Obesity and type 2 diabetes mellitus (T2D) are independent risk factors for endometrial cancer. While they are mainly considered a consequence of modifiable lifestyle choices, increasingly, genetic determinants are discovered. Genome-wide association studies (GWAS) have identified common variants that predispose individuals to a higher body mass index (BMI) or T2D. One study found that summing the number of BMI-increasing alleles from 26 unique loci into a genetic risk score (GRS) was associated with increased endometrial cancer risk among Chinese women. Since the majority of BMI and T2D variants were identified in populations of European descent, we explored whether the respective GRSs are associated with endometrial cancer risk among women of European ancestry.

We used data from an ongoing GWAS conducted by the Epidemiology of Endometrial Cancer Consortium. Samples were genotyped on the Illumina HumanOmniExpress, HumanOmni2.5, or Human660W chip. Over 2.5 million markers were imputed separately for each study using MACH software (r2 >0.80) and NCBI build 36 of Phase II HapMap CEU (release 22) as the reference panel. We selected all 32 independent variants validated and/or identified at P<5x10^-8 from a recent genome-wide meta-analysis for the BMI GRS. Similarly, we selected 36 independent polymorphisms near 35 loci that replicated in GWAS of T2D. Exported counts of each risk allele were used to calculate the BMI and T2D GRSs. Data were available for 2,656 Type I endometrial cancer cases and 2,730 control participants of European ancestry. Unconditional logistic regression examined the association of individual variants and GRSs with endometrial cancer risk or diabetes. Linear regression assessed genetic associations with BMI. All analyses were adjusted for age and study. BMI, diabetes, menopausal hormone therapy (HT) use were also considered. Binomial tests assessed whether the number of risk alleles associated with elevated endometrial cancer risk was more than expected by chance. Likelihood ratio tests assessed heterogeneity by age, BMI, and HT use strata.

Women with endometrial cancer were slightly older and more likely to have used HT. Cases also had a higher mean BMI and were more likely to have a personal history of diabetes. Among controls, the BMI GRS was strongly associated with BMI (beta=0.23; P=5.50x10^-16). Twenty-four of 32 obesity risk alleles displayed estimates consistent with increased endometrial cancer risk (binomial test, P=0.001). The BMI GRS was significantly associated with endometrial cancer risk. Per risk allele, a woman had a 2% increased risk of endometrial cancer (95% CI=1%-4%; P=0.004). After adjusting for BMI, the BMI GRS was no longer associated with endometrial cancer risk (per-allele OR=1.00; 95% CI=0.98-1.02; P=0.97). Heterogeneity was not noted by age, BMI, or HT use (P>=0.25).

Of 36 T2D risk alleles, the number associated with elevated endometrial cancer risk (N=12) was not more than expected by chance (binomial test, P=0.97). The T2D GRS was not associated with a personal history of diabetes among controls (P=0.25) or with endometrial cancer risk (P=0.06). Heterogeneity was not observed by age, BMI, or HT use (P>=0.10).

In summary, possessing a greater number of obesity risk alleles increases endometrial cancer risk among women of European ancestry. However, this risk can be eliminated by maintaining a healthy body weight. We did not find an association with the T2D GRS, with 65% power to detect a per-allele OR of 1.02.

Citation Format: Jennifer Prescott, Veronica W. Setiawan, Nicolas Wentzensen, Fredrick Schumacher, Herbert Yu, Ryan Delahanty, Stephen Chanock, Chu Chen, Monserrat Garcia-Closas, Christopher A. Haiman, Patricia Hartge, Pamela Horn-Ross, Loic Le Marchand, Jolanta Lissowska, Lingeng Lu, Harvey A. Risch, Xiao-Ou Shu, Giske Ursin, Noel S. Weiss, Hanna Yang, Peter Kraft, Immaculata De Vivo. Body mass index and type 2 diabetes genetic risk scores and endometrial cancer risk among women of European ancestry. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 14.