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

Abstract

Introduction: KRAS mutations (KRAS_mut), PIK3CA_mut, BRAF_mut, 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_mut; PIK3CA_mut; BRAF_mut; 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_mut colon cancer. In women, however, BMI and clothing-size were only associated with risk of KRAS_mut colon cancer (p-heterogeneity_{KRASmut 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 PIK3CA_mut 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.

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

Graphical presentation of KRAS_mut, PIK3CA_mut, BRAF_mut, 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 KRAS_mut, PIK3CA_mut, BRAF_mut, and dMMR (based on all CRC cases; n = 1934). c Venn diagram showing combinations of KRAS_mut, PIK3CA_mut, BRAF_mut, 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