Identification and characterization of novel associations in the CASP8/ALS2CR12 region on chromosome 2 with breast cancer risk

Abstract

Previous studies have suggested that polymorphisms in CASP8 on chromosome 2 are associated with breast cancer risk. To clarify the role of CASP8 in breast cancer susceptibility, we carried out dense genotyping of this region in the Breast Cancer Association Consortium (BCAC). Single-nucleotide polymorphisms (SNPs) spanning a 1 Mb region around CASP8 were genotyped in 46 450 breast cancer cases and 42 600 controls of European origin from 41 studies participating in the BCAC as part of a custom genotyping array experiment (iCOGS). Missing genotypes and SNPs were imputed and, after quality exclusions, 501 typed and 1232 imputed SNPs were included in logistic regression models adjusting for study and ancestry principal components. The SNPs retained in the final model were investigated further in data from nine genome-wide association studies (GWAS) comprising in total 10 052 case and 12 575 control subjects. The most significant association signal observed in European subjects was for the imputed intronic SNP rs1830298 in ALS2CR12 (telomeric to CASP8), with per allele odds ratio and 95% confidence interval [OR (95% confidence interval, CI)] for the minor allele of 1.05 (1.03-1.07), P = 1 × 10(-5). Three additional independent signals from intronic SNPs were identified, in CASP8 (rs36043647), ALS2CR11 (rs59278883) and CFLAR (rs7558475). The association with rs1830298 was replicated in the imputed results from the combined GWAS (P = 3 × 10(-6)), yielding a combined OR (95% CI) of 1.06 (1.04-1.08), P = 1 × 10(-9). Analyses of gene expression associations in peripheral blood and normal breast tissue indicate that CASP8 might be the target gene, suggesting a mechanism involving apoptosis.

Cross-Cancer Genome-Wide Analysis of Lung, Ovary, Breast, Prostate, and Colorectal Cancer Reveals Novel Pleiotropic Associations

“…3B), and was associated with melanoma in a previous GWAS (28). The region was previously identified as harboring variants associated with breast cancer risk (29–31) and the association found with breast cancer can be explained through LD (R 2 = 0.74) with one of these (rs1830298, P value for breast cancer association = 1.02 × 10 −7 ). The association with prostate cancer has not been previously reported and we replicated it in deCODE and iCOGS (OR = 1.05, 95% CI 1.03–1.08, P = 7.6 × 10 −5 ) (Fig.…”

“…This region is known to harbor breast cancer susceptibility loci: rs1045485, encoding the missense alteration D302H in CASP8 (adjacent to ALS2CR12) (29), rs1830298 (mentioned above) at ALS2CR12 and rs1045494 at CASP8 (30,31). Of these three variants, rs1830298 was found to have the most significant association with breast cancer (P = 1.02 × 10 −7 ) in our study, and was associated with prostate cancer risk (P = 5.2 × 10 −4 ); whereas rs1045485 and rs1045494 were not.…”

Discordant Haplotype Sequencing Identifies Functional Variants at the 2q33 Breast Cancer Risk Locus

“…However, equally important is how this information aligns and adds value to results from a traditional “fine-mapping” study. To achieve this, we aligned our cFSVs with those suggested by the fine-mapping study by the Breast Cancer Association Consortium (BCAC) that used 89,050 samples and 1,733 imputation fine-mapping SNPs across the same 1 Mb region(11). The BCAC study identified one region that achieved genome-wide significance (referred to as iCHAV1, p=1.1×10 −9 )(11).…”

“…The R package metaphor (http://cran.r-project.org/web/packages/metafor) was used to carry out a meta-analysis for the cFSVs, based on the odds ratios and 95% confidence intervals provided for 46,450 cases, 42,600 controls (BCAC) and 22,627 cases and 10,052 controls (9 GWAS) in Lin et al (11). …”

“…As proof-of-concept we present a discordant haplotype HTS DNAseq study in 38 individuals for the 2q33 ( CASP8/ALS2CR12 ) region, a breast cancer risk locus(11). In order to address the lack of knowledge surrounding gene regulation and better prioritize our sequence variants, we supplemented publicly available annotations with RNAseq in normal and tumor breast tissue, and identify three FSVs affecting enhancer activity.…”