Genetic Mechanisms of Immune Evasion in Colorectal Cancer

Catherine S. Grasso(University of California, Los Angeles), Marios Giannakis(Broad Institute), Daniel K. Wells(Parker Institute for Cancer Immunotherapy), Tsuyoshi Hamada(Dana-Farber Cancer Institute), Xinmeng Jasmine Mu(Broad Institute), Michael J. Quist(University of California, Los Angeles), Jonathan A. Nowak(Brigham and Women's Hospital), Reiko Nishihara(Brigham and Women's Hospital), Zhi Rong Qian(Dana-Farber Cancer Institute), Kentaro Inamura(Dana-Farber Cancer Institute), Teppei Morikawa(Dana-Farber Cancer Institute), Katsuhiko Nosho(Dana-Farber Cancer Institute), Gabriel Abril-Rodríguez(University of California, Los Angeles), Charles M. Connolly(Fred Hutch Cancer Center), Helena Escuin-Ordinas(University of California, Los Angeles), Milan S. Geybels(Fred Hutch Cancer Center), William M. Grady(University of Washington), Li Hsu(Fred Hutch Cancer Center), Siwen Hu‐Lieskovan(University of California, Los Angeles), Jeroen R. Huyghe(Fred Hutch Cancer Center), Yeon Joo Kim(University of California, Los Angeles), Paige Krystofinski(University of California, Los Angeles), Mark D.M. Leiserson(Brown University), Dennis Montoya(University of California, Los Angeles), Brian B. Nadel(University of California, Los Angeles), Matteo Pellegrini(University of California, Los Angeles), Colin C. Pritchard(University of Washington), Cristina Puig-Saus(University of California, Los Angeles), Elleanor H. Quist(University of California, Los Angeles), Benjamin J. Raphael(Brown University), Stephen J. Salipante(University of Washington), Daniel Sanghoon Shin(University of California, Los Angeles), Eve Shinbrot(Baylor College of Medicine), Brian H. Shirts(University of Washington), Sachet A. Shukla(Broad Institute), Janet L. Stanford(University of Washington), Wei Sun(Fred Hutch Cancer Center), Jennifer Tsoi(University of California, Los Angeles), Alexander Upfill‐Brown(University of California, Los Angeles), David A. Wheeler(Baylor College of Medicine), Catherine J. Wu(Broad Institute), Ming Yu(Fred Hutch Cancer Center), Syed Hassan Ejaz Zaidi(Ontario Institute for Cancer Research), Jesse M. Zaretsky(University of California, Los Angeles), Stacey Gabriel(Broad Institute), Eric S. Lander(Broad Institute), Levi A. Garraway(Broad Institute), Thomas J. Hudson(Ontario Institute for Cancer Research), Charles S. Fuchs(Brigham and Women's Hospital), Antoni Ribas(University of California, Los Angeles), Shuji Ogino(Broad Institute), Ulrike Peters(University of Washington)
Cancer Discovery
March 6, 2018
10.1158/2159-8290.cd-17-1327
Cited by 548Open Access
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Abstract

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

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