TY - JOUR
T1 - Association between mutational subgroups, Warburg-subtypes, and survival in patients with colorectal cancer
AU - Offermans, Kelly
AU - Jenniskens, Josien C A
AU - Simons, Colinda C J M
AU - Samarska, Iryna
AU - Fazzi, Gregorio E
AU - van der Meer, Jaleesa R M
AU - Smits, Kim M
AU - Schouten, Leo J
AU - Weijenberg, Matty P
AU - Grabsch, Heike I
AU - van den Brandt, Piet A
N1 - © 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
PY - 2023/1
Y1 - 2023/1
N2 - 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.
AB - 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.
KW - COHORT
KW - EXPRESSION
KW - KRAS
KW - METABOLISM
KW - MICROSATELLITE INSTABILITY
KW - PATHWAYS
KW - Warburg-effect
KW - colorectal cancer
KW - oncogenes
KW - prognosis
KW - survival
U2 - 10.1002/cam4.4968
DO - 10.1002/cam4.4968
M3 - Article
C2 - 35785488
SN - 2045-7634
VL - 12
SP - 1137
EP - 1156
JO - Cancer Medicine
JF - Cancer Medicine
IS - 2
ER -