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.
Highlights
Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries
Details of genotyping for each study are found in Supplementary Data 1 and individual studies described in the Supplementary Information
Using linkage disequalibrium (LD) score regression, we estimate that 93% of the observed test statistic inflation is due to polygenic signal, as opposed to population stratification
Summary
Endometrial cancer is the most commonly diagnosed cancer of the female reproductive tract in developed countries. We conduct a meta-GWAS including 12,906 endometrial cancer cases and 108,979 country-matched controls of European ancestry from 17 studies identified via the Endometrial Cancer Association Consortium (ECAC), the Epidemiology of Endometrial Cancer Consortium (E2C2) and the UK Biobank and report a further nine genome-wide significant endometrial cancer genetic risk regions. One of these risk regions on 12q24.12 was previously identified by meta-GWAS of endometrial and colorectal cancer. One of these risk regions on 12q24.12 was previously identified by meta-GWAS of endometrial and colorectal cancer9. eQTL and gene network analyses reveal candidate causal genes and pathways relevant for endometrial carcinogenesis
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