Energy Balance-related Factors and Risk of Colorectal Cancer Based on KRAS, PIK3CA, and BRAF Mutations and MMR Status

Introduction: KRAS mutations (KRAS), PIK3CA, BRAF, and mismatch repair deficiency (dMMR) have been associated with the Warburg-effect. We previously observed differential associations between energy balance-related factors (BMI, clothing-size, physical activity) and colorectal cancer (CRC) subtypes based on the Warburg-effect. We now investigated whether associations between energy balance-related factors and risk of CRC differ between subgroups based on mutation and MMR status.

Methods: Information on molecular features was available for 2349 incident CRC cases within the Netherlands Cohort Study (NLCS), with complete covariate data available for 1934 cases and 3911 subcohort members. Multivariable-adjusted Cox-regression was used to estimate associations of energy balance-related factors with risk of CRC based on individual molecular features (KRAS; PIK3CA; BRAF; dMMR) and combinations thereof (all-wild-type + MMR-proficient (pMMR); any-mutation/dMMR).

Results: In men, BMI and clothing-size were positively associated with risk of colon, but not rectal cancer, regardless of molecular features subgroups; the strongest associations were observed for PIK3CA colon cancer. In women, however, BMI and clothing-size were only associated with risk of KRAS colon cancer (p-heterogeneity = 0.008). Inverse associations of non-occupational physical activity with risk of colon cancer were strongest for any-mutation/dMMR tumors in men and women, and specifically for PIK3CA tumors in women. Occupational physical activity was inversely associated with both combination subgroups of colon cancer in men.

Conclusion: In men, associations did not vary according to molecular features. In women, a role of KRAS mutations in the etiological pathway between adiposity and colon cancer is suggested, and of PIK3CA mutations between physical activity and colon cancer.