10 Years of GWAS discovery in endometrial cancer: Aetiology, function and translation

Abstract

Endometrial cancer is a common gynaecological cancer with increasing incidence and mortality. In the last decade, endometrial cancer genome-wide association studies (GWAS) have provided a resource to explore aetiology and for functional interpretation of heritable risk variation, informing endometrial cancer biology. Indeed, GWAS data have been used to assess relationships with other traits through correlation and Mendelian randomisation analyses, establishing genetic relationships and potential risk factors. Cross-trait GWAS analyses have increased statistical power and identified novel endometrial cancer risk variation related to other traits. Functional analysis of risk loci has helped prioritise candidate susceptibility genes, revealing molecular mechanisms and networks. Lastly, risk scores generated using endometrial cancer GWAS data may allow for clinical translation through identification of patients at high risk of disease. In the next decade, this knowledge base should enable substantial progress in our understanding of endometrial cancer and, potentially, new approaches for its screening and treatment.

Keywords: Cross-trait analysis; Endometrial cancer; Functional analysis; Genome-wide association study (GWAS); Polygenic risk scores; Risk factors.

Figure 1

Pairwise genetic correlations among risk factors of endometrial cancer. Sex-combined GWAS summary statistics were used for type 2 diabetes (T2D), while female-stratified GWAS summary statistics were used for all other phenotypes (accessed from the GWAS Catalog https://www.ebi.ac.uk/gwas/summary-statistics). Genetic correlation with tumour necrosis factor could not be estimated due to its very low heritability; whereas genetic correlation with plasminogen activator inhibitor-1 was not included because GWAS summary statistics for this phenotype were not available. Abbreviations – T2D: type 2 diabetes; BMI: body mass index; LDL: low density lipoprotein; HDL: high density lipoprotein; SHBG: sex hormone binding globulin.

Fig. 2

Network of candidate target genes found at endometrial cancer risk loci. The network and gene enrichment analyses were performed using STRING version 11.5 (https://string-db.org/). Genes enriched in the Wikipathways “androgen receptor signaling pathway” are highlighted blue and genes belonging to the “reproductive structure development” ontology are highlighted red.