Abstract
INTRODUCTION: KRAS mutations (KRASmut), PIK3CAmut, BRAFmut, 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 (KRASmut; PIK3CAmut; BRAFmut; 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 PIK3CAmut colon cancer. In women, however, BMI and clothing-size were only associated with risk of KRASmut colon cancer (p-heterogeneityKRASmut versus all-wild-type+pMMR = 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 PIK3CAmut 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.
Original language | English |
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Pages (from-to) | 2723-2742 |
Number of pages | 20 |
Journal | Journal of Cancer Research and Clinical Oncology |
Volume | 148 |
Issue number | 10 |
Early online date | 11 May 2022 |
DOIs | |
Publication status | Published - Oct 2022 |
Keywords
- ASSOCIATIONS
- BODY-MASS INDEX
- COHORT
- COLON-CANCER
- Colorectal cancer
- Energy balance
- Etiological heterogeneity
- LIFE-STYLE FACTORS
- METAANALYSIS
- MICROSATELLITE INSTABILITY
- Mismatch repair
- Mutations
- OBESITY
- PHYSICAL-ACTIVITY
- PREVENTION
- Prospective cohort study
- microsatellite instability