Association between mutational subgroups, Warburg-subtypes, and survival in patients with colorectal cancer

Kelly Offermans; Josien C A Jenniskens; 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

doi:10.1002/cam4.4968

Association between mutational subgroups, Warburg-subtypes, and survival in patients with colorectal cancer

Cancer Med. 2023 Jan;12(2):1137-1156. doi: 10.1002/cam4.4968. Epub 2022 Jul 3.

Affiliations

¹ Department of Epidemiology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands.
² Department of Pathology, GROW School for Oncology and Reproduction, Maastricht University Medical Center+, Maastricht, The Netherlands.
³ Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
⁴ Department of Epidemiology, Care and Public Health Research Institute (CAPHRI), Maastricht University Medical Center+, Maastricht, The Netherlands.

Abstract

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 + MMR_proficient , KRAS_mut + MMR_proficient , KRAS_mut + PIK3CA_mut + MMR_proficient , PIK3CA_mut + MMR_proficient , BRAF_mut + MMR_proficient , BRAF_mut + MMR_deficient , other + MMR_proficient , and other + MMR_deficient . 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 + MMR_proficient CRC, patients with KRAS_mut + MMR_proficient , KRAS_mut + PIK3CA_mut + MMR_proficient , BRAF_mut + MMR_proficient , or other + MMR_proficient CRC had a statistically significant worse survival (HR_CRC-specific ranged from 1.29 to 1.88). In contrast, patients with other + MMR_deficient CRC had the most favorable survival (HR_CRC-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.

Keywords: Warburg-effect; colorectal cancer; oncogenes; prognosis; survival.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Class I Phosphatidylinositol 3-Kinases / genetics
Cohort Studies
Colorectal Neoplasms* / genetics
DNA Mutational Analysis
Humans
Mutation
Prognosis
Prospective Studies
Proto-Oncogene Proteins B-raf* / genetics
Proto-Oncogene Proteins p21(ras) / genetics

Substances

Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins p21(ras)
Class I Phosphatidylinositol 3-Kinases

Supplementary concepts

Turcot syndrome