Energy balance-related factors and risk of colorectal cancer based on KRAS, PIK3CA, and BRAF mutations and MMR status

Josien C A Jenniskens, Kelly Offermans, Colinda C J M Simons, Iryna Samarska, Gregorio E Fazzi, Jaleesa R M van der Meer, Kim M Smits, Leo J Schouten, Matty P Weijenberg, Heike I Grabsch*, Piet A van den Brandt*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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 languageEnglish
Pages (from-to)2723-2742
Number of pages20
JournalJournal of Cancer Research and Clinical Oncology
Issue number10
Early online date11 May 2022
Publication statusPublished - Oct 2022


  • Colorectal cancer
  • Energy balance
  • Etiological heterogeneity
  • Mismatch repair
  • Mutations
  • Prospective cohort study
  • microsatellite instability

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