  • Porcine sequence-grade modified trypsin was obtained from Promega (Promega Benelux B.V., Leiden, The Netherlands).
  • tumors were dissected, snap frozen and stored at -80 °C until use.
  • Electrophoresis was carried out at 200 V in NuPAGE MES SDS running buffer (50 mM Tris base, 50 mM MES, 0.1% w/v SDS, 1 mM EDTA, pH 7.3) until the dye front reached the end of the gel. Following electrophoresis, gels were fixed with a solution of 50% ethanol and 3% phosphoric acid. Staining was carried out in a solution of 34% methanol, 3% phosphoric acid, 15% ammonium sulfate and 0.1 % Coomassie Blue G- 250 (Bio-Rad, Hercules, CA) with subsequent destaining in milli-Q water.
  • NanoLC-MS/MS Peptides were separated by an Ultimate 3000 nanoLC system (Dionex LC-Packings, Amsterdam, The Netherlands) equipped with a 20 cm x 75 ⁇ ID fused silica column custom packed with 3 ⁇ 100 A ReproSil Pur CI 8 aqua (Dr. Maisch GMBH, Ammerbuch-Entringen, Germany) as described before 27 .
  • peptides were trapped at 30 ⁇ /min on a 0.5 cm x 300 ⁇ ID Pepmap CI 8 cartridge (Dionex LC- Packings, Amsterdam, The Netherlands) at 2% buffer B ( buffer A: 0.05% formic acid in MQ; buffer B: 80 % ACN + 0.05% formic acid in MQ) and separated at 300 nl/min in a 10- 40% buffer B gradient in 60 minutes. Eluting peptides were ionized at 1.7 kV in a Nanomate Tri versa Chip-based nanospray source using a Tri versa LC coupler (Advion, Ithaca, NJ).
  • Intact peptide mass spectra and fragmentation spectra were acquired on a LTQ-FT hybrid mass spectrometer (Thermo Fisher, Bremen, Germany). Intact masses were measured at resolution 50.000 in the ICR cell using a target value of 1 x 10 6 charges.
  • the top 5 peptide signals (charge-states 2+ and higher) were submitted to MS/MS in the linear ion trap (3 amu isolation width, 30 ms activation, 35% normalized activation energy, Q value of 0.25 and a threshold of 5000 counts). Dynamic exclusion was applied with a repeat count of 1 and an exclusion time of 30 seconds.
  • the scheduled SRM mode comprised the following parameters: SRM detection window of 420 sec, target scan time of 3.0 s, curtain gas of 15, ion source gas 1 of 15, declustering potential of 80, entrance potential of 10.
  • Ql resolution was set to unit and Q3 resolution to unit.
  • Pause between mass ranges was set to 1 ms.
  • Collision cell exit potentials was set to 36 for all transitions. Peak integration was performed using MultiQuantTM software version 2.1 (AB SCIEX, Foster City, CA) software and manually reviewed.
  • SRM assay development An SRM assay for the target proteins (NCAPD2, SIN3A, BAZ1B, TOP2A, TOP2B, PARP1) was developed using the MRMPilotTM software version 2.1 from AB SCIEX (Concord, ON, Canada).
  • the software requires an amino acid sequence of the protein of interest, a starter method containing the LC conditions and an empty SRM-IDA experiment.
  • the software performs an in-silico digest of the protein and creates a set of peptides that would result after full tryptic digestion. For each of these peptides, it will generate an SRM transition for the calculated m/z of the precursor ion and an appropriate fragment ion.
  • Assay development subsequently entails Verification of the peptides and CE-optimisation of the transitions, both in multiplexed LC-SRM analyses.
  • Verification the highest responding peptides/transitions at a theoretically calculated optimum CE-energy are determined, as well as the identity of the peptide via SRM triggered MS/MS.
  • CE-optimisation the transitions selected after verification are optimised during the chromatographic elution of the peptide.
  • Each of the 10 verification analyses was set up to detect 289 of all theoretically predicted transitions and their theoretically predicted optimum collision energy for all theoretically predicted peptides that can result after tryptic digestion of the candidate proteins.
  • the total scan time for each cycle of the instrument during verification was 3.757 seconds, resulting in a dwell time of 10 ms for each transition in the unscheduled verification analyses.
  • CE-optimisation All data of unscheduled analyses were uploaded to the MRMPilot, which was set to select the five best detected transitions for each peptide and assign a chromatographic retention time to each peptide. Subsequently collision energy for each transition was optimised in 13 LC-SRM-analyses, each analysis set-up to detect 104 scheduled transitions that resulted from verification, at 9 different collision energies, centered at 3 Volt intervals around the theoretically predicted optimum with a dwell time of 25ms. All data of CE-optimisation cycles were uploaded to the MRMPilot and for each peptide three transitions at the experimentally found optimum and the experimentally found retention time were included in the final assay.
  • the final assay contained 129 scheduled transitions, 3 for each peptide, 1-5 peptides for each of the 7 candidate proteins.
  • MS/MS spectra were searched against the human IPI database 3.31(67,511 entries) using Sequest (version 27, rev 12), which is part of the Bio Works 3.3 data analysis package (Thermo Fisher, San Jose, CA). MS/MS spectra were searched with a maximum allowed deviation of 10 ppm for the precursor mass and 1 amu for fragment masses. Methionine oxidation and cysteine caboxamidomethylation were allowed modifications, 2 missed cleavages were allowed and the minimum number of tryptic termini was 1. After database searching the DTA and OUT files were imported into Scaffold 1.07 (Proteome software, Portland, OR). Scaffold was used to organize the gel-band data and to
  • IP A Ingenuity Pathways Analysis
  • Proteins were uploaded and mapped to corresponding "gene objects" in the Ingenuity Pathways Knowledge Base. Functional analysis was performed to identify the high level biological functions that were most significantly associated to the differentially regulated proteins in the dataset. Significantly regulated proteins within the high level functions are displayed graphically as nodes (proteins/gene objects) and edges (the biological relationships between the nodes). All edges are supported by at least one reference from the literature, textbook or canonical information stored in the Ingenuity knowledgebase.
  • Ingenuity Pathways Analysis computes one or more p- values for each specific function within a high level function according to the fit of the user's set of significant proteins. The significance of functional enrichment is computed by a Fisher' s exact test. Finally, the Path Designer feature was used to create graphically rich network images. In addition, the COFECO tool was used for the mapping of significantly differentially regulated proteins to protein complexes 32 . The obtained complexes were further visualized using STRING 33 and Cytoscape, respectively.
  • Van de Vijver dataset 12 A validation study of a prognostic gene expression signature (MammaPrint®), which included 295 young patients with early stage breast cancer, of which 151 were lymph node negative, 226 were estrogen receptor-positive, and 110 had received adjuvant chemotherapy. p53 mutational status for 204 tumors was also retrieved from this dataset.
  • Van't Veer dataset 1 In this discovery study for a prognostic signature (MammaPrint®), the authors analyzed 18 BRCAl and 2 BRCA2 samples on the same platform used for the Van de Vijver dataset 12 .
  • E-UCON-1 dataset 10 (subsequently referred to as the Naderi dataset). This dataset was used for discovery of a prognosis profile in a set of women with early stage breast cancer representative of breast cancer demographics. Out of the 132 breast cancer tissues, a subset of 120 patients was used for survival analysis that had the same orientation in dye labeling concerning the reference and tumor samples and which also had associated survival data.
  • GSE2034 dataset 34 (subsequently referred to as Wang dataset). This was a discovery and validation analysis of a gene signature for the prediction of breast cancer patient outcomes. It consists of 286 lymph node-negative breast cancer patients who never received adjuvant chemotherapy and of which 209 were estrogen receptor-positive. The normalized intensity values were logged; zero mean and unit variance normalization were also performed.
  • GSE22133 dataset 8 (subsequently referred to as the Jonsson dataset). This discovery dataset consists of 359 breast tumors including 186 familial of which 22 were BRCAl -mutated, and 32 were BRCA2 mutated.
  • GSE19177 dataset 14 (subsequently referred to as the Waddell dataset). This dataset contains familial tumors only. 19 had a BRCAl mutation, 30 had a BRCA2 mutation while 25 did not have an identifiable mutation. One tumor was excluded from analysis because it had unknown mutational status.
  • a nearest centroid classifier was used to test the diagnostic and prognostic power of the mapped protein/gene signature on the public human gene expression datasets in combination with leave-one-out-cross-validation (LOOCV).
  • LOCV leave-one-out-cross-validation
  • a centroid classification scheme was used to assess BRCAl and homology-directed DNA repair deficiency, whereby centroids were built by taking the average expression value for each signature gene in the diagnostic groups, excluding the leave-out sample. The leave-out samples were then classified into different diagnostic groups using the nearest correlation criterion. For classification with a centroid on external datasets, genes were collapsed by taking the median across all probes.
  • centroid classification scheme was also used for classifications in the Kaplan-Meier survival analysis.
  • patients who survived 5 years or more constituted the good prognosis group (centroid), while patients who survived less than 5 years were used for the poor prognosis group (centroid) 10 ' 12 ' 34 .
  • the average expression value for each signature gene in the good and poor prognosis centroid was computed without the leave-out sample.
  • the leave-out samples were then classified into good or poor prognostic groups using the nearest correlation criterion. To see if a gene list performed better than random, both in the diagnostic and in the survival analysis, an analysis with 1000 random gene lists of the same size using the same scheme was run. Probes were only included on the arrays which were annotated with a gene symbol. The same scheme was applied for the prognostics mRNA based signatures used as a comparison.
  • B RC A 1 -deficient breast tumors often belong to the highly proliferative basal-like subtype, the abundance of protein markers known in basal-like breast cancer were examined in the dataset. In addition, known markers of human BRCA1 -deficiency were sought out.
  • Two basal cytokeratin markers (Krtl4 and Krt6b) were significantly up-regulated in the BRCA1 -deficient mouse tumors.
  • ALDH1 a cancer stem cell marker, was exclusively detected in BRCA1 -deficient mouse tumors, in accordance with previous findings 35 .
  • PCNA and KI67 two well-known proliferation markers , were also significantly up-regulated in the BRCA1 -deficient mouse tumors.
  • DNA repair pathways and protein complexes are associated with proteins up-regulated in BRCA1 -deficient mammary tumors
  • the COFECO tool 32 was employed to identify protein complexes underlying the differential proteins and to further dissect the DNA repair pathways.
  • the up- regulated proteins were linked to 53 significant protein complexes (corrected p- value ⁇ 0.05), of which 44 have a DNA repair(-associated) function.
  • 29 DNA repair(-associated) complexes were obtained.
  • the DNA repair complexes were involved in chromosome condensation, chromosome cohesion, chromosome remodeling, RNA processing, histone methylation, histone acetylation and the topoisomerase complex, amongst others.
  • DNA repair(-associated) complexes included the BRCAl Associated Complex (BASC), involved in double- stranded DNA repair 38 and the Condensin I-PARP1-XRCC1 complex with established functions in single-strand DNA repair 39 .
  • BASC BRCAl Associated Complex
  • 5 out of 7 members of the toposome complex including the drug targets TOPI and TOP2A were significantly up-regulated 40 .
  • chromatin remodeling complexes with a wide involvement in different types of DNA repair processes 41 , were highly prevalent in the dataset. Examples included the WINAC complex, the PBAF complex, the SWI/SNF complex, the GCN5-TRRAP histone acetyl- transferase complex and the DNMT3B histone methylation complex.
  • the signature includes PARP1, involved in single-strand base repair; TRRAP, a large adaptor protein involved in histone acetylation; TOP2A, a topoisomerase; SMC1 A and SMC4, involved in chromatid cohesion and condensation; BAZ1B and ATM, involved in phosphorylation of H2AX upon DNA damage; MSH2 and MSH6, involved in mismatch repair.
  • TRRAP a large adaptor protein involved in histone acetylation
  • TOP2A a topoisomerase
  • SMC1 A and SMC4 involved in chromatid cohesion and condensation
  • BAZ1B and ATM involved in phosphorylation of H2AX upon DNA damage
  • MSH2 and MSH6 involved in mismatch repair.
  • the Jonsson dataset containing 22 BRCAl and 32 BRCA2-mutated tumors and other familial and sporadic tumors was utilized first, since this whole genome gene expression dataset contained the largest number of BRCAl/2 mutated tumors.
  • Hierarchical clustering using all up-regulated proteins showed that the majority of BRCAl-mutated tumors were clustered within one branch of the resulting dendrogram, which coincides with the basal-like tumors.
  • the BRCA2 samples were also clustered largely together within the middle branch of the dendrogram. A clustering using the BRCAl -deficiency signature was also determined.
  • the cluster analysis indicates that the 45 protein BRCAl-deficiency signature shows specificity, not only for BRCAl-mutated tumors, but also for BRCA2 mutated tumors.
  • the nearest centroid classification method was employed to characterize more precisely the sensitivity and specificity of the mouse BRCAl-deficiency signature for BRCAl and BRCA2-mutated tumors, as well as for the list of all up-regulated proteins.
  • the classification results on the Jonsson dataset with leave-one-out cross validation (LOOCV) indicate that the sensitivities for BRCAl-mutated tumors were 77% and 82% for the 417 up- regulated proteins and the BRCAl-deficiency signature, respectively.
  • Classification for the combination of BRCAl and BRCA2-mutated tumors yielded a similar performance, 83% sensitivity for all up-regulated proteins and 81 % for the BRCAl-deficiency signature.
  • transcriptome data from which we also constructed a signature using the same network- based, in silico approach For example, sensitivities of the protein signature for selecting BRCAl deficient tumors were 81.8%, 94.4 %, and 68.4% in the Jonsson, combined Vijver and Van 't Veer and Waddell datasets, whereas these values were 63.6%, 50.0% and 57.9% for the transcriptome signature.
  • the set of all up-regulated proteins achieved the best performance for diagnosing BRCAl mutations in comparison to random (DNA repair) genes. BRCA2-deficient tumors were also classified, implying enrichment for homology-directed repair-deficient tumors in general.
  • the 45 protein signature and all up-regulated proteins also classify a number of familial tumors without BRCAl/2 mutation and sporadic patients as BRCAl/2-like, suggesting that these tumors might be deficient in homology- directed DNA repair.
  • BRCAl-deficiency signature proteins show prognostic power when mapped to human breast cancer gene expression datasets
  • the two mRNA signatures identified within their discovery cohort (MammaPrint® in the Van de Vijver cohort 1 ' 12 , and Naderi signature in the Naderi Cohort 10 ), outperformed all other signatures within their cohort.
  • the mapped BRCA1 -deficiency signature has highly significant prognostic value. Performance was comparable to the gene expression-based signatures in the three sporadic cohorts (the Van de Vijver, Wang and Caldas datasets). Importantly, in the dataset with an overrepresentation of familial (BRCAl/2) tumors (the Jonsson cohort), the mapped mouse BRCA1 -deficiency signature outperformed all human gene expression-based signatures, and performance was still significant when compared to random (DNA-repair) gene lists.
  • mouse BRCAl-deficiency protein signature when mapped to human gene expression data, has prognostic value and outperforms (commercial) gene expression-based signatures in a cohort enriched for breast cancer with defects in the homology-directed DNA repair pathway.
  • BRCA1 deficient breast tumors of the mouse model One gene was also included for which no probe was available on the microarray (TOP2A) and one protein for which protein and mRNA regulation was concordant (PARP1) in the mouse model. Of these gene products, SIN3A and TOP2B had also down-regulated mRNAs in the human dataset of Jonsson, whereas PARP1 was not regulated, TOP2A was upregulated and for NCAPD2 and BAZ1B no probes were available.
  • the protein regulations as revealed by the spectral count data in the discovery samples were confirmed using an independent measure of label-free protein quantitation i.e., the area under the curve of the extracted ion chromatograms.
  • targeted mass spectrometry was performed by SRM-MS in 10 independent mouse breast tumors, all carcinomas.
  • the regulation of SIN3A, NCAPD2, TOP2A, TOP2B and PARP1 was confirmed by SRM-MS in independent tumors, with all peptides being significantly up- regulated in BRCA1 deficient breast tumors whereas only BAZ1B was not significantly up- regulated.
  • Hierarchical clustering using all peptides from the discordant proteins clearly separated this pilot validation set according BRCA1 status.
  • RNA levels were discordant underscores the fact that RNA expression levels cannot always be simply translated to protein expression levels as well as the importance of analysis of the end products of genes by proteomics.
  • Up-regulated proteins in BRCAl -deficient mouse breast tumors contain basal like markers, multiple drug targets and DNA repair(-associated) proteins
  • a number of therapeutic targets were found to be up-regulated in the BRCAl -deficient tumors, including PARP1, TOPI , TOP2A and TOP2B.
  • PARP1 has been shown to be a bona fide drug target for human BRCAl -mutated tumors 43 .
  • Up-regulation of the PARP1 protein may be a marker for the loss of functional homology-directed DNA repair in general, and might therefore be a predictive marker for the efficacy of PARP1 inhibition.
  • the tumors of the BRCAl - deficient mice used in this study responded well to the PARP inhibitor olaparib, whereas the BRCAl -proficient mouse tumor models did not 49 .
  • TOPI , TOP2A and TOP2B are drug targets for topotecan (TOPI inhibitor) and doxorubicin (TOP2A and TOP2B inhibitor).
  • TOPI inhibitor drug targets for topotecan
  • TOP2A and TOP2B inhibitor drug targets for doxorubicin
  • telomere maintenance e.g. chromatin remodelling
  • the BRCAl-deficiency DNA repair signature showed prognostic power across a wide variety of breast cancer datasets. Moreover, the mouse protein signature outperformed two commercially available prognostic RNA-based signatures (MammaPrint ® and Oncotype DX ® ) in a dataset enriched for homology repair-deficient tumors. Finally, in breast cancer, proteins with prognostic power may have predictive value as well. Examples are the hormone receptor ESR1 and the receptor tyrosine kinase ERBB2, the expression of which predicts response to targeted therapy as well as prognosis 54 .
  • This signature shows specificity for BRCAl and homology-directed DNA repair deficiency and has high prognostic potential in breast cancer datasets enriched with homology repair deficient tumors.
  • Several up-regulated DNA repair proteins within this signature have been shown to be drug targets in "homology-directed DNA repair"-deficient tumors, suggesting that they may have predictive power for tailored therapies. Since multiple drug targets are up-regulated, these tumors might also benefit from combination therapy.
  • the BRCAl deficiency transcriptome signature that was obtained by mapping mouse BRCAl deficiency associated breast tumor proteins is novel and could not be obtained by using the published mouse transcriptome data 24 as a starting point.
  • this signature was developed using a publicly available ovarian cancer
  • transcriptomics dataset and with a pilot study for predictiveness based on only 10 BRCA mutated/reverted samples originating from 6 patients and this signature was not externally evaluated in multiple large (BRCA 1/2 deficient) breast cancer datasets. Together this underscores the utility of the BRCAness transcriptome signature that was obtained by mapping mouse BRCA1 deficiency associated breast tumor proteins.
  • Condensin I interacts with the PARP-l-XRCCl complex and functions in DNA single-strand break repair. Mol. Cell 21, 837-848.
  • the Jonsson dataset consists of 359 samples, each with 8,558 gene probes.
  • the dataset was pre-processed as follows: a single quantitative value of each gene was determined by taking the median value of its probes. This resulted in expression values of 8,050 genes.
  • centroid classification method was used. Four centroids were created for the four groups by averaging training samples in each group. To classify a new sample, its distances to the four centroids were computed, and subsequently, the new sample was assigned to group of the closest centroid. The Spearman distance was used.
  • Table 2 shows the ranking of the genes together with the error rates of the signatures constructed from the first ranked gene up to the each gene.
  • Table 5 shows the ranking of the genes together with the error rates signatures constructed from the first ranked gene up to the each gene.

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Abstract

L'invention concerne des signatures du dysfonctionnement du gène BRCA comprenant des protéines régulées de manière différentielle présentes dans des tumeurs dues au dysfonctionnement du gène BRCA1, et des signatures du dysfonctionnement du gène BRCA comprenant des acides nucléiques isolés des tumeurs dues au dysfonctionnement du gène BRCA1, ainsi que des méthodes d'utilisation de celles-ci.
PCT/IB2013/000670 2012-02-23 2013-02-25 Dysfonctionnement de la protéine brca et signatures arnm utiles dans l'identification de patients atteints de tumeurs dues au dysfonctionnement de la protéine brca et prévision des bénéfices d'une thérapie anti-cancer sur des patients atteints de cancer WO2013124740A2 (fr)

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