Breast cancer risk is influenced by rare coding variants in susceptibility genes such as BRCA1 and many common, mainly non-coding variants. However, much of the genetic contribution to breast cancer risk remains unknown. We report results from a genome-wide association study (GWAS) of breast cancer in 122,977 cases and 105,974 controls of European ancestry and 14,068 cases and 13,104 controls of East Asian ancestry1. We identified 65 new loci associated with overall breast cancer at p<5x10-8. The majority of credible risk SNPs in the new loci fall in distal regulatory elements, and by integrating in-silico data to predict target genes in breast cells at each locus, we demonstrate a strong overlap between candidate target genes and somatic driver genes in breast tumours. We also find that heritability of breast cancer due to all SNPs in regulatory features was 2-5-fold enriched relative to the genome-wide average, with strong enrichment for particular transcription factor binding sites. These results provide further insight into genetic susceptibility to breast cancer and will improve the utility of genetic risk scores for individualized screening and prevention.

Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. Through genome-wide association studies (GWAS), we have previously identified eight risk loci for endometrial cancer. Here, we present an expanded meta-analysis of 12,906 endometrial cancer cases and 108,979 controls (including new genotype data for 5624 cases) and identify nine novel genome-wide significant loci, including a locus on 12q24.12 previously identified by meta-GWAS of endometrial and colorectal cancer. At five loci, expression quantitative trait locus (eQTL) analyses identify candidate causal genes; risk alleles at two of these loci associate with decreased expression of genes, which encode negative regulators of oncogenic signal transduction proteins (SH2B3 (12q24.12) and NF1 (17q11.2)). In summary, this study has doubled the number of known endometrial cancer risk loci and revealed candidate causal genes for future study.

GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the ‘iCOGS’ genotyping array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as candidate causal variants at odds against >100:1. The best functional candidate, rs4442975, is associated with oestrogen receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95% confidence interval=0.84−0.87; P=1.7 × 10−43) per t-allele. This SNP flanks a transcriptional enhancer that physically interacts with the promoter of IGFBP5 (encoding insulin-like growth factor-binding protein 5) and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the g-allele confers increased breast cancer susceptibility through relative downregulation of IGFBP5, a gene with known roles in breast cell biology.

Background and Aims CALGB 80303 was a randomized, phase III study in advanced pancreatic cancer patients treated with gemcitabine plus either bevacizumab or placebo. We prospectively collected germline DNA and conducted a genome-wide association study (GWAS) using overall survival (OS) as the endpoint. Methods DNA from 351 patients was genotyped for >550,000 single nucleotide polymorphisms (SNPs). Associations between OS and SNPs were investigated using the log-linear two-way multiplicative Cox proportional-hazards model. The subset of 294 genetically European patients was used for the primary analysis. Results A nonsynonymous SNP in IL17F (rs763780, H161R) and an intronic SNP in strong linkage disequilibrium (rs7771466) were associated with OS using genome-wide criteria (p≤10−7). Median OS was significantly shorter (p 2.61×10−8) for the rs763780 heterozygotes (3.1 months, 95% CI 2.3–4.3) as compared to the patients without this variant (6.8 months, 5.8–7.3). After adjustment by stratification factors, the p value for the association was 9.51×10−7. Conclusions The variant 161R form of interleukin-17F is a natural antagonist of the anti-angiogenic effects of wild-type 161H interleukin-17F, and angiogenesis may play an important role in the metastatic spread of pancreatic cancer. In this preliminary study, we hypothesize that the angiogenesis potential of pancreatic cancers in patients with variant interleukin-17F is higher than that of tumors in patients with wild-type interleukin-17F, conferring worse prognosis. This exploratory GWAS may provide the foundation for testing the biology and clinical effects of novel genes and their heritable variants through mechanistic and confirmatory studies in pancreatic cancer.