A Molecular Epidemiology Study On The Association Of BRCA1 And BRCA1-related Genes Polymorphisms And The Susceptibility Of Breast Cancer

Breast cancer is by far the most frequent cancer of women worldwide(23% of all cancers), with an estimated 1.15 million new cases in the year2002. Although the incidence rate of breast cancer in China is aboutone-third of that in the United States, it has been significantly increasingin the last two decades in both urban and rural areas, especially in bigcityies as Shanghai and Beijing. A wide diversity of genetic damageinduced by endogenous metabolites and exogenous carcinogens maycontribute to the etiology of breast cancer. However, the exact molecularmechanisms underlying genetic susceptibility to breast cancer are stillunder intensive investigation. The known genetic alterations-identifiedhuman familial breast cancer susceptibility genes, such as BRCA1/2, onlyaccount for less than 5% of all breast cancer cases. Thus, it is crucial toinvestigate other genetic risk factors of breast cancer in generalpopulation.BRCA1 is a large protein with multiple functional domains and interactswith numerous proteins that are involved in many important biologicalprocesses/pathways. Mounting evidence indicates that BRCA1 isinvolved in all phases of the cell cycle and regulates orderly events during cell cycle progression. BRCA1 interacts directly or indirectly withnumerous molecules, whose loss of function mutations can result in thedestruction of tumor suppression functions and genome instability. Thus,we conducted a case-control study aiming to investigate the association ofBRCA1 and BRCA1-related genes polymorphisms, that is, BARD1, BRIP1,and ZNF350, and the susceptibility of breast cancer in generalpopulations in China.PartⅠThe coding SNPs of BRCA1 gene are not associated withbreast cancer risk but associated with axillary lymph nodesmetastasis riskBRCA1 was mapped in 1990 and was subsequently cloned in 1994. Itsproduct is a large protein playing roles in many important biologicalprocesses/pathways including cell cycle checkpoint, translationsuppressions, DNA damage response and so on. Germline mutations inBRCA1 have been detected in approximately half of familial breast cancercases and most cases of combined familial breast/ovarian cancers. BRCA1mutation carriers have 50-80% risk to develop breast cancer by the age of70. But the mutation frequencies of BRCA1 were very low in generalpopulations and only account for less than 5% of all breast cancer, thusthe polymorphisms may play more important roles in breast cancergenesis indeed.As the coding SNPs of BRCA1 were in very strong linkage disequilibrium,we chose a tag SNP (rs799917) to cover other untyped cSNPs. We foundno association between the tag SNP genotypes and breast cancer risk evenafter adjusting by confounder factors in multifactor logistic analysis. Instratified analysis by age, family cancer history in first degree relatives,BMI, menarche and menopause status, there were still no association be observed. However, the TT genotype frequencies of the tagging SNP,rs799917, were significantly different between with or without axillarylymph nodes metastasis groups (16.58% in metastasis group vs. 10.09%in no metastasis group, P=0.028). The TT genotype was associated with a1.86 fold (95%CI 1.06-3.25) and 1.77 fold (95%CI 1.06-2.97) evaluatedaxillary lymph nodes metastasis risk compared with CC and CC/CTgenotype, respectively.PartⅡCommon non-synonymous polymorphisms in the BRCA1Associated RING Domain (BARD1) gene are associated withbreast cancer susceptibility: a case-control analysisThe BRCA1 Associated RING Domain (BARD1) gene has beenidentified as a high penetrance gene for breast cancer, whose germlineand somatic mutations were reported in both non-BRCA1/2 hereditarysite-specific and sporadic breast cancer cases. BARD1 plays a crucial rolein tumor repression, along with its heterodimeric partner BRCA1. In thecurrent study, we tested the hypothesis that common non-synonymouspolymorphisms in BARD1 are associated with breast cancer susceptibilityin a case-control study of 507 patients with incident breast cancer and 539frequency-matched cancer-free controls in Chinese women. Wegenotyped all three common (minor allele frequency＞0.10)non-synonymous polymorphisms (Pro24Ser, Arg378 Ser, and Val507Met)in BARD1.We found that the BARD1 Pro24Ser variant genotypes (24Pro/Ser and24Ser/Ser) and Arg378Ser variant homozygote 378Ser/Ser were associated with a significantly decreased breast cancer risk, comparedwith their wild-type homozygotes, respectively. Furthermore, asignificant locus-locus interaction was evident between Pro24Ser andArg378Ser (Pint=0.032). Among the 378Ser variant allele carriers, the24Pro/Pro wild-type homozygote was associated with a significantlyincreased breast cancer risk (adjusted OR=1.81, 95% CI=1.11-2.95),but the subjects having 24Pro/Ser or Ser/Ser variant genotypes had asignificantly decreased risk (adjusted OR=0.74, 95% CI=0.56-0.99). Instratified analysis, this locus-locus interaction was more evident amongsubjects without family cancer history, those with positive estrogenreceptor (ER) and individuals with negative progesterone receptor (PR).These findings indicate that the potentially functional polymorphismsPro24Ser and Arg378Ser in BARD1 may jointly contribute to thesusceptibility of breast cancer.PartⅢPolymorphisms of ZNF350 and BRCA1 gene may jointlycontribute to the susceptibility of breast cancerBRIP1 and ZNF350 gene were all found mutated in non-BRCA1/2mutation familial and sporadic breast cancers and thus indicated as newbreast cancer candidate genes. BRIP1 can directly bind to the BRCTrepeats domain of BRCA1 in vivo and contribute to the DNA damageresponse and repair function of BRCA1, while together with BRCA1,ZNF350 is a transcription suppressor that can recognize a specificsequence in target genes. Thus, it is probably that the sequence variationsof these two genes may result in loss function of themselves and/ordestruction of the interaction between them and BRCA1. In this case-control study, we investigated the association between BRIP1and ZNF350 polymorphisms and breast cancer risk, and the potentialinteractions of them and BRCA1 in Chinese women. We found noassociation between BRIP1 Pro919Ser, a potentially functional SNP, andZNF350 polymorphisms and breast cancer risk. But we did observe acombined effect of ZNF350 and BRCA1 polymorphisms on breast cancerrisk. Among BRCA1 rs799917 variant homozygotes TT carriers, thevariant genotypes of tSNP Asp35Asp of ZNF350 confered a significantlyincreased cancer risk (OR=2.03, 95 % CI=1.02-4.05), compared with wildtypes. The polymorphisms of ZNF350 and BRCA1 genes may jointlycontribute to the susceptibility of breast cancer.