WO2013151413A1 - Procédés et compositions pour la détermination du risque accru de cancer du sein - Google Patents

Procédés et compositions pour la détermination du risque accru de cancer du sein Download PDF

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WO2013151413A1
WO2013151413A1 PCT/MY2013/000054 MY2013000054W WO2013151413A1 WO 2013151413 A1 WO2013151413 A1 WO 2013151413A1 MY 2013000054 W MY2013000054 W MY 2013000054W WO 2013151413 A1 WO2013151413 A1 WO 2013151413A1
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breast cancer
snps
individual
snp
risk
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PCT/MY2013/000054
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English (en)
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Kaur Chahil JAGDISH
Lian Wee LER
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Infovalley Life Science Sdn. Bhd.
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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
    • C12Q2600/156—Polymorphic or mutational markers

Definitions

  • the present invention relates to method(s) and composition(s) for assessing genetic predisposition to breast cancer in a subject and in particular but not exclusively by using microarray.
  • breast cancer is the most common and frequently diagnosed cancer worldwide. Clinico-pathologically, breast cancer is a cancer that starts in the tissues of the breast. Damaged DNA triggers uncontrolled cell division which eventually accumulates to form lump. The breast is divided into ducts and lobes. Most breast cancers are ductal carcinomas which start in mammary ducts. The other type which is also the least common one is the lobular carcinoma that starts in milk producing glands, called lobules and can localize at other areas of the breast tissues. Breast cancer relates to a variety of cancers that originate in the breast.
  • breast cancer In Malaysia, breast cancer has been reported as the most frequent cancers in Peninsular Malaysia 1 and its incidence is still increasing 2 . It was reported that in Malaysian females, the most frequent cancer was breast cancer (31.3%) 1 .
  • the peak age of diagnosis for breast cancer in Malaysia is the range of 50-59 years of age. Of the total number of women with breast cancer, the incidence per 100,000 population was only about 0.3 for those diagnosed with breast cancer at the age below 20; 3.7 between 20 and 29; 37.3 between 30 and 39; 117.4 between 40 and 49; 154 between 50 and 59; 141.5 between 60 and 69; and 105.1 above 70 years of age 1 .
  • cancer is the third most common cause of death in Malaysian hospitals registered under the Ministry of Health after Heart Diseases and Septicaemia 3 .
  • breast cancer accounts for 23% (1.38 million) of the total new cancer cases and 14% " (458,400) of the total cancer deaths in 2008 4 .
  • the American Cancer Society estimates that 226,870 new cases of breast cancer are expected to be diagnosed in women in 2012 5 in the United States alone. It is estimated that about 1 in 8.23 women in the United States (12.15%) will develop invasive breast cancer over the course of her lifetime 6 .
  • breast cancer screening and diagnosis may involve some invasive measures.
  • Currently available methods include clinical breast examination ranging from needle biopsy to mammogram, as well as lab tests of tumor markers (e.g. CA15-3/CA27.29, CEA) and hormone receptor status (HER2, ER+/PR) alongside commercial molecular tests on the tumor tissues (Mammaprint, Oncotype DX). Awareness and early detection through mammography have shown reduced incidence in developed countries. Improved treatment options have saved lives, but these approaches are cost prohibitive and may not be feasible in many developing countries 4 .
  • tumor markers e.g. CA15-3/CA27.29, CEA
  • HER2, ER+/PR hormone receptor status
  • Awareness and early detection through mammography have shown reduced incidence in developed countries. Improved treatment options have saved lives, but these approaches are cost prohibitive and may not be feasible in many developing countries 4 .
  • the method of the present invention may provide polymorphisms that affect the functional efficiency of the genes, and inadvertently may predispose individuals to the development of breast cancer, and as such be used to identify women who are at high risk of developing breast cancer.
  • the polymorphisms according to any aspect of the present invention may contribute to the genetic predisposition for breast cancer across the Asian population.
  • the present invention relates to a method of establishing the risk of predisposition to breast cancer in an individual of Asian descent, the method comprising detecting the presence of SNPs rs10434, rs1045761 , rs1051 130, rs10917589, rs11096956, rs11556218, rs11639960, rs13181 , rs153109, rs1641537, rs1799964, rs1800630, rs1882881 , rs1979276, rs2009658, rs2107538, rs2228526, rs2242661 , rs2243250, rs2250889, rs2749817, rs2844482, rs2857653, rs3087399, rs3731348, rs3803662, rs3817198, rs41115, rs4778889, rs
  • the present invention provides microarrays, chips, kits and/or uses comprising at least one probe capable of hybridizing to at least one SNP in at least one method according to any aspect of the present invention.
  • Figure 1 is a line graph showing the distribution of risk scores in cases of breast cancer (solid line) and controls (dotted line).
  • Figure 2 is a receiver operating characteristic (ROC) curve of sensitivity versus 1- specificity.
  • ROC receiver operating characteristic
  • allele refers to one of two or more different nucleotide sequences that occur or are encoded at a specific locus, or two or more different polypeptide sequences encoded by such a locus. For example, a first allele can occur on one chromosome, while a second allele occurs on a second homologous chromosome, e.g., as occurs for different chromosomes of a heterozygous individual, or between different homozygous or heterozygous individuals in a population.
  • Asian descent used interchangeably with the term “of Asian descent” is herein defined to be a person having origins in any of the original peoples of the Far East, Southeast Asia, or the Indian subcontinent.
  • an individual of “Asian descent” includes a person of Chinese ancestry, Malay ancestry and/or Indian ancestry.
  • label or “label containing moiety” refers in a moiety capable of detection, such as a radioactive isotope or group containing same and non-isotopic labels, such as enzymes, biotin, avidin, streptavidin, digoxygenin, luminescent agents, dyes, haptens, and the like.
  • Luminescent agents depending upon the source of exciting energy, can be classified as radio luminescent, chemiluminescent, bio luminescent, and photo luminescent (including fluorescent and phosphorescent).
  • a probe described herein can be bound, for example, chemically bound to label-containing moieties or can be suitable to be so bound.
  • the probe can be directly or indirectly labeled.
  • locus is herein defined to be a specific location of a gene or DNA sequence on a chromosome. A variant of the DNA sequence at a given locus is called an allele.
  • the ordered list of loci known for a particular genome is called a genetic map. Gene mapping is the process of determining the locus for a particular biological trait.
  • a “marker,” “molecular marker” or “marker nucleic acid” refers to a nucleotide sequence or encoded product thereof (e.g., a protein) used as a point of reference when identifying a locus or a linked locus.
  • a marker can be derived from genomic nucleotide sequence or from expressed nucleotide sequences ⁇ e.g., from an RNA, nRNA, mRNA, a cDNA, etc.), or from an encoded polypeptide.
  • the term also refers to nucleic acid sequences complementary to or flanking the marker sequences, such as nucleic acids used as probes or primer pairs capable of amplifying the marker sequence.
  • a “marker probe” is a nucleic acid sequence or molecule that can be used to identify the presence of a marker locus, e.g., a nucleic acid probe that is complementary to a marker locus sequence. Nucleic acids are "complementary” when they specifically hybridize in solution, e.g., according to Watson-Crick base pairing rules.
  • a “marker locus” is a locus that can be used to track the presence of a second linked locus, e.g., a linked or correlated locus that encodes or contributes to the population variation of a phenotypic trait.
  • a marker locus can be used to monitor segregation of alleles at a locus, such as a quantitative trait locus (QTL), that are genetically or physically linked to the marker locus.
  • QTL quantitative trait locus
  • a "marker allele,” ' alternatively an “allele of a marker locus” is one of a plurality of polymorphic nucleotide sequences found at a marker locus in a population that is polymorphic for the marker locus.
  • the present invention provides marker loci correlating with a phenotype of interest, e.g., breast cancer susceptibility/ resistance.
  • Each of the identified markers is expected to be in close physical and genetic proximity (resulting in physical and/or genetic linkage) to a genetic element, e.g., a QTL, which contributes to the relevant phenotype.
  • a genetic element e.g., a QTL
  • Markers corresponding to genetic polymorphisms between members of a population can be detected by methods well-established in the art.
  • PCR-based sequence specific amplification methods include, e.g., PCR-based sequence specific amplification methods, detection of restriction fragment length polymorphisms (RFLP), detection of isozyme markers, detection of allele specific hybridization (ASH), detection of single nucleotide extension, detection of amplified variable sequences of the genome, detection of self-sustained sequence replication, detection of simple sequence repeats (SSRs), detection of single nucleotide polymorphisms (SNPs), or detection of amplified fragment length polymorphisms (AFLPs).
  • RFLP restriction fragment length polymorphisms
  • ASH allele specific hybridization
  • SSRs simple sequence repeats
  • SNPs single nucleotide polymorphisms
  • AFLPs amplified fragment length polymorphisms
  • probe is herein defined to be an oligonucleotide.
  • a probe can be single stranded at the time of hybridization to a target.
  • Probes include but are not limited to primers, i.e., oligonucleotides that can be used to prime a reaction, for example at least in a PCR reaction.
  • polymorphism is herein defined to be the occurrence of genetic variations that account for alternative DNA sequences and/or alleles among individuals in a population.
  • a "polymorphism” is a locus that is variable; that is, within a population, the nucleotide sequence at a polymorphism has more than one version or allele.
  • polymorphic site is herein defined to be a genetic locus wherein one or more particular sequence variations occur.
  • a polymorphic site can be one or more base pairs.
  • a "single nucleotide polymorphism (SNP)" is a polymorphism that occurs at a single nucleotide position in a genome (the nucleotide at the specified position varies between individuals or populations). SNP is defined as a genetic variation that occurs in more than 1 % of the general population. The functional effect of an individual polymorphism is relatively low. However, the combination of functionally related polymorphisms may contribute to an increase in the development of certain diseases.
  • reference nucleotide sequence used interchangeably with the term “reference sequence” is herein defined to be for a nucleotide sequence of a particular gene for example, in NCBI databases (www.ncbi.nlm.nih.gov). Alleles that differ from the reference are referred to as “variant” alleles.
  • the polypeptide encoded by the reference nucleotide sequence is the "reference” polypeptide with a particular reference amino acid sequence, and polypeptides encoded by variant alleles are referred to as “variant” polypeptides with variant amino acid sequences. Nucleotide sequence variants can result in changes affecting properties of a polypeptide.
  • sequence differences when compared to a reference nucleotide sequence, include insertions, deletions, conversions and substitutions: e.g. an insertion, a deletion or a conversion may result in a frame shift generating an altered polypeptide; a substitution of at least one nucleotide may result in a premature stop codon, amino acid change or abnormal mRNA splicing; the deletion of several nucleotides, resulting in a deletion of one or more amino acids encoded by the nucleotides; the insertion of several nucleotides, such as by unequal recombination or gene conversion, resulting in an interruption of the coding sequence of a reading frame; duplication of all or a part of a sequence; transposition; or a rearrangement of a nucleotide sequence.
  • NG_012623.1 is a reference nucleotide sequence for TOX3 that may be used.
  • Other reference sequences may be used.
  • reference sequences NM_000201.2 for ICAM1 and the like may be used.
  • a non-limiting list of genes to reference sequences is provided in Table 6.
  • sample is herein defined to include but is not limited to be blood, sputum, saliva, mucosal scraping, tissue biopsy and the like.
  • breast cancer is herein defined to include breast cancers that are either confined within the ducts (ductal carcinoma) or lobules (lobular carcinoma). Ductal carcinoma constitutes the majority of breast cancers. Also included are other breast cancers having characteristics of both ductal and lobular carcinomas or have unspecified origins. Most breast cancers are invasive, or infiltrating. These cancers started in the lobules or ducts of the breast but have broken through the duct or glandular
  • the method comprises detecting the presence of at least one SNP selected from the group consisting of rs10434, rs1045761 , rs1051130, rs10917589, rs11096956, rs11556218, rs11639960, rs13181 , rs153109, rs1641537, rs1799964, rs1800630, rs1882881 , rs1979276, rs2009658, rs2107538, rs2228526, rs2242661 , rs2243250, rs2250889, rs2749817, rs2844482, rs2857653, rs3087399, rs3731348, rs3803662, rs3817198, rs411 15, rs477
  • the individual may be of Asian descent. Genetic differences among the various racial and ethnic groups usually show the differences in the distribution of polymorphic traits which occur at different frequencies in different populations between and within the racial groups. However, such differences may be prevalent outside of genetics as well. These varying distributions of polymorphisms in genes among the racial and ethnic groups, especially receptors and/or enzymes may affect an individual's predisposition to a disease and/or reaction to a drug against the disease. Similarly, different polymorphisms in the genes associated with breast cancer exist in different racial and ethnic groups. Specific polymorphisms in these genes in the Asian population may be used in the detection of breast cancer and/or the predisposition to breast cancer.
  • these polymorphisms may be SNPs. More in particular, out of these hundreds of SNPs known in the art only 36 may be related to the predisposition to breast cancer in the Asian population. Even more in particular, the SNP may be selected from the group consisting of: rs10434, rs1045761 , rs1051130, rs10917589, rs11096956, rs11556218, rs11639960, rs13181 , rs153109, rs1641537, rs1799964, rs1800630, rs1882881 , rs1979276, rs2009658, rs2107538, rs2228526, rs2242661 , rs2243250, rs2250889, rs2749817, rs2844482, rs2857653, rs3087399, rs3731348, rs3803662, rs104
  • SNP rs1641537 located on Sex hormone-binding globulin (SHBG) gene may have a high susceptibility towards breast cancer development with reference to the calculated odds ratio (OR) as this gene plays a key role in controlling the amount of estrogen that is available throughout the body.
  • SHBG Sex hormone-binding globulin
  • SNPs according to any aspect of the present invention that were identified to be significantly associated with breast cancer may be involved in many biochemical pathways as shown in Table 1. Amino acid
  • APC Adenomatous polyposis coli
  • CCL2 Chemokine (C-C motif) ligand 2
  • CCL5 Chemokine (C-C motif) ligand 5
  • CCND3 Cyclin D3
  • CD93 CD93 molecule
  • CDK6 Cyclin-dependent kinase 6
  • CYP19A1 Cytochrome P450, family 19, subfamily A polypeptide 1
  • DDR2 Discoidin domain receptor tyrosine kinase 2
  • ERCC2 Excision repair cross-complementing rodent repair deficiency, complementation group 2
  • ERCC6 Excision repair cross-complementing rodent repair deficiency, complementation group 6
  • HSPS13 Heat shock protein 70kDa family, member 13; ICAM1 Intercellular adhesion molecule 1; IL4: Interleukin 4; IL16: Interleukin 16; IL27: Interieukin 27; LSP1: Lymphocyte-specific protein 1; LTA
  • Table 1 Description and predicted functionality based on gene pathway of 36 SNPs that are associated with breast cancer risk
  • the SNPs according to any aspect of the present invention are in genes involved in various pathways and which may contribute to breast cancer development. These SNPs may be suitable for the generation of a risk model for screening women with high or low risk of developing breast cancer in particular, for screening women in the Asian population.
  • the method for establishing risk of predisposition to breast cancer in an individual of Asian descent comprising, consisting of or consisting essentially of detecting the presence of at least one SNP in any one of the genes disclosed.
  • the method involves the detection of at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35 or 36 SNPs in any one of the genes according to any aspect of the present invention.
  • the method according to any aspect of the present invention may involve the detection of at least one SNP in an individual of Asian descent, the method comprising detecting the presence of at least SNP rs866006 in a sample of the individual.
  • the method may be in vitro or in vivo.
  • the SNP may be determined by a microarray analysis. This is advantageous as it is efficient and more accurate then the methods known in the art.
  • the method according to any aspect of the present invention may further comprise a step of correlating results of the detection of SNPs with one or more clinicopathological data to implement a particular cancer prevention strategy for the individual.
  • the clinicopathological data may be selected from the group consisting of the individual's age, lifestyle, previous personal and/or familial history of breast cancer, previous personal and/or familial history of response to medications, any genetic or biochemical predisposition to breast cancer and the like.
  • a microarray and/or DNA chip comprising, consisting of or consisting essentially of at least one probe capable of hybridizing to at least one SNP of any one of the genes according to any aspect of the present invention in a sample nucleic acid of an individual, wherein the SNP may be selected from the group consisting of rs10434, rs1045761 , rs1051130, rs10917589, rs1 1096956, rs11556218, rs11639960, rs13181 , rs153109, rs1641537, rs1799964, rs1800630, rs1882881 , rs1979276, rs2009658, rs2107538, rs2228526, rs2242661 , rs2243250, rs2250889, rs2749817, rs2844482, rs2857653, rs30873
  • the individual may be of Asian descent and the SNP may selected from the group consisting of rs10434, rs1045761 , rs1051130, rs10917589, rs1 1096956, rs11556218, rs11639960, rs13181 , rs153109, rs1641537, rs1799964, rs1800630, rs1882881 , rs1979276, rs2009658, rs2107538, rs2228526, rs2242661 , rs2243250, rs2250889, rs2749817, rs2844482, rs2857653, rs3087399, rs3731348, rs3803662, rs3817198, rs41115, rs4778889, rs5498, rs662, rs6983267, rs712665,
  • the SNP according to any aspect of the present invention as a genetic marker for determining the genetic predisposition of an individual of Asian descent to breast cancer.
  • genomic DNA was extracted by using QIAamp® DNA Blood Mini Kit (QIAGEN®, Germany). The concentration and purity of the isolated DNA was determined by using Smart SpecTM plus spectrophotometer (Bio-Rad, Inc) and the integrity of the DNA was assessed by using 0.8% agarose gel electrophoresis. Genotyping was carried out according to the manufacturer's protocols using the lllumina® BeadArray System (lllumina® Inc., San Diego). A total of 768 SNPs of interest were identified. These SNPs were reported to be associated with or known to be involved in the development of multiple cancers. All SNPs underwent designability check by lllumina Inc.
  • GenomeStudioTM software version 201 1.3 (lllumina® Inc., San Diego) was used for automated genotype clustering and calling. SNPs that have call rates of less than 95%, SNPs that deviated from Hard-Weinberg Equilibrium (PHWE- P value ⁇ 0.05) and monoallelic SNPs were excluded from further analysis.
  • a risk score based on the calculated OR was given to genotypes of each SNP that had significant effects on the development of breast cancer. Risk score of 0, positive and negative value were given to a normal, susceptibility and protective genotype respectively. A risk score of 2 was also added for subjects with family history of breast cancer. The final score, which was the sum of all the risk scores, was calculated for each cancer patient and control subject.
  • the sensitivity and specificity of the risk - predictive model was determined by the receiver operation characteristic (ROC) curve analysis. Using ROC curve analysis, the area under the curve (AUC) was calculated. The AUC measured how well the model can be used to discriminate women with high risk and low risk of developing breast cancer, indicative of the model's risk-predictive power. All the statistical analyses were performed by using STATA version 10 (Texas, USA). Results
  • Table 2 Baseline characteristics between case and controls The cases and controls were comparable with respect to demographic characteristics.
  • the 768 SNPs were successfully genotyped and investigated for association with breast cancer. The output was filtered for failed SNPs and SNPs with monoallelic genotype. SNPs that failed the test for deviation from Hardy-Weinberg equilibrium (P ⁇ 0.05) and SNPs with a less than 95% successful call rate were excluded. Analysis was further continued with 633 (82.4%) remaining SNPs.
  • Table 3 Significant SNPs associated with breast cancer risk in Malaysian population based on dominant model
  • Table 4 Significant SNPs associated with breast cancer risk in Malaysian population based on recessive model
  • ROC curve was used to examine the performance of the model in classifying women with high and low risk of developing breast cancer. The model was based on scores tabulated from log OR
  • Table 5 The sensitivity, specificity, positive prevalence value and negative prevalence value at various risk scores of the risk-predictive model
  • Pathy NB Yip CH, Taib NA, et al. Breast cancer in a multi-ethnic Asian setting: results from the Singapore-Malaysia hospital-based breast cancer registry. Breast 2011 ; 20

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Abstract

L'invention concerne un procédé de détermination d'une prédisposition vis-à-vis du cancer du sein chez un individu d'origine asiatique, le procédé comprenant la détection de la présence d'au moins un polymorphisme de nucléotide unique (SNP) dans un échantillon de l'individu.
PCT/MY2013/000054 2012-04-02 2013-03-20 Procédés et compositions pour la détermination du risque accru de cancer du sein WO2013151413A1 (fr)

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US10407738B2 (en) 2005-11-29 2019-09-10 Cambridge Enterprise Limited Markers for breast cancer
US11072830B2 (en) 2009-06-01 2021-07-27 Genetic Technologies Limited Methods for breast cancer risk assessment
RU2795100C1 (ru) * 2022-10-06 2023-04-28 Федеральное государственное автономное образовательное учреждение высшего образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ") Способ прогнозирования повышенного риска развития рака молочной железы 1-2 стадий у женщин на основе полиморфизма гена матриксной металлопротеиназы 9

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Cited By (11)

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Publication number Priority date Publication date Assignee Title
US10407738B2 (en) 2005-11-29 2019-09-10 Cambridge Enterprise Limited Markers for breast cancer
US11072830B2 (en) 2009-06-01 2021-07-27 Genetic Technologies Limited Methods for breast cancer risk assessment
WO2016049694A1 (fr) * 2014-09-30 2016-04-07 Genetic Technologies Limited Procédés pour évaluer le risque de développer un cancer du sein
JP2017529859A (ja) * 2014-09-30 2017-10-12 ジェネティック テクノロジーズ リミテッド 乳癌発症リスクを評価する方法
AU2015327756B2 (en) * 2014-09-30 2018-01-04 Genetic Technologies Limited Methods for assessing risk of developing breast cancer
US10683549B2 (en) 2014-09-30 2020-06-16 Genetic Technologies Limited Methods for assessing risk of developing breast cancer
US10920279B2 (en) 2014-09-30 2021-02-16 Genetic Technologies Limited Method for modifying a treatment regimen of a human female subject
IL251376B (en) * 2014-09-30 2022-09-01 Genetic Tech Limited Methods for assessing the risk of developing breast cancer
RU2795244C1 (ru) * 2022-10-05 2023-05-02 Федеральное государственное автономное образовательное учреждение высшего образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ") Способ прогнозирования риска развития рака молочной железы у женщин с ожирением
RU2795100C1 (ru) * 2022-10-06 2023-04-28 Федеральное государственное автономное образовательное учреждение высшего образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ") Способ прогнозирования повышенного риска развития рака молочной железы 1-2 стадий у женщин на основе полиморфизма гена матриксной металлопротеиназы 9
RU2795726C1 (ru) * 2023-02-07 2023-05-11 Федеральное государственное автономное образовательное учреждение высшего образования "Белгородский государственный национальный исследовательский университет" (НИУ "БелГУ") Способ прогнозирования риска развития рака молочной железы у женщин без ожирения

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