Obesity shapes selection for driver mutations in cancer

Abstract

Obesity is a leading risk factor for cancer, but whether obesity is linked to specific genomic subtypes of cancer is unknown. Here, we examined the relationship between obesity and tumor genotype in two large clinicogenomic corpora. Obesity was associated with specific driver mutations in lung adenocarcinoma, endometrial carcinoma, and cancers of unknown primary, independent of clinical covariates and genetic ancestry. Obesity is therefore a putative driver of etiologic heterogeneity across cancers.

Fig. 1:. Oncogenic mutations are associated with body mass index.

a) Statistical association between continuous BMI and genotype across gene-cancer-type pairs. −log₁₀ p-values and estimates sizes from univariate logistic regression on the y and x-axis, respectively. Statistically significant pairs in black. b) Multivariate regression demonstrates that BMI categories are associated with KRAS mutations independent of other clinical factors. Result for multivariate regression with BMI as a continuous variable is in Supplemental Table 3. c) KRAS mutation frequency in lung adenocarcinoma patients categorized by BMI and genetic ancestry. ASJ = Ashkenazi Jewish. EAS = East Asian. EUR = European. d) EGFR (top) and KRAS (bottom) mutation frequency in BMI categories in MSKCC cohort. e) EGFR (top) and KRAS (bottom) mutation frequency in BMI categories in DFCI cohort. f) EGFR (left) and KRAS (right) are not associated with pre-diagnosis weight loss in lung adenocarcinoma.