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Cancer Discov. 2018 Jun;8(6):730-749. doi: 10.1158/2159-8290.CD-17-1327. Epub 2018 Mar 6.

Genetic Mechanisms of Immune Evasion in Colorectal Cancer.

Author information

1
Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles, and the Jonsson Comprehensive Cancer Center, Los Angeles, California. cgrasso@mednet.ucla.edu.
2
Parker Institute for Cancer Immunotherapy, San Francisco, California.
3
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts.
4
Broad Institute of MIT and Harvard, Cambridge, Massachusetts.
5
Department of Oncologic Pathology, Dana-Farber Cancer Institute, Boston, Massachusetts.
6
Department of Medicine, Division of Hematology-Oncology, University of California, Los Angeles, and the Jonsson Comprehensive Cancer Center, Los Angeles, California.
7
Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
8
Program in MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
9
Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
10
Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
11
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
12
Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
13
Department of Medicine, University of Washington School of Medicine, Seattle, Washington.
14
Department of Computer Science and Center for Computational Molecular Biology, Brown University, Providence, Rhode Island.
15
Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, California.
16
Department of Laboratory Medicine, University of Washington, Seattle, Washington.
17
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas.
18
Department of Statistics, Iowa State University, Ames, Iowa.
19
Department of Epidemiology, School of Public Health, University of Washington, Seattle, Washington.
20
Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California.
21
Ontario Institute for Cancer Research, MaRS Centre, Toronto, Ontario, Canada.
22
AbbVie Inc., Redwood City, California.
23
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
24
Yale Cancer Center, New Haven, Connecticut.
25
Department of Medicine, Yale School of Medicine, New Haven, Connecticut.
26
Smilow Cancer Hospital, New Haven, Connecticut.
#
Contributed equally

Abstract

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/β-catenin signaling genes were significantly mutated in all colorectal cancer subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale 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.Significance: This multi-omic analysis of 1,211 colorectal cancer primary tumors reveals that it should be possible to better monitor resistance in the 15% of cases that respond to immune blockade therapy and also to use WNT signaling inhibitors to reverse immune exclusion in the 85% of cases that currently do not. Cancer Discov; 8(6); 730-49. ©2018 AACR.This article is highlighted in the In This Issue feature, p. 663.

PMID:
29510987
PMCID:
PMC5984687
DOI:
10.1158/2159-8290.CD-17-1327
[Indexed for MEDLINE]
Free PMC Article

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