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. 2022 Oct;148(10):2723-2742.
doi: 10.1007/s00432-022-04019-9. Epub 2022 May 11.

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

Josien C A Jenniskens  1 , Kelly Offermans  1 , Colinda C J M Simons  1 , Iryna Samarska  2 , Gregorio E Fazzi  2 , Jaleesa R M van der Meer  2 , Kim M Smits  2 , Leo J Schouten  1 , Matty P Weijenberg  1 , Heike I Grabsch  3   4 , Piet A van den Brandt  5   6
Affiliations

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

Josien C A Jenniskens et al. J Cancer Res Clin Oncol. 2022 Oct.

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.

Keywords: Colorectal cancer; Energy balance; Etiological heterogeneity; Mismatch repair/microsatellite instability; Mutations; Prospective cohort study.

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Conflict of interest statement

H. I. Grabsch: Honorarium from Astra Zeneca and BMS for scientific advisory board activities not related to the current study.

Figures

Fig. 1
Fig. 1
Flow diagram of the number of CRC cases and subcohort members; NLCS, 1986–2006. CRC colorectal cancer; NA not applicable; PALGA Dutch Pathology Registry; FFPE formalin-fixed paraffin-embedded; TMA tissue microarray; QC quality control; H&E Hematoxylin & Eosin; pan-CK pan-cytokeratin; MMR mismatch repair
Fig. 2
Fig. 2
Graphical presentation of KRASmut, PIK3CAmut, BRAFmut, and MMR status in CRC cases from the NLCS. a Pie chart showing the distribution of the all-wild-type + pMMR and any-mutation/dMMR subgroups (based on all CRC cases; n = 1934). b Bar chart showing frequencies of KRASmut, PIK3CAmut, BRAFmut, and dMMR (based on all CRC cases; n = 1934). c Venn diagram showing combinations of KRASmut, PIK3CAmut, BRAFmut, and dMMR (based on any-mutation/dMMR subgroup; n = 1142). The color intensity indicates the frequency: a darker color indicates more cases; a lighter color indicates fewer cases. d/pMMR mismatch repair deficiency/proficiency; mut mutation; CRC colorectal cancer; NLCS Netherlands Cohort Study
See this image and copyright information in PMC

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