Genetic mechanisms of immune evasion in colorectal cancer

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. HuygheYeon 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

Research output: Contribution to journalArticlepeer-review

338 Scopus citations


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 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. 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.

Original languageEnglish (US)
Pages (from-to)730-749
Number of pages20
JournalCancer Discovery
Issue number6
StatePublished - Jun 2018
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology


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