Grasso et al. studied 1211 colorectal cancer (CRC) primary tumors, including both microsatellite high (MSI-high) and microsatellite stable (MSS) subtypes, to evaluate mechanisms of immune evasion. WNT/β-catenin signaling was demonstrated to be significantly mutated in both subtypes, and inversely correlated with T cell infiltration. B2M mutations were demonstrated in both subtypes, while mutations in immune-related genes were only found in MSI-high. These results support the overall poor response to anti-PD-1 therapy in CRC.

To understand the genetic drivers of immune recognition and evasion in colorectal cancer (CRC), we analyzed 1,211 CRC primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas CRC cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of CRC, had a high rate of significantly mutated genes in important immune modulating pathways and in the antigen presentation machinery, including biallelic losses of B2M and HLA genes due to copy number alterations and copy-neutral loss of heterozygosity (CN-LOH). WNT/beta-catenin signaling genes were significantly mutated in all CRC subtypes, and activated WNT/beta-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of CRC demonstrates that MSI-high cases frequently undergo an immunoediting process that provides them with genetic events allowing immune escape despite high mutational load and frequent lymphocytic infiltration, and furthermore, that CRC tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.

Author Info: (1) Department of Medicine, Divi sion of Hematology - Oncology, University of California Los Angeles cgrasso@mednet.ucla.edu. (2) Department of Medical Oncology, Dana-Farber Cancer Institute. (3)

Author Info: (1) Department of Medicine, Divi sion of Hematology - Oncology, University of California Los Angeles cgrasso@mednet.ucla.edu. (2) Department of Medical Oncology, Dana-Farber Cancer Institute. (3) Parker Institute for Cancer Immunotherapy. (4) Department of Oncologic Pathology, Dana-Farber Cancer Institute. (5) Department of Medical Oncology, Dana-Farber Cancer Institute. (6) Department of Medicine, Divi sion of Hematology - Oncology, University of California Los Angeles. (7) Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital. (8) Department of Oncologic Pathology, Dana-Farber Cancer Institute. (9) Department of Oncologic Pathology, Dana-Farber Cancer Institute. (10) Department of Medical Oncology, Dana-Farber Cancer Institute. (11) Department of Medical Oncology, Dana-Farber Cancer Institute. (12) Department of Medical Oncology, Dana-Farber Cancer Institute. (13) Department of Medicine, Divi sion of Hematology - Oncology, University of California Los Angeles. (14) Public Health Scienc es Division, Fred Hutchinson Cancer Research Center. (15) Department of Medicine, Divi sion of Hematology - Oncology, University of California Los Angeles. (16) Public Health Scienc es Division, Fred Hutchinson Cancer Research Center. (17) Clinical Research Division, Fred Hutchinson Cancer Research Center. (18) Public Health Sciences Division, Fred Hutchinson Cancer Research Center. (19) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (20) Public Health Sciences Division, Fred Hutchinson Cancer Research Center. (21) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (22) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (23) Department of Computer Science and Center for Computational Molecular Biology, Brown University. (24) Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles. (25) Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles. (26) Department of Molecular, Cell, and Developmental Biology, University of California Los Angeles. (27) Department of Laboratory Medicine, University of Washington. (28) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (29) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (30) Department of Computer Science and Center for Computational Molecular Biology, Brown University. (31) Department of Laboratory Medicine, University of Washington. (32) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (33) Human Genome Sequencing Center, Baylor College of Medicine. (34) Department of Laboratory Medicine, University of Washington. (35) Department of Medical Oncology, Dana-Farber Cancer Institute. (36) Public Health Sciences Division, Fred Hutchinson Cancer Research Center. (37) Public Health Sciences Division, Fred Hutchinson Cancer Research Center. (38) Department of Molecular and Medical Pharmacology, University of California Los Angeles. (39) Department of Medi. Department of Medicine, Division of Hematology-Oncologycine, University of California Los Angeles. (40) Human Genome Sequencing Center, Baylor College of Medicine. (41) Department of Medical Oncology, Dana-Farber Cancer Institute. (42) Clinical Research Division, Fred Hutchinson Cancer Research Center. (43) Ontario Institute for Cancer Research. (44) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (45) Broad Institute of MIT and Harvard. (46) Cancer Program, Broad Institute of MIT and Harvard. (47) Department of Medical Oncology, Dana-Farber Cancer Institute. (48) Ontario Institute for Cancer Research. (49) Yale Cancer Center. (50) Department of Medicine, Division of Hematology-Oncology, University of California Los Angeles. (51) Broad Institute of MIT and Harvard. (52) Public Health Sciences Division, Fred Hutchinson Cancer Research Center.

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