Year: 2026
Type: article
Study design: Observational Study
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.
Source: Cancer Medicine
DOI: 10.1002/cam4.72411
Language: English
Subfield: Oncology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $4,700
Awards: Elucidating the role of transcriptomics in driving ethnicity and ancestry-related disparities in colorectal cancer, Adding Hispanics to Ongoing GWAS in Colorectal Cancer, G362094, Translational Research Program in Colorectal Cancer Disparities, Biological determinants of colorectal cancer outcomes in Latinos of diverseýancestral origins, 2/2 Ponce Health Sciences University-Moffitt Cancer Center Partnership, (1/2) Ponce Health Sciences University-Moffitt Cancer Center Partnership #, Colon Cancer Family Registry Cohort, Moffitt Cancer Center Support Grant, USC PE-GCS: Optimizing Engagement of Hispanic Colorectal Cancer Patients in Cancer Genomic Characterization Studies, Translational Research Program in Cancer Differences across Populations, 3/3 Florida-California Cancer Research, Education and Engagement (CaRE2) Health Center, University of Southern California Norris Comprehensive Cancer Center Support Grant (CCSG)
OpenAlex ID: W7223399340