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

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 p...

Full description

Saved in:

Bibliographic Details
Published in:	Cancer medicine (Malden, MA) MA), 2023-01, Vol.12 (2), p.1137-1156
Main Authors:	Offermans, Kelly, Jenniskens, Josien C. A., Simons, Colinda C. J. M., Samarska, Iryna, Fazzi, Gregorio E., Meer, Jaleesa R. M., Smits, Kim M., Schouten, Leo J., Weijenberg, Matty P., Grabsch, Heike I., Brandt, Piet A.
Format:	Article
Language:	eng
Subjects:	Class I Phosphatidylinositol 3-Kinases - genetics Cohort Studies colorectal cancer Colorectal Neoplasms - genetics DNA Mutational Analysis Humans Mutation oncogenes Prognosis Prospective Studies Proto-Oncogene Proteins B-raf - genetics Proto-Oncogene Proteins p21(ras) - genetics survival Warburg‐effect
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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. In this large, population‐based series of CRC patients, we have shown that mutational subgroups, based on the observed mutation frequencies of RAS (KRAS, NRAS, HRAS), BRAF, PIK3CA, and MET, as well as patients’ MMR status, are associated with important differences in survival. Warburg‐subtypes did not provide additional prognostic information within these mutational subg
ISSN:	2045-7634 2045-7634