Endometrial Cancer

Endometrial cancer starts in the endometrium, the lining of the uterus, and is the most common cancer of the female reproductive tract in high-income countries. Most cases occur after menopause, and the leading risk factor is prolonged exposure to oestrogen unopposed by progesterone — from obesity, certain hormone therapies, or conditions such as polycystic ovary syndrome.

The largest study, and a rare follow-through

The genetic study behind this page combined three genome-wide association studies and two further follow-up phases, totalling 7,737 endometrial cancer cases and 37,144 controls of European ancestry — the largest genetic study of this cancer at the time. It identified five new risk loci, and this page holds two.

The strongest of the two, rs11841589 at 13q22.1, sits near KLF5, a transcription factor gene already known to matter in the development of the uterus. Rather than stopping at the statistical association, the researchers went further: they showed that the DNA around this locus sits in a region of active chromatin — the open, accessible state DNA takes when it is being used to regulate a gene — and that it physically interacts with the KLF5 promoter region, the switch that turns the gene on. A closely linked variant at the same locus, when carrying its protective version, suppressed KLF5 gene expression in a laboratory test. That is a rare thing for a genome-wide finding to have: not just a position correlated with disease, but direct evidence for what the position does and which gene it reaches.

The second variant, rs2498796 at 14q32.33, sits in AKT1 — a gene at the centre of a cell-growth signalling pathway that is disrupted in many cancers, making its appearance here biologically unsurprising even without the same functional follow-up.

A larger study nearly doubled the count again

O'Mara et al. 2018 expanded the search further still: 12,906 cases against 108,979 controls, roughly double the case count of the study above. It found 9 new loci, doubling the number of known endometrial cancer risk loci at the time. At five of the nine, follow-up analysis identified a likely causal gene; at two of those five, the risk allele lowered expression of a gene that normally restrains cancer-driving cell signaling — a "less braking, more growth signal" mechanism. This page's five variants from that study — rs113998067 (GNL2), rs1740828 (SOX4), rs9668337 (SSPN), rs10850382 (LOC107984437), and rs7981863 (KLF5) — are not the two with that specific mechanistic evidence. rs7981863's gene is worth noting on its own: KLF5 is the same gene rs11841589, above, already discusses in detail. Two independent studies have now each found a separate risk variant near KLF5 for this cancer.

Two suggestive findings, flagged as such

Painter et al. 2018 asked a different question: not "which variants raise endometrial cancer risk," but whether endometrial cancer and endometriosis, a separate condition, share genetic risk factors at all. Using genetic correlation analysis across both diseases' GWAS data, they found a moderate but real correlation, and a cross-disease meta-analysis that flagged 13 loci shared between the two conditions at a suggestive statistical threshold. Only one of those 13, near PTPRD, cleared full genome-wide significance; this page's rs6782972 (RARB) and rs2218868 (OR9Q1) are two of the other twelve — real findings from the same analysis, but below the significance bar every other variant on this page clears. They are included because the same underlying genetic-correlation finding — that endometriosis and endometrial cancer share some biology — is itself the interesting result here, more than either individual locus.