Impact of RAS / BRAF V600E Mutations on the Tumor Immune Microenvironment in Mismatch Repair–Deficient/Microsatellite Instability Colorectal Cancers

作者：Mohamed E. Salem, Alberto Puccini, Elizabeth Mauer, Thierry André, Thomas J. George, Josep Tabernero, Frank A. Sinicrope, Jeanne Tie, Scott Kopetz, Eric Van Cutsem, Sara Lonardi, Michael J. Overman, David Foureau · 发表于：Clinical Cancer Research · 年份：2025 · DOI：10.1158/1078-0432.ccr-25-2160 · 被引用次数：4 · 研究领域：Genetic factors in colorectal cancer、Colorectal Cancer Treatments and Studies、Cancer Immunotherapy and Biomarkers

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, BRAFV60...