Identification of nine new susceptibility loci for endometrial cancer

Abstract

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.

Genetic predisposition to mosaic Y chromosome loss in blood is associated with genomic instability in other tissues and susceptibility to non-haematological cancers

“…Summary statistics for the ovarian cancer analysis were from GWAS studies of 25,509 ovarian cancer cases and 48,941 controls conducted by the Ovarian Cancer Association Consortium (OCAC) 82 . The endometrial cancer results were from GWAS studies of 12,906 endometrial cancer cases and 108,979 controls from the Endometrial Cancer Association Consortium (ECAC) 83 . In addition, MRs for breast and ovarian cancer risk specifically in carriers of a BRCA1 or a BRCA2 mutation were carried out using results from GWAS studies conducted by the CIMBA consortium 81,82 .…”

Analysis of promoter-associated chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci

“…the lead variant and other correlated variants) at these loci are non-coding and likely mediate their effects through gene regulation (as reviewed in [4]). Indeed, we previously found that a majority of endometrial cancer risk CVs from ten recently discovered GWAS loci were coincident with promoter-or enhancer-associated epigenetic features in relevant cell lines or tissues [1]. Notably, the overlap between CVs and these elements was significantly greater for features observed in endometrial cancer cell lines after stimulation with estrogen [1], one of the most established risk factors for endometrial cancer [5][6][7].…”

“…To determine if promoter-associated HiChIP loops (i.e. those potentially involved with gene regulation) are enriched for heritability of endometrial cancer at a genome-wide level, we applied stratified linkage disequilibrium (LD) score regression analysis to the GWAS summary statistics from the largest study of endometrial cancer performed to date [1]. All four endometrial cell lines demonstrated an enrichment of endometrial cancer heritability in the anchors of promoterassociated loops ( Table 2), although the enrichment in Ishikawa did not reach statistical significance (Bonferroni threshold, p <0.0125).…”

“…After 10 min, cells were placed on ice and the formaldehyde was quenched by washing twice with 125 mM glycine in PBS. Cells were removed from the dish with a cell scraper and washed with PBS before the storage of cell pellets at -80 o C. As we had previously observed greater enrichment of endometrial cancer GWAS variation in epigenomic features observed after estrogen stimulation, including those found in Ishikawa and JHUEM-14 endometrioid endometrial cancer cell lines [1], these two cell lines were stimulated with 10 nM estradiol for 3 h prior to fixation, as previously [1]. Normal endometrium is considered estrogen responsive [47], so E6E7hTERT (a normal immortalised endometrial cell line) cells were also stimulated with estradiol.…”

“…To date, 16 loci have been found to robustly associate with endometrial cancer risk by genome wide association studies (GWAS) [1][2][3]. As for other GWAS, the vast majority of credible variants (CVs; i.e.…”