RAS–Pathway Mutation Profiles and Clinical Outcomes Among Patients With Colorectal Cancer
5 affiliations
- 1Cedars‐Sinai Cancer, Cedars‐Sinai Health Sciences University
- 2Cleveland Clinic Research
- 3Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine
- 4Ponce Research Institute, Ponce Health Sciences University
- 5H. Lee Moffitt Cancer Center & Research Institute
Abstract
Background Somatic alterations in the RAS–RAF–MAPK and PI3K pathways are key in colorectal cancer (CRC), yet their distribution, co‐occurrence patterns, and clinical significance remain incompletely defined. We characterized RAS/MAPK‐ and PI3K‐pathway alterations in a large cohort and assessed their prognostic implications. Methods We analyzed whole‐exome sequencing data from 1243 paired samples from patients with CRC. Somatic variants in KRAS, NRAS, HRAS, BRAF, and PIK3CA were analyzed to quantify frequencies, codon‐level distributions, and co‐occurrence patterns. Descriptive somatic mutation status and demographic and clinical characteristics were evaluated using chi‐square or Fisher exact tests, and associations with overall survival (OS) were evaluated using multivariable Cox proportional hazards models. Results Any RAS‐family mutation was detected in 507 tumors (40.8%); KRAS, NRAS, and HRAS mutations occurred in 35.3%, 5.4%, and 0.6%, respectively. BRAF V600E was detected in 85 tumors (6.8%), PIK3CA in 221 (17.8%), and KRAS G12C in 38 (3.1%). KRAS codon 12 was the dominant RAS hotspot. KRAS‐PIK3CA co‐mutations occurred in 126 tumors (10.1% overall; 28.7% of KRAS‐mutant tumors), whereas KRAS‐BRAF and KRAS‐NRAS co‐mutations were uncommon, consistent with MAPK pathway mutual exclusivity. RAS‐mutant tumors were enriched in right‐sided and microsatellite‐stable disease (p < 0.001 for both). KRAS, BRAF V600E, and PIK3CA mutation frequencies were higher in right‐sided than left‐sided tumors. In unadjusted analyses, Hispanic patients had lower KRAS, BRAF V600E, and PIK3CA mutation frequencies than non‐Hispanic patients. After adjustment for age, sex, tumor location, and MSI status, the associations with KRAS and PIK3CA were attenuated, whereas the lower frequency of BRAF V600E among Hispanic patients persisted (p < 0.01). Mutation status was not significantly associated with 5‐year overall survival. Conclusions RAS/MAPK and PI3K pathway alterations in CRC varied primarily by tumor subtype and molecular context, with clinically relevant co‐mutation patterns and a targetable KRAS G12C subset. These findings may support future clinical trials targeting the BRAF–RAS axis.
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BibTeX
@article{kazemian2026raspathway,
title = {{RAS–Pathway Mutation Profiles and Clinical Outcomes Among Patients With Colorectal Cancer}},
author = {Elham Kazemian and Louisa Liu and Barliz Waissengrin and Marco Matejcic and Daniel Sobieski and Ya‐Yu Tsai and Nicole C. Loroña and Nathalie T. Nguyen and José A. Oliveras Torres and W. Douglas Cress and Edna R. Gordián and Erin M. Siegel and Jamie K. Teer and Stephanie L. Schmit and Jane C. Figueiredo},
journal = {Cancer medicine},
year = {2026},
month = oct,
doi = {10.1002/cam4.72411},
url = {https://europepmc.org/article/PMC/PMC13691186},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - RAS–Pathway Mutation Profiles and Clinical Outcomes Among Patients With Colorectal Cancer
AU - Elham Kazemian
AU - Louisa Liu
AU - Barliz Waissengrin
AU - Marco Matejcic
AU - Daniel Sobieski
AU - Ya‐Yu Tsai
AU - Nicole C. Loroña
AU - Nathalie T. Nguyen
AU - José A. Oliveras Torres
AU - W. Douglas Cress
AU - Edna R. Gordián
AU - Erin M. Siegel
AU - Jamie K. Teer
AU - Stephanie L. Schmit
AU - Jane C. Figueiredo
PY - 2026
DA - 2026/10/01
JO - Cancer medicine
DO - 10.1002/cam4.72411
UR - https://europepmc.org/article/PMC/PMC13691186
AB - Background Somatic alterations in the RAS–RAF–MAPK and PI3K pathways are key in colorectal cancer (CRC), yet their distribution, co‐occurrence patterns, and clinical significance remain incompletely defined. We characterized RAS/MAPK‐ and PI3K‐pathway alterations in a large cohort and assessed their prognostic implications. Methods We analyzed whole‐exome sequencing data from 1243 paired samples from patients with CRC. Somatic variants in KRAS, NRAS, HRAS, BRAF, and PIK3CA were analyzed to quantify frequencies, codon‐level distributions, and co‐occurrence patterns. Descriptive somatic mutation status and demographic and clinical characteristics were evaluated using chi‐square or Fisher exact tests, and associations with overall survival (OS) were evaluated using multivariable Cox proportional hazards models. Results Any RAS‐family mutation was detected in 507 tumors (40.8%); KRAS, NRAS, and HRAS mutations occurred in 35.3%, 5.4%, and 0.6%, respectively. BRAF V600E was detected in 85 tumors (6.8%), PIK3CA in 221 (17.8%), and KRAS G12C in 38 (3.1%). KRAS codon 12 was the dominant RAS hotspot. KRAS‐PIK3CA co‐mutations occurred in 126 tumors (10.1% overall; 28.7% of KRAS‐mutant tumors), whereas KRAS‐BRAF and KRAS‐NRAS co‐mutations were uncommon, consistent with MAPK pathway mutual exclusivity. RAS‐mutant tumors were enriched in right‐sided and microsatellite‐stable disease (p < 0.001 for both). KRAS, BRAF V600E, and PIK3CA mutation frequencies were higher in right‐sided than left‐sided tumors. In unadjusted analyses, Hispanic patients had lower KRAS, BRAF V600E, and PIK3CA mutation frequencies than non‐Hispanic patients. After adjustment for age, sex, tumor location, and MSI status, the associations with KRAS and PIK3CA were attenuated, whereas the lower frequency of BRAF V600E among Hispanic patients persisted (p < 0.01). Mutation status was not significantly associated with 5‐year overall survival. Conclusions RAS/MAPK and PI3K pathway alterations in CRC varied primarily by tumor subtype and molecular context, with clinically relevant co‐mutation patterns and a targetable KRAS G12C subset. These findings may support future clinical trials targeting the BRAF–RAS axis.
SN - 2045-7634
ER -