Endometrial cancer is the most common gynaecological cancer in developed countries and the cancer type most strongly linked to obesity. Up to 60% of endometrial cancer cases can be attributed to excess weight, yet the biological reasons for this relationship remain poorly understood. Not all obese women develop endometrial cancer, and not all women with endometrial cancer are obese — suggesting that individual risk is shaped by both environment and genetics.
To better understand how obesity contributes to endometrial cancer, we used data from the largest genome-wide association study (GWAS) of endometrial cancer to date (involving over 17,000 cases) alongside multiple measures of obesity, including BMI, body fat percentage, and adipose distribution. Our goal was to separate genetic factors that increase endometrial cancer risk because of obesity, from those that act independently of body weight.
We identified two distinct sets of genetic signals. The majority were independent of obesity and may reflect other biological pathways involved in endometrial cancer development. A smaller set of signals appeared to act specifically in the context of obesity and were enriched near genes involved in metabolism, inflammation, and hormonal regulation. Several of these were located at regions of the genome previously linked to both obesity and cancer risk.
These findings provide new insight into the biology that connects obesity to endometrial cancer. Understanding these pathways could help identify women most at risk, improve prevention efforts, and support the development of treatments that target obesity-related cancer mechanisms.