Association Analysis Of Single-nucleotide Polymorphisms Of Breast Cancer Susceptibility Genes In FANCD2Pathway With Breast Cancer Risk

Part1:Association analysis of individual single-nucleotide polymorphism in FANCD2-DNA damage repair pathway genes with breast cancer riskPurpose:The aim of the study was to estimate breast cancer risk conferred by individual single-nucleotide polymorphism (SNP) of breast cancer susceptibility genes in the monoubiquitinated FANCD2-DNA damage repair pathway.Methods:We selected48tagging SNPs (tSNPs) from eight breast cancer susceptibility genes (TP53、PTEN、NBS1、BRIP1、PALB2、 ATM、CHEK2and RAD50) involved in the monoubiquitinated FANCD2-DNA damage repair pathway.The48tSNPs were genetyped by SNPscan in734women with breast cancer(534sporadic cases and200early-onset and familial cases) and672sex-and age-matched healthy controls from Hunan and Sichuan Province of China.The odds ratio were calculated by logistic regression analysis under co-dominant model、 dominant model and recessive model respectively.Results:Forty-five tSNPs were successfully genotyped by SNPscan, and the call rates for each tSNP were above98.9%. We found that13tSNPs of five genes (PALB2, TP53, NBS1, PTEN, and BRIP1) were significantly associated with breast cancer risk. A total of five tSNPs (rs2299941of PTEN, rs2735385, rs6999227, rs1805812, and rs1061302of NBS1) were tightly associated with breast cancer risk in sporadic cases, and five other tSNPs (rs1042522of TP53, rs2735343of PTEN, rs7220719, rs16945628, and rs11871753of BRIP1) were tightly associated with breast cancer risk in early-onset and familial cases. We have not found significant tSNPs in the other three genes (ATM, RAD50, and CHEK2).Three tSNPs of TP53(rs12951053, rs1042522and rs8064946),three tSNPs of BRIP1(rs16945628, rs7220719and rs11871753) and rs2735343of PTEN can significantly increase the risk of breast cancer,especially in early-onset and familial cases.Four tSNPs of NBS1(rs2735385, rs6999227, rs1805812and rs1061302),rs2299941of PTEN and rs513313of PALB2can significantly decrease the risk of breast cancer,especially in sporadic cases.Conclusions:Some of the tSNPs of five breast cancer susceptibility genes (PALB2, TP53, NBS1, PTEN, and BRIP1) involved in the monoubiquitinated FANCD2-DNA damage repair pathway were significantly associated with breast cancer risk in women from Hunan and Sichuan Province of China.Some Iocuses(rs12951053, rs1042522, rs8064946, rs16945628, rs7220719, rs11871753and rs2735343) can increase breast cancer risk,and others(rs2735385, rs6999227, rs1805812, rs1061302, rs2299941and rs513313) can decrease breast cancer risk.But the majority of the tSNPs are located in the intron domain and their functions are unknown, so larger studies are needed to research the functions of these genes further. Part2:Haplotype analysis of eight genes of the monoubiquitinated FANCD2-DNA damage-repair pathway in breast cancer patientsPurpose:To analyse13haplotype blocks in eight breast cancer susceptibility genes in the monoubiquitinated FANCD2-DNA damage repair pathway to estimate the breast cancer risk conferred by individual haplotype.Methods:We selected48tagging SNPs (tSNPs) from eight breast cancer susceptibility genes (TP53、PTEN、NBS1、BRIP1、PALB2、 ATM、CHEK2and RAD50) involved in the monoubiquitinated FANCD2-DNA damage repair pathway.The48tSNPs were genetyped by SNPscan in734women with breast cancer(534sporadic cases and200early-onset and familial cases) and672sex-and age-matched healthy controls from Hunan and Sichuan Province of China. Haplotype blocks were constructed with tagging SNPs successfully genetyped, and the odds ratio were calculated by logistic regression analysis in each haplotype.Results:Forty-five tSNPs were successfully genotyped by SNPscan, and call rates for each tSNP were above98.9%. Thirteen haplotype blocks of eight genes were constructed with41successfully genotyped tSNPs. We found that seven haplotypes from four haplotype blocks located within three genes (NBS1, PTEN, and BRIP1) were significantly associated with breast cancer risk. Among these, four haplotypes (ATC in block1of NBS1, GCCCC and GCCCT in block2of NBS1, and GCT in block2of BRIP1) were correlated with breast cancer risk in sporadic cases (OR(95%CI)1.350(1.124-1.623),0.752(0.584-0.969),0.803(0.649-0.993), and0.776(0.604-0.997), respectively), and only one haplotype (GGCCT in block2of NBS1) was significantly associated with breast cancer risk in familial and early-onset cases (OR(95%CI)1.902(1.134-3.191).Conclusions:Several haplotypes within three genes (NBS1、PTEN and BRIP1) involved in the monoubiquitinated FANCD2-DNA damage-repair pathway are significantly associated with breast cancer risk, especially in sporadic breast cancer,while one haplotype GGCCT within block2of NBS1is only correlated with an increased risk of early-onset and familial breast cancer.