WO2021000667A1 - Utilisation de rbm46 en tant que marqueur du cancer du sein triple-négatif - Google Patents

Utilisation de rbm46 en tant que marqueur du cancer du sein triple-négatif Download PDF

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WO2021000667A1
WO2021000667A1 PCT/CN2020/092586 CN2020092586W WO2021000667A1 WO 2021000667 A1 WO2021000667 A1 WO 2021000667A1 CN 2020092586 W CN2020092586 W CN 2020092586W WO 2021000667 A1 WO2021000667 A1 WO 2021000667A1
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rbm46
mrna
protein
breast cancer
detection agent
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PCT/CN2020/092586
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Chinese (zh)
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刘年
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北京太东生物科技有限公司
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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
    • 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
    • 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
    • C12Q2600/118—Prognosis of disease development
    • 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 present disclosure relates to the field of medical diagnosis, in particular to the application of Rbm46 as a triple-negative breast cancer marker.
  • TNBC triple-negative breast cancer
  • ER estrogen receptor
  • PR progesterone receptor
  • Her-2 human epidermal growth factor receptor 2
  • TNBC non-triple-negative breast cancer
  • breast cancer screening, early diagnosis, surgery, radiotherapy, chemotherapy, endocrine and immunotherapy and other comprehensive diagnosis and treatment modes have gradually reduced the mortality of patients, but a considerable number of patients will still experience recurrence and metastasis.
  • the earliest breast cancer detection methods available include the use of clinical breast examinations or mammography. However, before the tumor is palpable or can be detected by a mammogram, there must usually be a significant tumor size. The density and age of breast tissue are important indicators for screening the accuracy of mammography.
  • the present disclosure is based in part on the specific identification of mRNAs that are differentially expressed in breast cancer cells relative to normal control cells, and then found that Rbm46 mRNA or protein is significantly low expressed in three-negative breast tumor cells and tissues, and its expression level The clinicopathological parameters of tumors are significantly correlated, indicating that Rbm46 is a specific tumor marker.
  • the present disclosure relates to the application of a quantitative detection agent for Rbm46 mRNA or protein in the preparation of reagents or kits for the diagnosis and/or prognosis evaluation of triple-negative breast cancer.
  • the present disclosure relates to a quantitative detection agent for Rbm46 mRNA or protein, which is used for the application of triple-negative breast cancer diagnosis and/or prognosis assessment.
  • the present disclosure also relates to a method for diagnosing and/or evaluating triple-negative breast cancer, including: measuring the expression of Rbm46 mRNA or protein in a sample, and analyzing the measurement result of Rbm46 mRNA or protein to evaluate triple-negative breast cancer.
  • Figure 1 shows the expression of Rbm46 mRNA in breast cancer in an embodiment of this application
  • FIG. 1 The expression of Rbm46 protein in breast cancer in an example of the present application; wherein 1#, 2#, 3#, 4# represent different sample numbers.
  • the present disclosure relates to the application of a quantitative detection agent for Rbm46 mRNA or protein in the preparation of reagents or kits for the diagnosis and/or prognosis evaluation of triple-negative breast cancer.
  • the reduced expression of Rbm46 mRNA is an indication of poor diagnosis and/or poor prognosis of triple-negative breast cancer.
  • Rbm46 mRNA or protein provides a new marker for prognostic evaluation and judgment of triple-negative breast cancer: Rbm46 mRNA or protein. It is confirmed by clinical studies that its expression in triple-negative breast cancer is lower than that of normal tissues. Patients with low levels of Rbm46 mRNA or protein in cancer tissues have shorter survival periods and higher mortality. Accordingly, Rbm46 mRNA or protein as a biomarker effectively improves the positive rate of prognostic judgment of triple-negative breast cancer using kits in clinic.
  • the term “prognosis” is a medical term that predicts disease, particularly breast cancer, and more particularly predicts the possible or expected development of triple-negative breast cancer, including whether symptoms and signs will improve or worsen over time ( And how fast) or remain stable; expectations for the quality of life, such as the ability to carry out daily activities; the likelihood of complications and related health problems; and the likelihood of survival (including life expectancy).
  • diagnosis is the process of determining which disease or condition can explain the symptoms and signs of an individual. The information needed for diagnosis is usually collected from the medical history and physical examination of the individual seeking medical care.
  • Rbm46 protein is RNA binding motif protein 46. There is no record of Rbm46 mRNA/protein as a marker in triple-negative breast cancer in the prior art. The inventors of the present disclosure unexpectedly discovered that the expression of Rbm46 mRNA or protein in triple-negative breast cancer and adjacent tissues is significantly different, suggesting that Rbm46 mRNA or protein can be used as a diagnostic and/or prognostic evaluation marker for triple-negative breast cancer.
  • Rbm46 mRNA or protein is of animal origin, such as primates, such as humans.
  • subject is an animal, such as a mammal, such as a primate, such as a human.
  • the term "quantitative detection agent for Rbm46 mRNA" in the present disclosure should not only be understood as a detection agent for Rbm46 mRNA, but should include other detection reagents known to those skilled in the art that can reflect the expression level of Rbm46 mRNA.
  • the expression of Rbm46 mRNA can be indirectly detected by quantitatively detecting the cDNA obtained by reverse transcription of Rbm46 mRNA, or the polypeptide fragment obtained by transcription thereof.
  • triple-negative breast cancer refers to breast cancer in which the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 subtype (Her-2) are all negative.
  • ER estrogen receptor
  • PR progesterone receptor
  • Her-2 human epidermal growth factor receptor 2 subtype
  • Rbm46 mRNA and Rbm46 protein can be referred to as “markers”, “marker genes” (specifically Rbm46 mRNA), “biochemical markers”, and “marker polypeptides” ( Specifically refers to Rbm46 protein), “triple negative breast cancer tumor marker” or “triple negative breast cancer cancer marker”. It specifically refers to a molecule to be used as a target for the analysis of a patient's experimental sample.
  • the Rbm46 mRNA used as a marker in the present disclosure is expected to include its full-length ribonucleotide sequence, or naturally-occurring variants, or full-length sequences and fragments of variants, especially fragments whose specific sequences can be detected and determined , For example, a segment that can be distinguished from other RNA sequences in breast tissue. For example, comprising at least 7, 8, 9, 10, 11, 12, 15 or 20 consecutive ribonucleotides of the full-length ribonucleotide sequence.
  • the Rbm46 protein used as a marker in the present disclosure is expected to include naturally-occurring variants of the protein and fragments of the protein or the variants, particularly immunologically detectable fragments.
  • the immunologically detectable fragment contains, for example, at least 5, 6, 7, 8, 9, 10, 11, 12, 15 or 20 consecutive amino acids of the marker polypeptide.
  • the expression "Rbm46 protein” includes the complete protein sequence of Rbm46 and the marker polypeptide defined above.
  • ribonucleotides/proteins/polypeptides released by cells or ribonucleotides present in the extracellular matrix may be damaged (for example, during inflammation), and may be degraded or Cut into fragments like this.
  • mRNA, protein or fragments thereof may also be present as part of the complex.
  • Such a complex can also be used as a marker in the sense of the present disclosure.
  • the marker polypeptide or variants thereof may carry post-translational modifications.
  • post-translational modifications are glycosylation, acylation and/or phosphorylation.
  • “Naturally occurring variants” should be understood to mean that higher animal genes are usually accompanied by high frequency polymorphisms. There are also many molecules that produce isotypes that contain mutually different amino acid sequences during splicing. Any gene associated with cancer-related diseases that has an activity similar to that of the marker gene is included in the marker gene, even if it has a nucleotide sequence difference due to polymorphism or isotype.
  • RNA quantitative detection reagents can be selected from reagents known to those skilled in the art, such as nucleic acids that can hybridize to the RNA and labeled with fluorescent labels; in common cases, RNA detection reagents can be selected from RT-PCR primers, and Primers for the amplification of RT-PCR products-cDNA;
  • the quantitative detection agent for Rbm46 mRNA includes a reagent suitable for at least one of the following methods:
  • Fluorescent dye method digital PCR, resonance light scattering method, real-time fluorescent quantitative PCR, sequencing or biological mass spectrometry.
  • the quantitative detection agent for Rbm46 mRNA is a probe or primer that can specifically bind to Rbm46 mRNA or Rbm46 cDNA.
  • the probe or primer has a detectable label.
  • the detection target (reverse transcript of DNA or RNA) is hybridized with a probe labeled with a fluorescent dye and a quencher that absorbs fluorescence.
  • a probe labeled with a fluorescent dye and a quencher that absorbs fluorescence.
  • Taq polymerase degrades the probe with its 5'-3' exonuclease activity
  • the fluorescent dye and the quencher are separated from each other, thereby detecting fluorescence.
  • Real-time detection of fluorescence By simultaneously measuring a standard sample in which the copy number of the target is known, the cycle number (in which PCR amplification is linear) can be used to determine the copy number of the target in the subject sample.
  • the cycle number in which PCR amplification is linear
  • the PCR amplification monitoring method can be performed using any appropriate method.
  • the quantitative detection agent for Rbm46 mRNA is a qRT-PCR primer for Rbm46 mRNA
  • the upstream primer is gatcccagagttacttcatgcc, as shown in SEQ ID NO:1
  • the downstream primer is gagctgcgatggaaattgtagt, as SEQ ID NO: 2 is shown.
  • the quantitative detection agent for Rbm46 protein is a reagent required to specifically measure Rbm46 protein.
  • the reagent (specific binding agent) required to specifically measure Rbm46 protein is, for example, a ligand or receptor (if present) for Rbm46 protein, binding to Rbm46 Protein lectins, aptamers that bind to Rbm46 protein, or antibodies and antibody fragments that bind to Rbm46 protein.
  • Specific binding agent having an affinity of at least 10 7 l / mol for its corresponding target molecule.
  • Specific binding agent to its target molecule for example, 10 8 l / mol, e.g., affinity or 10 9 l / mol of.
  • specific means that other biomolecules present in the sample do not significantly bind to the specific binding agent of the Rbm46 protein.
  • the level of binding to biomolecules other than the target molecule produces a binding affinity that is at most only 10% or less, only 5% or less, only 2% or more of the affinity to the target molecule, respectively. Less, or only 1% or less.
  • a specific binding agent will simultaneously meet the above minimum criteria for affinity and specificity.
  • antibody includes polyclonal antibodies and monoclonal antibodies, and the term “antibody fragment” includes antigen compound binding fragments of these antibodies, including Fab, F(ab') 2 , Fd, Fv, scFv, bispecific antibodies and antibodies The smallest recognition unit, and single-chain derivatives of these antibodies and fragments, such as scFv-Fc, etc.
  • the type of antibody can choose IgG1, IgG2, IgG3, IgG4, IgA, IgM, IgE, IgD.
  • antibody includes naturally-occurring antibodies and non-naturally-occurring antibodies, including, for example, chimeric, bifunctional, humanized, and human antibodies, and related synthetic antibodies. Isoforms.
  • antibody can be used interchangeably with "immunoglobulin”.
  • the antibodies or antibody fragments can be obtained by immunizing Rbm46 protein or fragments thereof as an antigen.
  • the immunized subjects can be selected to include humans and all livestock (such as domestic animals and pets) and wild animals. Animals and birds, which include, without limitation, cattle, horses, dairy cows, pigs, sheep, goats, rats, mice, dogs, cats, rabbits, camels, donkeys, deer, minks, chickens, ducks, geese, fire Chicken, cockfighting, etc.
  • the antibody or antibody fragment is labeled with an indicator showing signal intensity.
  • the kit for preparing a quantitative detection agent for Rbm46 mRNA also includes another detection agent for one or more breast cancer diagnostic markers.
  • one or more means 1-50, such as 1-20, such as 2, 3, 4, 5, 6, 7, 8, 9, 10, 12, or 15.
  • the breast cancer diagnostic marker is selected from CEA, c-kit, p53, VEGF, Ki67, KAI-1, EGFR, CYFRA 21-1, CA 19-9, ErbB-2, CK5/6/17 and CA15-3.
  • the Rbm46 mRNA provided in the present disclosure can be combined with the above-mentioned molecular markers to detect triple-negative breast cancer more accurately.
  • the kit for preparing a quantitative detection agent for Rbm46 mRNA also includes reverse transcription reagents, internal reference primers, fluorescent substances for indicating the amount of DNA synthesis, qPCR reaction buffer, dNTPs , DNA polymerase, one or more of water.
  • the internal reference primer is selected from primers of GAPDH, tubulin or actin.
  • the water is nuclease-free water, such as reverse osmosis water, distilled water, and deionized water.
  • the DNA polymerase is selected from Taq, Tma, Tih, Tf1, Pwo, Kod, Mth, Bst, Vent, Phi29, Pfu, Tru, Tth, Tl1, Tac, Any of Tne, Pho, ES4 DNA polymerase, Sac, Sso, Poc, Pab, Klenow fragments.
  • the present disclosure also provides methods for the diagnosis and/or prognostic assessment of triple-negative breast cancer, including:
  • the method for diagnosing and/or evaluating the prognosis of triple-negative breast cancer includes:
  • step (c) Use the measurement result of step (a) and the measurement result of step (b) to evaluate triple negative breast cancer
  • Rbm46 mRNA or protein is an indication of triple-negative breast cancer.
  • the other breast cancer markers are selected from CEA, c-kit, p53, VEGF, Ki67, KAI-1, EGFR, CYFRA 21-1, CA 19-9, ErbB- 2. CK5/6/17 and CA15-3.
  • the method for diagnosing and/or evaluating the prognosis of triple-negative breast cancer includes:
  • the expression level of Rbm46 mRNA or protein in the subject sample is lower than the expression level of Rbm46 mRNA or protein in the control sample is an indication for triple-negative breast cancer.
  • control sample is a sample from a healthy subject, a sample from a subject with non-triple-negative breast cancer, or a tissue adjacent to cancer.
  • the subject is a mammal, such as a primate, such as a human.
  • the sample is breast tissue.
  • the measurement of the Rbm46 mRNA is performed by qRT-PCR using the Rbm46 mRNA primer.
  • the upstream primer of the Rbm46 mRNA primer is shown in SEQ ID NO:1
  • the downstream primer is shown in SEQ ID NO: shown in 2.
  • the present disclosure also relates to a method of evaluating triple-negative breast cancer, the method comprising:
  • step (a) measuring the expression level of Rbm46 mRNA or protein in the sample, (b) optionally, measuring the concentration of one or more other breast cancer markers in the sample, and (c) using step (a)
  • the measurement results of and optional step (b) are used to evaluate triple-negative breast cancer, where the reduced expression of Rbm46 mRNA or protein is an indication (one of) for triple-negative breast cancer.
  • step a) in step a), the above-mentioned reagents required for specific quantitative measurement of Rbm46 mRNA or protein are used for measurement.
  • the ideal scenario for diagnosis is a situation where a single event or process can cause various diseases. In all other cases, the correct diagnosis can be very difficult, especially when the etiology of the disease is not fully understood.
  • a diagnosis without biochemical markers is 100% specific and 100% sensitive.
  • the determination of whether the subject sample has triple-negative breast cancer compared with the normal control sample can be performed by statistical methods known in the art, and the confidence interval and/or p-value are used for confirmation.
  • the confidence interval is 90%, 95%, 97.5%, 98%, 99%, 99.5%, 99.9%, or 99.99% and the p-value is 0.1, 0.05, 0.025, 0.02, 0.01, 0.005, 0.001 or 0.0001.
  • biochemical markers for example, CEA, c-kit, p53, VEGF, Ki67, KAI-1, EGFR, CYFRA 21-1, CA 19-9, ErbB-2, CK5/6/17, and CA15- 3.
  • Rbm46 mRNA or protein
  • the method is used for prognostic evaluation of triple negative breast cancer.
  • Quantitative PCR was used to detect the expression of Rbm46 gene in breast cancer tissues.
  • Triple-negative breast cancer tissues and normal adjacent tissues were taken from the tumor hospital, placed in RNAlater reagent, and stored in a refrigerator at -80°C. First, extract total cellular RNA. Keep all operations and related reagents on ice.
  • Trizol reagent to extract total cell RNA, the specific steps are as follows:
  • the first step is to prepare to extract total RNA.
  • the cells were digested and lysed directly with Trizol, and the volume of Trizol added was 10 cm 2 /ml. After adding Trizol to the cells, place them at room temperature for 5 minutes to fully lyse them. Use a high-speed refrigerated centrifuge to centrifuge at 12000 rpm at 4°C for 5 minutes, and discard the precipitate. Add chloroform according to 200 ⁇ l chloroform/ml Trizol, shake and mix for 15min, and place at room temperature for 15min. Centrifuge for 15 min at 12000g at 4°C in a high-speed refrigerated centrifuge again. Then suck the upper water phase into another centrifuge tube.
  • isopropanol Trizol add isopropanol and mix well, and place at room temperature for 10 min. Centrifuge at 12000g for 10 minutes in a high-speed refrigerated centrifuge again at 4°C, discard the supernatant, and sink the RNA at the bottom of the tube. Add 1ml of 75% ethanol and gently shake the centrifuge tube to suspend the pellet. Centrifuge at 8000g at 4°C for 5 minutes in a high-speed refrigerated centrifuge, discard the supernatant as much as possible, dry the remaining RNA under an ultra-clean workbench for 3 minutes, and add 50ul H 2 O to dissolve the RNA sample. By measuring the OD value to determine the quality and concentration of RNA, the A260/A280 value of 1.6 to 1.8 can ensure the purity of RNA.
  • PrimeScriptTM RT Reagent reverse transcription kit (TaKaRa) to synthesize cDNA.
  • the specific steps are as follows: put all operations and related reagents on ice. Add the reagents and concentrations indicated in the kit instructions to the PCR reaction tube and finally add the RNA sample.
  • the reaction conditions were set in the PCR machine as follows: 42°C for 15 minutes (reverse transcription), 85°C for 5 seconds (heat shock termination reaction).
  • the third step is to identify the expression level of Rbm46 gene by quantitative PCR.
  • the specific steps are as follows: put all operations and related reagents on ice. Add the reagents and concentrations shown in the table below to the PCR reaction tube and finally add the RNA sample.
  • the reaction conditions were set in the PCR machine as follows: pre-denaturation at 94°C for 10s, denaturation at 94°C for 5s, annealing/extension at 60°C for 34s, a total of 40 cycles, with GAPDH as a relative quantitative internal control.
  • Data processing and analysis Calculate the relative gene expression using the 2- ⁇ Ct method.
  • the Western blot method was used to detect the protein level expression in the above breast cancer tissues and adjacent normal tissues.
  • the specific methods are as follows:
  • Glue Assemble clean glass plates into electrophoresis plates. Separate glue 7ml per piece, concentrated glue 3ml per piece of glue, pour it on the separating glue, insert a comb, and let it stand at room temperature for 30 minutes to solidify.
  • Electrophoresis Perform electrophoresis at 80V constant voltage, when bromophenol blue runs into the separation gel, switch to 120V constant voltage electrophoresis, and wait until the bromophenol blue dye runs to the bottom of the gel;
  • Electric transfer Install in the electric transfer glue folder in the following order: anode ⁇ sponge layer ⁇ filter paper three layers ⁇ NC (PVDF) membrane ⁇ gel ⁇ filter paper three layers ⁇ sponge layer ⁇ cathode, remove the glue, membrane and filter paper Clamp the air bubbles between them and move them into the electroporation tank, inject electroporation buffer, and electroporate at 200mA constant current on ice for 2 hours;
  • PVDF PVDF
  • RBM46 protein in breast cancer tumors is shown in Figure 2.
  • the expression level of RBM46 protein in tumor tissues is significantly lower than that in adjacent tissues (p ⁇ 0.05).
  • the present disclosure provides a new marker, Rbm46 mRNA or protein, for the diagnosis or typing of breast cancer.
  • Rbm46 mRNA or protein is suitable for prognostic evaluation and clinical diagnosis of triple-negative breast cancer.
  • the method of using the marker Rbm46 mRNA or protein provided in the present disclosure to diagnose or prognose breast cancer is an economical and effective way, and is particularly expected to replace expensive X-ray photography.

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Abstract

L'invention concerne l'utilisation d'un réactif de détection quantitative d'un ARNm ou d'une protéine Rbm46 dans la préparation d'un réactif ou d'un kit pour l'évaluation pronostique et/ou diagnostic du cancer du sein triple-négatif.
PCT/CN2020/092586 2019-07-03 2020-05-27 Utilisation de rbm46 en tant que marqueur du cancer du sein triple-négatif WO2021000667A1 (fr)

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Citations (2)

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CN110241216A (zh) * 2019-07-03 2019-09-17 北京太东生物科技有限公司 Rbm46作为三阴性乳腺癌标志物的应用

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WO2017203526A1 (fr) * 2016-05-23 2017-11-30 Yissum Research Development Company Of The Hebrew University Of Jerusalem Ltd. Méthodes de diagnostic du cancer à l'aide d'antigènes testiculaires du cancer
CN110241216A (zh) * 2019-07-03 2019-09-17 北京太东生物科技有限公司 Rbm46作为三阴性乳腺癌标志物的应用

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GRIGORLADLS A. ET AL.: "CT-X antigen expression in human breast cancer", PNAS, vol. 106, no. 32, 11 August 2009 (2009-08-11), XP055102095, DOI: 20200826062543X *
RAGHAVENDRA A. ET AL.: "Expression of MAGE-A and NY-ESO-1 cancer/testis antigens is enriched in triple-negative invasive breast cancers", HISTOPATHOLOGY, vol. 73, no. 1,, 14 April 2018 (2018-04-14), XP055771398, DOI: 20200826062447X *

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