Identification of a Breast Cancer Susceptibility Locus at 4q31.22 Using a Genome-Wide Association Study Paradigm

More than 40 single nucleotide polymorphisms (SNPs) for breast cancer susceptibility were identified by genome-wide association studies (GWASs). However, additional SNPs likely contribute to breast cancer susceptibility and overall genetic risk, prompting this investigation for additional variants. Six putative breast cancer susceptibility SNPs identified in a two-stage GWAS that we reported earlier were replicated in a follow-up stage 3 study using an independent set of breast cancer cases and controls from Canada, with an overall cumulative sample size of 7,219 subjects across all three stages. The study design also encompassed the 11 variants from GWASs previously reported by various consortia between the years 2007–2009 to (i) enable comparisons of effect sizes, and (ii) identify putative prognostic variants across studies. All SNP associations reported with breast cancer were also adjusted for body mass index (BMI). We report a strong association with 4q31.22-rs1429142 (combined per allele odds ratio and 95% confidence interval = 1.28 [1.17–1.41] and Pcombined = 1.5×10−7), when adjusted for BMI. Ten of the 11 breast cancer susceptibility loci reported by consortia also showed associations in our predominantly Caucasian study population, and the associations were independent of BMI; four FGFR2 SNPs and TNRC9-rs3803662 were among the most notable associations. Since the original report by Garcia-Closas et al. 2008, this is the second study to confirm the association of 8q24.21-rs13281615 with breast cancer outcomes.全基因组关联研究（genome-wide association studies, GWASs）已鉴定出40余个与乳腺癌易感性相关的单核苷酸多态性（single nucleotide polymorphisms, SNPs）。然而，仍有更多的SNPs可能参与乳腺癌易感性与整体遗传风险的构成，因此本研究旨在挖掘额外的相关变异位点。本团队此前报道的一项两阶段GWAS中鉴定出的6个疑似乳腺癌易感SNPs，在后续的第三阶段研究中得到了验证；该阶段研究使用了来自加拿大的独立乳腺癌病例与对照人群队列，全部三个阶段的累计总样本量达7219名受试者。本研究设计同时纳入了2007至2009年间多个研究联盟既往通过GWAS报道的11个变异位点，以实现两个研究目标：一是对效应量进行比较分析，二是在多项研究中筛选疑似预后相关变异位点。所有已报道的与乳腺癌相关的SNP关联分析均针对体重指数（body mass index, BMI）进行了校正。在校正BMI后，本研究发现4q31.22区域rs1429142位点与乳腺癌存在显著关联（合并等位基因比值比及95%置信区间为1.28[1.17–1.41]，合并P值为1.5×10^-7）。在各联盟报道的11个乳腺癌易感基因座中，有10个在本研究以高加索人群为主的队列中同样呈现出关联信号，且该关联不受BMI影响；其中4个FGFR2基因的SNPs以及TNRC9-rs3803662位点的关联最为显著。自2008年Garcia-Closas等人首次报道以来，本研究是第二项证实8q24.21区域rs13281615位点与乳腺癌预后相关的研究。