Genetic mechanisms of immune evasion in colorectal cancer.

Cancer Discov
Authors
Abstract

To understand the genetic drivers of immune recognition and evasion in colorectal cancer (CRC), we analyzed 1,211 CRC primary tumor samples, including 179 classified as microsatellite instability-high (MSI-high). This set includes The Cancer Genome Atlas CRC cohort of 592 samples, completed and analyzed here. MSI-high, a hypermutated, immunogenic subtype of CRC, 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 (CN-LOH). WNT/β-catenin signaling genes were significantly mutated in all CRC subtypes, and activated WNT/β-catenin signaling was correlated with the absence of T-cell infiltration. This large-scale genomic analysis of CRC 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 CRC tumors have genetic and methylation events associated with activated WNT signaling and T-cell exclusion.

Year of Publication
2018
Journal
Cancer Discov
Date Published
2018 Mar 06
ISSN
2159-8290
DOI
10.1158/2159-8290.CD-17-1327
PubMed ID
29510987
Links
Grant list
R35 CA197735 / CA / NCI NIH HHS / United States
U54 HG003067 / HG / NHGRI NIH HHS / United States
P01 CA087969 / CA / NCI NIH HHS / United States
P01 CA055075 / CA / NCI NIH HHS / United States
R01 CA151993 / CA / NCI NIH HHS / United States
U01 CA137088 / CA / NCI NIH HHS / United States
R35 CA197633 / CA / NCI NIH HHS / United States
UM1 CA186107 / CA / NCI NIH HHS / United States
UM1 CA167552 / CA / NCI NIH HHS / United States
P01 CA168585 / CA / NCI NIH HHS / United States
P50 CA127003 / CA / NCI NIH HHS / United States
K07 CA190673 / CA / NCI NIH HHS / United States
R01 CA194663 / CA / NCI NIH HHS / United States
Additional Materials