Abstract
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 P combined = 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.
Highlights
Breast cancer is the most common cancer in women in the developed world, with 22,700 new cases and 5,100 deaths anticipated in Canada for 2012 [1]
SNPs and samples used In this replication study, we investigated associations of the six putative breast cancer susceptibility SNPs (4q31.22rs1429142, 5p15.2-rs1092913, 16q23.2-rs1981867, ZNF577rs10411161, ZNF577-rs3848562 and ZNF577-rs11878583) [21], that we reported in our previous two-stage genome-wide association studies (GWASs)
We evaluated the potential prognostic values of SNPs with breast cancer outcomes, such as recurrence-free survival (RFS) and overall survival (OS), by fitting Cox proportional hazards models available in the ‘‘survival’’ package [29] implemented in R 2.15.1 [30], adjusted for body mass index (BMI)
Summary
Breast cancer is the most common cancer in women in the developed world, with 22,700 new cases and 5,100 deaths anticipated in Canada for 2012 [1]. Linkage and family-based studies have identified high and moderate penetrance mutations in genes such as BRCA1 [4], BRCA2 [5], PTEN [6], ATM [7], TP53 [8], BRIP1 [9], PALB2 [10] and CHEK2 [11] contributing to hereditary breast cancer; these mutations occur rarely in the general population. Linkage studies failed to identify additional genes/mutations associated with high or moderate risk of breast cancer. A large-scale candidate gene study identified an additional locus (caspase 8 coding SNP, rs1045485) associated with breast cancer risk [23]. The low penetrance common SNPs identified to date explain less than 10% of the genetic risk of breast cancer [22]. Pathogenic germline mutations and low penetrance variants identified far only account for a small fraction of the genetic risk of breast cancer, suggesting that additional variants remain to be identified [24]
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