Impact of RAS/BRAFV600E Mutations on the Tumor Immune Microenvironment in Mismatch Repair-Deficient/Microsatellite Instability Colorectal Cancers

Salem, ME; Puccini, A; Mauer, E; Andr&#233;, T; George, TJ; Tabernero, J; Sinicrope, FA; Tie, J; Kopetz, S; Van Cutsem, E; Lonardi, S; Overman, MJ; Foureau, D

Author(s): Salem, ME; Puccini, A; Mauer, E; André, T; George, TJ; Tabernero, J; Sinicrope, FA; Tie, J; Kopetz, S; Van Cutsem, E; Lonardi, S; Overman, MJ; Foureau, D;
Details: Publication Year 2026-01-16,Volume 32,Issue #2,Page 417-427
Journal Title: Clinical Cancer Research
Publication Type: Research article
Abstract: PURPOSE: Routine testing for mismatch repair deficiency (dMMR)/microsatellite instability (MSI) in colorectal cancers is recommended for Lynch syndrome screening, prognosis, and treatment guidance. In the metastatic setting, RAS/BRAF mutations guide treatment decisions. The impact of these mutations on the tumor immune microenvironment (TiME) in MSI/dMMR colorectal cancer is not known. EXPERIMENTAL DESIGN: The study involved retrospective analysis of 448 patients with stage I to IV MSI/dMMR colorectal cancer profiled using next-generation sequencing (Tempus xT DNA sequencing of 595-648 genes at 500x coverage and Tempus xR whole-exome capture RNA sequencing). MSI status was determined by assessing 44 or 239 loci using next-generation sequencing. dMMR was determined using IHC. Tumor mutational burden, tumor neoantigen burden (NTB), PD-L1, immune infiltration, and canonical immune pathways (76 gene set signatures) were analyzed. RESULTS: The median age at diagnosis was 67 years (range, 21-86); 59% of patients were female, and 70% were stage III to IV. Among the 448 patients, 100 (22%) harbored RAS mutations (RASmut), 119 (27%) a BRAFV600E mutation, and 229 (51%) were double wild type. RASmut exhibited lower NTB (median, 12 vs. 15 vs. 16; P = 0.003) and PD-L1 (3.6% vs. 13% vs. 24%; P < 0.001) than BRAFV600E and wild-type tumors, respectively. The RASmut TiME had lower overall inflammation and fewer infiltrating CD8+ T cells than wild-type or BRAFV600E tumors. In contrast, BRAFV600E tumors exhibited hyperproliferative characteristics associated with broad metabolic reprogramming but a similarly inflamed TiME compared with wild-type tumors. CONCLUSIONS: Our data suggest that MSI/dMMR colorectal cancers harboring RASmut are less immunogenic, and the TiME contains a lower inflammatory profile than wild-type or BRAFV600E tumors. Further analysis and validation are required to confirm these findings.
Publisher: American Association for Cancer Research
Keywords: Humans; *Tumor Microenvironment/immunology/genetics; *Proto-Oncogene Proteins B-raf/genetics; *Microsatellite Instability; Female; Male; Aged; *Colorectal Neoplasms/genetics/immunology/pathology; Middle Aged; *Mutation; *DNA Mismatch Repair/genetics; Adult; Retrospective Studies; Aged, 80 and over; Biomarkers, Tumor/genetics; Prognosis; B7-H1 Antigen
Department(s): Medical Oncology
Publisher's Version: https://doi.org/10.1158/1078-0432.Ccr-25-2160
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2026-01-08 05:22:14

Last Modified: 2026-02-03 03:57:05