Distinct genomic landscapes of mismatch-repair deficiency (dMMR)/microsatellite instability-high (MSI-H) gastrointestinal (GI) cancer depending on tumor mutation burden (TMB) levels
Year: 2026
Type: article
Study design: Observational Study
Abstract: Purpose Tumor mutation burden (TMB) is a predictive biomarker for immune checkpoint inhibitor (ICI) treatment in mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) cancers. We aimed to characterize specific molecular features of dMMR/MSI-H gastrointestinal (GI) tumors with a range of TMB levels.Experimental design A total of 2272 GI tumors tested as dMMR/MSI-H were analyzed using next-generation sequencing (NGS) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, Arizona, USA). Molecular features were compared in four groups (TMB <10 vs 10–20 vs 20–50 vs ≥50 mutations/Mb) using Fisher’s exact test or χ 2 and adjusted for multiple comparisons by Benjamini-Hochberg. The impact of TMB on tumor immune environment and clinical outcomes of ICI treatment was analyzed using the TCGA and PUCH cohorts, respectively.Results Tumors with TMB over 10, 20, 50 mutations/Mb were observed in 95.38%, 86.05% and 14.48%, respectively, in the dMMR/MSI-H GI cohort. Mutation rates in MSH3, RNF43, KMT2D, MSH6, BCL9, CIC, KMT2C, FANCM, JAK1, PRKDC, FLCN, PTEN, PTCH1, SPEN, SETD2, and NBN were the highest in the dMMR/MSI-H GI tumors with TMB over 50 mutations/Mb, while TP53 mutations showed the highest rate in TMB below 10 mutations/Mb (all Padj <0.01). Among them, RNF43 and PTCH1 mutations were identified as the positive predictors for survival benefit from ICI treatment, while TP53 was a negative predictor. We further combined the mutational status of RNF43, PTCH1, and TP53, and found TP53-wild-type patients with any mutations in RNF43 and PTCH1 showed a superior clinical benefit for DCB (100% vs 35.7%, p=0.006), PFS (NR vs 3.17 months, HR=0.16, 95% CI 0.046 to 0.57, p=0.0045), and OS (NR vs 12.37 months, HR=0.15, 95% CI 0.033 to 0.67, p=0.015) patients with RNF43/PTCH1-WT or TP53-MT.Conclusions This is the largest study to investigate the distinct molecular landscape of dMMR/MSI-H GI cancers with different levels of TMB. These data may inform our understanding of the efficacy of ICI in the dMMR/MSI-H GI tumors.
Authors: Jingyuan Wang, Joanne Xiu, Alex P Farrell, Francesca Battaglin, Hiroyuki Arai, Yan Yang, Shivani Soni, Wu Zhang, Joshua Millstein, Anthony F Shields, Axel Grothey, Benjamin A Weinberg, John Marshall, Emil Lou, Moh’d Khushman, Davendra P S Sohal, Michael J Hall, Tianshu Liu, Matthew James Oberley, David Spetzler, Heinz-Josef Lenz
Institutions: University of Southern California, Fudan University, USC Norris Comprehensive Cancer Center, Zhongshan Hospital, Caris Life Sciences (United States), Wayne State University, The Barbara Ann Karmanos Cancer Institute, West Cancer Center, Georgetown University Medical Center, Georgetown Lombardi Comprehensive Cancer Center, University of Minnesota, Washington University in St. Louis, University of Cincinnati, Fox Chase Cancer Center
Language: English
Subfield: Pathology and Forensic Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $2,490
Funders: Dhont Family Foundation, Shanghai Municipal Health Commission, Gloria Borges WunderGlo Foundation, National Natural Science Foundation of China, China Postdoctoral Science Foundation, National Institutes of Health, National Postdoctoral Program for Innovative Talents, National Cancer Institute
OpenAlex ID: W7222159400