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Background: Previous research suggests that Warburg‐subtypes are related to potentially important survival differences in colorectal cancer (CRC) patients. In the present study, we investigated whether mutational subgroups based on somatic mutations in RAS, BRAF, PIK3CA, and MET, which are known to promote the Warburg‐effect, as well as mismatch repair (MMR) status, hold prognostic value in CRC. In addition, we investigated whether Warburg‐subtypes provide additional prognostic information, independent of known prognostic factors like TNM stage. Methods: CRC patients (n = 2344) from the prospective Netherlands Cohort Study (NLCS) were classified into eight mutually exclusive mutational subgroups, based on observed mutations in RAS, BRAF, PIK3CA, and MET, and MMR status: All‐wild‐type + MMRproficient, KRASmut + MMRproficient, KRASmut + PIK3CAmut + MMRproficient, PIK3CAmut + MMRproficient, BRAFmut + MMRproficient, BRAFmut + MMRdeficient, other + MMRproficient, and other + MMRdeficient. Kaplan–Meier curves and Cox regression models were used to investigate associations between mutational subgroups and survival, as well as associations between our previously established Warburg‐subtypes and survival within these mutational subgroups. Results: Compared to patients with all‐wild‐type + MMRproficient CRC, patients with KRASmut + MMRproficient, KRASmut + PIK3CAmut + MMRproficient, BRAFmut + MMRproficient, or other + MMRproficient CRC had a statistically significant worse survival (HRCRC‐specific ranged from 1.29 to 1.88). In contrast, patients with other + MMRdeficient CRC had the most favorable survival (HRCRC‐specific 0.48). No statistically significant survival differences were observed for the Warburg‐subtypes within mutational subgroups. Conclusion: Our results highlight the prognostic potential of mutational subgroups in CRC. Warburg‐subtypes did not provide additional prognostic information within these mutational subgroups. Future larger‐scale prospective studies are necessary to validate our findings and to examine the potential clinical utility of CRC subtyping based on mutational subgroups. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]