Genetic Mechanisms of Immune Evasion in Colorectal Cancer
Name
nihms948429.pdf
Description
Accepted version
Size
1.22 MB
Format
Adobe PDF
Checksum (MD5)
e3d6c3e897a3eb45f1de61204a075244
Author(s)
Grasso, Catherine S.
Giannakis, Marios
Wells, Daniel K.
Hamada, Tsuyoshi
Mu, Xinmeng Jasmine
Quist, Michael
Nowak, Jonathan A.
Nishihara, Reiko
Qian, Zhi Rong
Inamura, Kentaro
Date Issued
March 2018
Journal
Cancer Discovery
Publisher
American Association for Cancer Research (AACR)
Citation
Grasso, Catherine S. et al. "Genetic Mechanisms of Immune Evasion in Colorectal Cancer." Cancer Discovery 8, 6 (March 2018): 730–49 © 2018 American Association for Cancer Research
Version
Author's final manuscript
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 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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
Broad Institute of MIT and Harvard
Terms of Use
Creative Commons Attribution-Noncommercial-Share Alike
Persistent DSpace Link
DOI of Published Version
https://doi.org/10.1158/2159-8290.cd-17-1327
