WO2012158533A1 - Découverte d'un gène de sensibilité aux rayons - Google Patents

Découverte d'un gène de sensibilité aux rayons Download PDF

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WO2012158533A1
WO2012158533A1 PCT/US2012/037556 US2012037556W WO2012158533A1 WO 2012158533 A1 WO2012158533 A1 WO 2012158533A1 US 2012037556 W US2012037556 W US 2012037556W WO 2012158533 A1 WO2012158533 A1 WO 2012158533A1
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rsl
radiation therapy
individual
genes
radiation
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Barry S. ROSENSTEIN
Harry OSTRER
Richard G. STOCK
Nelson N. STONE
Sarah L. KERNS
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Rosenstein Barry S
Ostrer Harry
Stock Richard G
Stone Nelson N
Kerns Sarah L
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Application filed by Rosenstein Barry S, Ostrer Harry, Stock Richard G, Stone Nelson N, Kerns Sarah L filed Critical Rosenstein Barry S
Publication of WO2012158533A1 publication Critical patent/WO2012158533A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C12Q1/6886—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material for cancer
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/106—Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/156—Polymorphic or mutational markers
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers

Definitions

  • the inventors have developed a predictive mix of SNPs that correspond to both normal tissue adverse and tumor eradication outcomes. No other SNP -based assay is available that is capable of predicting the radiotherapy response of individuals or individual cancers.
  • This disclosure provides genes and gene regions associated with radiation sensitivity/ toxicity of non-cancerous tissues in an individual. This disclosure further presents genes and gene regions associated with tumor responsiveness to radiation damage.
  • This disclosure provides methods for predicting increased risk of radiation therapy side effects in an individual, by identifying genetic variants and SNPs listed in Tables 1A and IB in a sample from the individual. The presence of a genetic variant or SNP in the individual predicts increased risk of radiation therapy side effects.
  • This disclosure further provides methods for predicting increased tumor resistance to radiation in an individual, by identifying genetic variants and SNPs listed in Tables 1A and IB in a sample from the individual. The presence of a genetic variant or SNP in the individual predicts increased tumor resistance to radiation therapy.
  • the cancer is prostate cancer
  • the side effect is one or more of urinary morbidity, erectile dysfunction, and proctitis/ rectal bleeding
  • the increased tumor resistance is indicated by increased time to serum levels of PSA ⁇ 0.3ng.
  • kits for predicting increased tumor resistance to radiation therapy or increased risk of radiation therapy side effects in an individual comprising a plurality of nucleic acid probes that hybridize to the genes or SNPs listed in Tables 1A and IB.
  • This disclosure additionally provides methods for testing a candidate compound for ability to increase tumor sensitivity to radiation treatment in a patient or ability to protect a patient from side effects of radiation treatment, said method comprising testing the ability of said candidate compound to alter the expression or function of the genes in Tables 1A and IB.
  • This disclosure provides DNA chips for predicting increased risk of radiation therapy side effects in an individual, the DNA chips including: a supporting means for supporting a synthesized DNA probe; and a plurality of genetic markers supported on the supporting means, where the plurality of the genetic markers include SNP markers at one or more of the SNP loci in Tables 1A and IB.
  • This disclosure also provides DNA chips for predicting increased tumor resistance to radiation in an individual, the DNA chips including: a supporting means for supporting a synthesized DNA probe; and a plurality of genetic markers supported on the supporting means, where the plurality of the genetic markers include SNP markers at one or more of the SNP loci in Tables 1A and IB.
  • Fig. 1 Two-stage genome-wide association study design for investigation of genetic predictors of radiation toxicity.
  • Fig. 2 Manhattan plots showing the p-values from Stage 1 of the study looking at radiation toxicity outcomes. Stage 1 was carried out among the discovery cohort samples which were genotyped for approximately 600,000 SNPs using genome-wide arrays.
  • Fig. 3 Two-stage genome-wide association study design for investigation of genetic predictors of time to PSA decrease as a measure of tumor response to radiotherapy.
  • Fig. 4 Distribution of times to PSA decrease (in days) among all patients included in the
  • Fig. 5 Manhattan plots showing the p-values from Stage 1 of the study of PSA decrease.
  • Stage 1 was carried out among the discovery cohort samples which were genotyped for approximately 600,000 SNPs using genome-wide arrays.
  • Fig. 6 Survival curves from the Cox regression model including age and SNPs identified as predictive of time to PSA decrease.
  • the cumulative SNP score used in the model is the sum total of risk alleles for the top 10 SNPs found to be predictive of time to PSA decrease.
  • Radiotherapy can provide a sustainable cure for prostate cancer and has become accepted as a standard treatment option.
  • some men develop long-term side effects following treatment, including urinary morbidity, proctitis and erectile dysfunction (ED), which have a substantial effect on quality of life.
  • the inventors have identified a genetic basis for development of such side effects, and this disclosure presents a predictive tool incorporating these genetic determinants to assist clinicians in identifying individuals at risk for side effects.
  • the inventors have identified single nucleotide polymorphisms (SNPs) and copy number polymorphisms (CNPs) associated with the development of severe urinary morbidity, proctitis and ED resulting from radiotherapy treatment for prostate cancer.
  • SNPs single nucleotide polymorphisms
  • CNPs copy number polymorphisms
  • side effects of radiation therapy include, but are not limited to, urinary morbidity, proctitis, and erectile dysfunction. Other side effects of radiation therapy, such as hair loss, nausea, are also encompassed by this disclosure. Side effects may last 1-4 weeks, 1-2 years, 1-3 years, 1-4 years, 1-5 years, 3-5 years, or more than five years.
  • urinary morbidity is defined using the International Prostate Symptom Score (IPSS).
  • IPSS International Prostate Symptom Score
  • a score of 1-7 indicates mildly symptomatic/ mild urinary morbidity; a score of 8-19 indicates moderately symptomatic/ moderate urinary morbidity; and a score of 20-35 indicates severely symptomatic/ severe urinary morbidity.
  • proctitis is defined as an inflammation of the rectum that causes discomfort, bleeding, and can also cause a discharge of mucus or pus.
  • erectile dysfunction is defined as regular or repeated inability to obtain or maintain an erection.
  • the term "genetic marker” as used herein refers to a region of a nucleotide sequence (e.g., in a chromosome) that is subject to variability (i.e., the region can be polymorphic for a variety of alleles).
  • a "single nucleotide polymorphism” (SNP) in a nucleotide sequence is a genetic marker that is polymorphic for two (or in some cases, three or four) alleles.
  • An SNP is a single base position in DNA at which different alleles, or alternative nucleotides, exist in a population.
  • SNPs can be present within a coding sequence of a gene, within noncoding regions of a gene and/or in an intergenic (e.g., intron) region of a gene.
  • a SNP in a coding region in which both allelic forms lead to the same polypeptide sequence is termed synonymous (i.e., a silent mutation) and if a different polypeptide sequence is produced, the alleles of that SNP are non-synonymous.
  • SNPs that are not in protein coding regions can still have effects on gene splicing, transcription factor binding and/or the sequence of the non-coding RNA.
  • a "genetic variant" is an alteration from a common sequence in the population that may have direct effects on the expression or function of a gene or may be tightly linked to another variant that may have direct effects on the expression or function of a gene.
  • Radioisotopic/ radiative cancer therapies refers to any method of treatment involving use of radioisotopic/ radiative cancer therapies.
  • the radiation therapy is brachytherapy (permanent seed implantation) or external beam irradiation.
  • brachytherapy permanent seed implantation
  • external beam irradiation external beam irradiation.
  • the assays and genetic markers described herein are useful tools for diagnosis, monitoring, and/or treatment of an individual patient or tumor response to any of a variety of cancers, including leukemias; lymphomas; multiple myelomas; bone and connective tissue sarcomas; brain tumors; breast cancer; adrenal cancer; thyroid cancer; pancreatic cancer;
  • pituitary cancers eye cancers; vaginal cancers; cervical cancers; uterine cancers; ovarian cancers; esophageal cancers; stomach cancers; colon cancers; rectal cancers; liver cancers;
  • the cancer is prostate cancer.
  • the tissue samples may be samples of any of the tissues described herein, such as prostate, breast, colon, pancreatic, lung, gastric, or bladder cells.
  • PSA or "prostate specific antigen” is a protein present at low levels in male and female serum. Increased levels of PSA in male serum are associated with prostate cancer and other prostate disorders. In prostate cancer patients, response to radiation therapy correlates with reduction in PSA levels.
  • RT radiation therapy
  • patients treated with radiation therapy experience varying adverse effects on normal tissue and varying rapidity of PSA response as the tumor shrinks.
  • These genetic factors form the basis of an assay to measure an individual patient's "radiosensitivity" profile which can then be used to personalize therapy to achieve maximal therapeutic index (i.e. maximize tumor killing while sparing normal tissues).
  • a better understanding of the molecular pathways involved in radiation response of the tissues involved in prostate cancer therapy can also provide the basis for development of radio-sensitizing or radio-protective agents.
  • the inventors have identified genetic variants associated with development of adverse tissue response, particularly urinary morbidity, erectile dysfunction, and/or proctitis/rectal bleeding, to radiation therapy.
  • the inventors have further identified genetic variants predictive of tumor response to radiation therapy, as measured by time to decrease in PSA levels.
  • the inventors' goal was to utilize both genetic and clinical information to build predictive models that can be used to personalize patient treatment.
  • the terms "individual”, “subject” and “patient” are used interchangeably and refer to an animal, preferably a mammal such as a non-primate (e.g., cows, pigs, horses, cats, dogs, rats etc.) and a primate (e.g., monkey and human), and most preferably a human.
  • a non-primate e.g., cows, pigs, horses, cats, dogs, rats etc.
  • a primate e.g., monkey and human
  • This disclosure presents methods of detecting at least one genetic variant within a gene or gene subset which can correlate with increased risk of radiation therapy side effects in a subject. Genetic variants are also identified herein that correlate with increased tumor resistance to radiation in a subject.
  • GWAS gene wide association study
  • RG Comparison of intraoperative dosimetric implant representation to post-implant dosimetry in patients receiving prostate brachytherapy. Brachytherapy 2(1): 17-25, 2003. ; Stock RG, Stone
  • the combination of data allowed the inventors to identify dose/ normal tissue adverse outcomes and thus identify the subsets of patients where these relationships do not account for the increased (or decreased) morbidity.
  • the well-characterized patient population combined with long follow-up, has made investigation of potential candidate genes particularly possible.
  • This disclosure presents genes and gene regions associated with radiation sensitivity/ toxicity of non-cancerous tissues in an individual.
  • increased tissue-specific radiation sensitivity is seen in adverse side effects including urinary morbidity, erectile dysfunction, and rectal bleeding/proctitis.
  • the inventors have developed methods and assays, utilizing these identified genes and gene regions, to predict the probability that an individual will develop side effects following standard courses of radiation therapy.
  • prostate epithelial tissues largely consisting of tumor cells in the case of prostate cancer, to radiation damage.
  • These genes and gene regions have been identified by correlating the rapidity in the fall in serum prostate specific antigen (PSA) to genes screened through the GWAS. Identification of genetic variants of these genes and gene regions can be used to predict which patients have an increased risk of resistance to standard radiation doses (for tumor eradication).
  • PSA serum prostate specific antigen
  • the inventors have performed prostate biopsies on a subset of patients (about 600) 2 plus years after completing their radiation treatment. This data set, the largest in the world of this type, has allowed the inventors to analyze the local effects (in the primary tumor) of the radiation therapy's ability to eradicate the cancer.
  • patients can be analyzed for probability of tumor resistance to radiation therapy and need for additional or higher doses of radiation therapy.
  • the subset of patients who might require these augmented doses would also have their blood "genotyped" for side effect risk using assays developed by the inventors as discussed above, and thus can be screened for risk of side effects.
  • This disclosure presents a unique set of genes and gene regions associated with radiation side effects and PSA response. Utilizing these identified genes and gene regions, the inventors have developed assays to predict the response of patients diagnosed with prostate cancer based upon the possession of certain single nucleotide polymorphisms (SNPs) as to the likely effectiveness of radiotherapy and the probability that the patient will develop adverse effects following a standard course of radiotherapy.
  • SNPs single nucleotide polymorphisms
  • Tables 1A and IB Top SNPs and genes identified from two-stage genome-wide association study. SNPs were selected on the basis of Fisher combined p-values from both the discovery and replication cohorts.
  • rsl0485845 CNTNAP2 rsl0967965, rsl7779457, rsl0812604, rsl537712, MOBKL2B rs774354, rs774352, rs700782, rs2453552
  • Genetic variation is measured by testing a sample from a subject, such as a sample of blood, urine or other bodily fluids, or any solid tissue, for polymorphism at one or more genetic or SNP loci identified in Table 1.
  • the subject may have, or have had in the past, a cancer diagnosis, such as a diagnosis of prostate cancer.
  • Genes associated with specific outcomes are listed below and in Table 1 ; as Table 1 illustrates, there are also SNPs associated with specific outcomes.
  • DNA analysis Any method for determining genetic variation or SNP polymorphism can be used for determining the patient genotype in the present invention. Such methods include, but are not limited to, amplimer sequencing, DNA sequencing, fluorescence spectroscopy, fluorescence resonance energy transfer (or "FRET")-based hybridization analysis, high throughput screening, mass spectroscopy, microsatellite analysis, nucleic acid hybridization, polymerase chain reaction (PCR), RFLP analysis and size chromatography (e.g., capillary or gel chromatography), all of which are well known to one of skill in the art. In particular, methods for determining nucleotide polymorphisms, particularly single nucleotide polymorphisms, are described in U.S. Pat.
  • Genes and SNPs associated with increased risk of radiation therapy side effects are listed below and in Tables 1 A and IB.
  • An "increased risk" of side effects means an increase by 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, or 100% or more over the risk of the same side effects occurring in a subject that does not have the genetic variant or SNP.
  • Genes associated with urinary morbidity include TTLL7, AGL/SLC35A3, C2orf55,
  • MRPS9 TNS1, NSUN3, GRID2, CREB5, MAGI2, CNTNAP2, MOBKL2B, GADD45G,
  • Genes associated with erectile dysfunction include N 5A2/PTP C, AHCTF 1 ,M YT 1 L, DYSF/CYP26B1, CDCP1, KCNN2/YTHDC2, PKHD1, RIMS1/KCNQ5, CNKSR3,
  • Genes associated with proctitis include ST6GALNAC3, SLAMF9/PIGM,
  • CDC73/KCNT2 KCNF1/PDIA6, THUMPD2/SLC8A1 , ZNF804A/FLJ44048, SR140, TNIK, LOC646316/PCDH18, TBC1D9, CDH12, FLJ23152/LOC 100130360, TAC1/ACN9, DPYSL2, LOC727677/MYC, SLClAl/C9orf68, UHRF2/TPD52L3, CTNNA3, INCENP,
  • non-radiative therapies include chemotherapeutic agents such as small molecule toxins or enzymatically active toxins of bacterial, fungal, plant or animal origin, including fragments and/or variants thereof.
  • Non-radiative therapies further include removal of cancerous tissue or cells by surgery, biopsy, or other means.
  • the recommended dosages of the cancer agents currently used for the prevention, treatment, and/or management of cancer can be obtained from any reference in the art including, but not limited to, Hardman et al., eds., Goodman & Gilman's The Pharmacological Basis Of Therapeutics, 10th ed, Mc-Graw-Hill, N.Y., 2001; and Physician's Desk Reference (60 th ed., 2006), which are incorporated herein by reference in their entirety.
  • Genes and SNPs associated with decreased tumor response to radiation are listed below and in Table 1.
  • An "increased time" can be an increase in 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, or 24 or more months over the time to reach the same PSA levels in a subject that does not have the genetic variant or SNP.
  • PSA measurement can be made by any method known in the art.
  • Genes associated with decreased tumor response/ increased time to PSA decrease include
  • a prediction of increased tumor resistance must be weighted against a prediction of increased risk of radiation therapy side effects. For example, if increased tumor resistance is predicted in the absence of indicators of increased risk of radiation side effects, increasing the dosage, frequency, and/or duration of radiation therapy would be more acceptable than if increased risk of side effects is predicted. If increased tumor resistance is predicted, and increased risk of radiation side effects is also predicted, non-radiative therapies are
  • Kits This disclosure further provides kits for predicting increased tumor resistance to radiation therapy or increased risk of radiation therapy side effects in an individual.
  • the kit includes a plurality of nucleic acid probes that hybridize to two or more of the following human SNPs: rsl7158178, rsl0508230, rs7088654, rsl0903668, rs958640, rsl325999, rs2813427, rsl2571964, rs2688388, rs7011009, rs2407190, rsl7071931, rsl 1776192, rsl467980, rs7846266, rsl472331, rsl998471, rs9594943, rsl410942, rs2825233, rs2824959, rs7281316, rs41442149, rsl3047582, rs2824922, rs2704342, rs6756236,
  • rsl3000157 rs2147100, rs957722, rs2241122, rs2148407, rs4904509, rs9935515, rs9934964, rsl2621723, rs6719357, rs2722609, rs6740178, rs2564046, rsl346608, rs299847, rsl27822, rsl61405, rsl61407, rsl740721, rs224765, rsl323618, rs9600896, rs9574082, rs927597, rs9593240, rs9318488, rs479116, rsl0871105, rs9990565, rs9990959, rsl7380093, rsl0192455, rsl0496298, rsl2619848, rs6728097
  • the kit includes a plurality of nucleic acid probes that hybridize to two or more genes chosen from the group consisting of: ADARB2, CSMD1, ENOX1, PRSS7, FSHR, FOXN3, ERCC4, SOX11, ZNF274, PARD3, SCEL, D4S234E/NEEP21, SUCLG1, ZNF329, SHROOM4, CUGBP2, A2BP1/RBFOX1, ACCN1, ODZ3/ODZ4, DCC, MSC, LSAMP, BMP2, SH3RF3, LUZP2, STYKl, GLRX3, NR3C2, RGS22, RIT2, PFDN4, SLC4A3, and/or any genes listed in Table 1 A. Presence of a genetic variant of one or more genes from the group predicts increased tumor resistance to radiation therapy or increased risk of radiation therapy side effects in the individual being tested.
  • DNA chips for predicting increased risk of radiation therapy side effects in an individual, the DNA chips including: a supporting means for supporting a synthesized DNA probe; and a plurality of genetic markers supported on the supporting means, where the plurality of the genetic markers include SNP markers at one or more of the SNP loci in Tables 1A and IB.
  • This disclosure also provides DNA chips for predicting increased tumor resistance to radiation in an individual, the DNA chips including: a supporting means for supporting a synthesized DNA probe; and a plurality of genetic markers supported on the supporting means, where the plurality of the genetic markers include SNP markers at one or more of the SNP loci in Tables 1A and IB.
  • Drug discovery Identification of the protein products and molecular pathways coded for by these genetic changes associated with radiation sensitivity opens the door to the potential for drug discovery that could protect the patient from side effects or increase the likelihood of responsiveness to the radiation therapy.
  • the potential for drug discovery includes, for example, molecules that would increase radiation response (for patients who may require higher radiation doses as identified by the assays herein disclosed) or that would provide radiation protection for organs at risk for radiation injury.
  • Such compounds can also be useful as a generalized radiation "protection" agent to be given to individuals who are exposed to high radiation doses as was experienced in Daiichi, Japan in 2011.
  • candidate compound refers to any compound that can alter the expression or activity of one or more of the genes listed in Tables 1A and IB.
  • the candidate compound may be a protein or fragment thereof, a small molecule, or even a nucleic acid molecule.
  • One may also acquire, from various commercial sources, small molecule libraries that are believed to meet the basic criteria for useful drugs in an effort to "brute force" the candidate compound.
  • Candidate compounds may include fragments or parts of naturally-occurring compounds, or may be found as active combinations of known compounds, which are otherwise inactive. It is proposed that compounds isolated from natural sources, such as animals, bacteria, fungi, plant sources, including leaves and bark, and marine samples may be assayed as candidates for the presence of potentially useful pharmaceutical agents. It will be understood that the
  • candidate compounds to be screened could also be derived or synthesized from chemical compositions or man-made compounds.
  • candidate compound identified by the present invention may be peptide, polypeptide, polynucleotide, small molecule inhibitors or any other compounds that may be designed through rational drug design starting from known inhibitors or stimulators.
  • This disclosure provides methods for testing a candidate compound for ability to increase tumor sensitivity to radiation treatment in a patient.
  • the methods iinclude testing the ability of a candidate compound to alter the expression or function of one or more of the following genes: CSMD1, P SS7, FOXN3, ERCC4, ZNF274, PARD3, SCEL, D4S234E/NEEP21, SUCLG1, ZNF329, SHROOM4, ACCN1, ODZ3/ODZ4, DCC, and/or any genes listed in Table 1A.
  • a compound that alters the expression or function of one or more of these genes is a candidate compound for increasing tumor sensitivity to radiation treatment.
  • This disclosure further provides methods for testing a candidate compound for ability to protect a patient from side effects of radiation treatment.
  • the methods include testing the ability of a candidate compound to alter the expression or function of one or more of the following genes: ADA B2, CSMD1, ENOX1, PRSS7, FSHR, FOXN3, ERCC4, SOX11, ZNF274, PARD3, SCEL, D4S234E/NEEP21, SUCLG1, ZNF329, SHROOM4, CUGBP2,
  • a compound that alters the expression or function of one or more of these genes is a candidate compound for protecting a patient from side effects of radiation treatment.
  • results to Date The inventors identified 807 patients out of the 905 patients enrolled in the study who fit inclusion criteria as cases and/or controls for at least one of the outcomes assessed. To date, SNP and CNP microarrays have been run for 801 patients with urinary morbidity outcome data, 260 ED cases and 205 controls, and 80 proctitis cases and 655 controls. After quality control filtering, the average genotyping rate is 98.7% among the discovery cohort and >99% among the replication cohort. The inventors next identified SNPs that were found to be significant predictors of radiation toxicity across both the discovery and replication cohorts
  • Urinary Morbidity UM is represented by the change in IPSS score from post-RT relative to pre-RT. All patients with elevated IPSS (International Prostate Symptom Score) obtained at least lyr following treatment were included in analysis; any change in score, either increasing or decreasing from previous score, as a continuous measure was considered relevant. Analysis was adjusted for pre-RT IPSS, hypertension, treatment modality, and ancestry.
  • Outcome Change in IPSS score (relative to pre-RT) at each follow-up assessment between 1 year and 5 years after treatment. For example, if a patient has an IPSS of 8 prior to radiotherapy and they end up with a score of 20 following radiotherapy, then they experienced worsening of symptoms by a measure of 12 points (i.e. their change in IPSS is 12). So to test for association of SNPs with UM, linear regression is performed with change in IPSS as the dependent variable and the SNP as the independent variable.
  • ⁇ (Urinary Score) ⁇ 0 + pi(SNPi) + p 2 (SNP 2 ) + p 3 (SNP 3 ) + p 4 (Ancestry) + p 5 (pre-RT urinary status) + P6(Hypertension)
  • results of this study provide the basis for development of a clinically relevant predictive test to identify patients at increased risk for development of adverse events following radiotherapy.
  • Such a tool can be used to aid clinicians in personalizing dosage to improve the therapeutic index of radiotherapy treatment for prostate cancer.
  • EBRT external beam RT
  • germline DNA from 164 of the men was analyzed for approximately 450
  • 5 ⁇ p-value used is the lowest from four genetic models: allelic, genotypic, dominant, and recessive
  • Non-genetic variables associated with time to PSA decrease below 0.3ng following radiotherapy * HR for each clinical factor is adjusted for the other three clinical factors; HR for each SNPs is adjusted for clinical factors, ** reference category for Treatment is
  • brachytherapy + EBRT , ⁇ reference category for SNPs is homozygous for the common allele.
  • Multivariable Cox regression model including genetic and non-genetic predictors of time to PSA decrease below 0.3ng.
  • Reference category for Treatment is brachytherapy + EBRT.
  • P-values and Beta values are from multivariate linear regression including ethnicity, pre-RT urinary symptom score, and

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Abstract

La présente invention concerne des variants génétiques associés à l'apparition d'une réponse tissulaire indésirable, notamment une morbidité urinaire, une dysérection et/ou une proctite/un saignement anal, suite à une radiothérapie. L'invention concerne, en outre, des variants génétiques permettant de prédire la réponse tumorale à une radiothérapie, comme mesuré par la durée nécessaire à une baisse du taux de PSA. Les dosages et les marqueurs génétiques décrits ici constituent des outils utiles de diagnostic, de suivi et/ou de traitement d'un patient particulier ou d'analyse de la réponse tumorale de l'un quelconque de divers cancers sur la base des modèles prédictifs de l'invention à des fins de personnalisation du traitement proposé au patient.
PCT/US2012/037556 2011-05-13 2012-05-11 Découverte d'un gène de sensibilité aux rayons WO2012158533A1 (fr)

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EP3135771A1 (fr) * 2015-08-27 2017-03-01 Commissariat A L'energie Atomique Et Aux Energies Alternatives Procédé pour évaluer la radiosensibilité individuelle et le risque d'effets secondaires
CN111979337A (zh) * 2020-09-02 2020-11-24 刘学峰 一种羊多胎性状分子标记及其应用
CN113337603A (zh) * 2021-04-23 2021-09-03 深圳市龙华区人民医院 Suclg1基因或其表达产物的应用、检测试剂盒
EP3960876A1 (fr) * 2020-08-31 2022-03-02 Koninklijke Philips N.V. Prédiction d'une réponse d'un sujet atteint d'un cancer de la prostate soumis à une radiothérapie basée sur les gènes corrélés pde4d7
CN114231622A (zh) * 2021-01-22 2022-03-25 南京世和基因生物技术股份有限公司 局限期小细胞肺癌放疗毒副作用标志物

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Publication number Priority date Publication date Assignee Title
EP3135771A1 (fr) * 2015-08-27 2017-03-01 Commissariat A L'energie Atomique Et Aux Energies Alternatives Procédé pour évaluer la radiosensibilité individuelle et le risque d'effets secondaires
WO2017032865A1 (fr) * 2015-08-27 2017-03-02 Commissariat A L'energie Atomique Et Aux Energies Alternatives Procédé d'évaluation de la radiosensibilité individuelle et du risque d'effets indésirables
CN105969887A (zh) * 2016-06-30 2016-09-28 华南农业大学 一种与番鸭产蛋相关的snp位点及其应用
CN105969887B (zh) * 2016-06-30 2019-10-22 华南农业大学 一种与番鸭产蛋相关的snp位点及其应用
EP3960876A1 (fr) * 2020-08-31 2022-03-02 Koninklijke Philips N.V. Prédiction d'une réponse d'un sujet atteint d'un cancer de la prostate soumis à une radiothérapie basée sur les gènes corrélés pde4d7
WO2022043120A1 (fr) * 2020-08-31 2022-03-03 Koninklijke Philips N.V. Prédiction d'une réponse d'un sujet atteint d'un cancer de la prostate à une radiothérapie basée sur des gènes corrélés à pde4d7
CN111979337A (zh) * 2020-09-02 2020-11-24 刘学峰 一种羊多胎性状分子标记及其应用
CN114231622A (zh) * 2021-01-22 2022-03-25 南京世和基因生物技术股份有限公司 局限期小细胞肺癌放疗毒副作用标志物
CN113337603A (zh) * 2021-04-23 2021-09-03 深圳市龙华区人民医院 Suclg1基因或其表达产物的应用、检测试剂盒

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