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Overweight and obesity are strongly associated with endometrial cancer. Several independent genome-wide association studies recently identified two common polymorphisms,  FTO  rs9939609 and  MC4R  rs17782313, that are linked to increased body weight and obesity. We examined the association of  FTO  rs9939609 and  MC4R  rs17782313 with endometrial cancer risk in a pooled analysis of nine case-control studies within the Epidemiology of Endometrial Cancer Consortium (E2C2). This analysis included 3601 non-Hispanic white women with histologically-confirmed endometrial carcinoma and 5275 frequency-matched controls. Unconditional logistic regression models were used to assess the relation of  FTO  rs9939609 and  MC4R  rs17782313 genotypes to the risk of endometrial cancer. Among control women, both the  FTO  rs9939609  A  and  MC4R  rs17782313  C  alleles were associated with a 16% increased risk of being overweight (p = 0.001 and p = 0.004, respectively). In case-control analyses, carriers of the  FTO  rs9939609  AA  genotype were at increased risk of endometrial carcinoma compared to women with the  TT  genotype [odds ratio (OR)  = 1.17; 95% confidence interval (CI): 1.03–1.32, p = 0.01]. However, this association was no longer apparent after adjusting for body mass index (BMI), suggesting mediation of the gene-disease effect through body weight. The  MC4R  rs17782313 polymorphism was not related to endometrial cancer risk (per allele OR = 0.98; 95% CI: 0.91–1.06; p = 0.68).  FTO  rs9939609 is a susceptibility marker for white non-Hispanic women at higher risk of endometrial cancer. Although  FTO  rs9939609 alone might have limited clinical or public health significance for identifying women at high risk for endometrial cancer beyond that of excess body weight, further investigation of obesity-related genetic markers might help to identify the pathways that influence endometrial carcinogenesis.

The Obesity-Associated Polymorphisms FTO rs9939609 and MC4R rs17782313 and Endometrial Cancer Risk in Non-Hispanic White Women