American Association for Cancer Research
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Supp. Figures and Legends from Genetic Mechanisms of Immune Evasion in Colorectal Cancer

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journal contribution
posted on 2023-04-03, 21:43 authored by Catherine S. Grasso, Marios Giannakis, Daniel K. Wells, Tsuyoshi Hamada, Xinmeng Jasmine Mu, Michael Quist, Jonathan A. Nowak, Reiko Nishihara, Zhi Rong Qian, Kentaro Inamura, Teppei Morikawa, Katsuhiko Nosho, Gabriel Abril-Rodriguez, Charles Connolly, Helena Escuin-Ordinas, Milan S. Geybels, William M. Grady, Li Hsu, Siwen Hu-Lieskovan, Jeroen R. Huyghe, Yeon Joo Kim, Paige Krystofinski, Mark D.M. Leiserson, Dennis J. Montoya, Brian B. Nadel, Matteo Pellegrini, Colin C. Pritchard, Cristina Puig-Saus, Elleanor H. Quist, Ben J. Raphael, Stephen J. Salipante, Daniel Sanghoon Shin, Eve Shinbrot, Brian Shirts, Sachet Shukla, Janet L. Stanford, Wei Sun, Jennifer Tsoi, Alexander Upfill-Brown, David A. Wheeler, Catherine J. Wu, Ming Yu, Syed H. Zaidi, Jesse M. Zaretsky, Stacey B. Gabriel, Eric S. Lander, Levi A. Garraway, Thomas J. Hudson, Charles S. Fuchs, Antoni Ribas, Shuji Ogino, Ulrike Peters

Supplementary Figures S1-S12 (with legends)



Dana-Farber Harvard Cancer Center

The Parker Institute for Cancer Immunotherapy

Ressler Family Fund

Samuels Family Fund

Garcia-Corsini Family Fund

KL2/Catalyst Medical Research Investigator Training award

Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant

American Society of Clinical Oncology (ASCO)

Tumor Immunology

National Cancer Institute

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Ontario Institute for Cancer Research

NIH-NLM National Cancer Institute



R.A.C.E. Charities and the Gensch family

Parker Institute for Cancer Immunotherapy (PICI)



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