Journal
CANCER DISCOVERY
Volume 8, Issue 6, Pages 730-749Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2159-8290.CD-17-1327
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Funding
- NIH [U01 CA137088, U54 HG003067, P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552, P50 CA127003, R35 CA197735, R01 CA151993, K07 CA190673, 1R01CA194663-01, R35 CA197633, P01 CA168585]
- Dana-Farber Harvard Cancer Center
- Parker Institute for Cancer Immunotherapy
- Ressler Family Fund
- Samuels Family Fund
- Garcia-Corsini Family Fund
- Project P Fund
- Friends of the Dana-Farber Cancer Institute
- Bennett Family Fund
- Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance
- KL2/Catalyst Medical Research Investigator Training award NIH [KL2 TR001100]
- Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant [SU2C-AACR-DT22-17]
- American Society of Clinical Oncology (ASCO)
- Tower Cancer Research Foundation
- Hope Foundation
- UCLA KL2 Award
- Tumor Immunology training grant [4T32CA009120-40]
- Conquer Cancer Foundation ASCO Young Investigator Award
- Ontario Institute for Cancer Research through Ontario Ministry of Research and Innovation
- Biomedical Big Data training grant from the NIH-NLM National Cancer Institute
- PHS [5T32LM012424-03]
- NIAMS [3P50AR063020-03S1]
- R. A. C. E. Charities
- Gensch family, STTR Translational Research grant
- Parker Institute for Cancer Immunotherapy (PICI) [20163828]
- Grants-in-Aid for Scientific Research [16K08679] Funding Source: KAKEN
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To understand the genetic drivers of immune recognition and evasion in colorectal cancer, we analyzed 1,211 colorectal cancer primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas colorectal cancer cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of colorectal cancer, 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. WNT/beta-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/beta-catenin signaling was correlated with the absence of T-cell infiltration. This largescale genomic analysis of colorectal cancer 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 colorectal cancer tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion. (c) 2018 AACR.
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