@article{7dfc0be3fc174ce0b642a082adf932e0,
title = "Genetic mechanisms of immune evasion in colorectal cancer",
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.",
author = "Grasso, {Catherine S.} and Marios Giannakis and Wells, {Daniel K.} and Tsuyoshi Hamada and Mu, {Xinmeng Jasmine} and Michael Quist and Nowak, {Jonathan A.} and Reiko Nishihara and Qian, {Zhi Rong} and Kentaro Inamura and Teppei Morikawa and Katsuhiko Nosho and Gabriel Abril-Rodriguez and Charles Connolly and Helena Escuin-Ordinas and Geybels, {Milan S.} and Grady, {William M.} and Li Hsu and Siwen Hu-Lieskovan and Huyghe, {Jeroen R.} and Kim, {Yeon Joo} and Paige Krystofinski and Leiserson, {Mark D.M.} and Montoya, {Dennis J.} and Nadel, {Brian B.} and Matteo Pellegrini and Pritchard, {Colin C.} and Cristina Puig-Saus and Quist, {Elleanor H.} and Raphael, {Ben J.} and Salipante, {Stephen J.} and Shin, {Daniel Sanghoon} and Eve Shinbrot and Brian Shirts and Sachet Shukla and Stanford, {Janet L.} and Wei Sun and Jennifer Tsoi and Alexander Upfill-Brown and Wheeler, {David A.} and Wu, {Catherine J.} and Ming Yu and Zaidi, {Syed H.} and Zaretsky, {Jesse M.} and Gabriel, {Stacey B.} and Lander, {Eric S.} and Garraway, {Levi A.} and Hudson, {Thomas J.} and Fuchs, {Charles S.} and Antoni Ribas and Shuji Ogino and Ulrike Peters",
note = "Funding Information: We would like to thank the participants and staff of the Nurses{\textquoteright} Health Study and the Health Professionals Follow-up Study for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, IA, ID, IL, IN, KY, LA, MA, MD, ME, MI, NC, ND, NE, NH, NJ, NY, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA, and WY. The authors assume full responsibility for analyses and interpretation of these data. This work was supported by NIH grants U01 CA137088 to U. Peters; U54 HG003067 to E.S. Lander and S.B. Gabriel; P01 CA87969 to M.J. Stampfer; UM1 CA186107 to M.J. Stampfer; P01 CA55075 to W.C. Willett; UM1 CA167552 to W.C. Willett; P50 CA127003 to C.S. Fuchs; R35 CA197735 to S. Ogino; R01 CA151993 to S. Ogino; K07 CA190673 to R. Nishihara; 1R01CA194663-01 W.M. Grady; R35 CA197633 and P01 CA168585 to A. Ribas and C.S. Grasso; the Nodal Award from the Dana-Farber Harvard Cancer Center to S. Ogino; The Parker Institute for Cancer Immunotherapy, the Ressler Family Fund, the Samuels Family Fund, and the Garcia-Corsini Family Fund to A. Ribas and C.S. Grasso; and by grants from the Project P Fund, The Friends of the Dana-Farber Cancer Institute, Bennett Family Fund, and the Entertainment Industry Foundation through the National Colorectal Cancer Research Alliance. M. Giannakis was supported by a KL2/Catalyst Medical Research Investigator Training award NIH Award KL2 TR001100. M. Giannakis and C.S. Fuchs were supported by the Stand Up To Cancer Colorectal Cancer Dream Team Translational Research Grant (grant number SU2C-AACR-DT22-17). Stand Up To Cancer (SU2C) is a program of the Entertainment Industry Foundation and the research grant is administered by the American Association for Cancer Research, a scientific partner of SU2C. S. Hu-Lieskovan was supported by a Career Development Award from the American Society of Clinical Oncology (ASCO), a Tower Cancer Research Foundation Grant, a Dr. Charles Coltman Fellowship Award from the Hope Foundation, and a UCLA KL2 Award. D.S. Shin was supported by the Tumor Immunology 4T32CA009120-40 training grant and 2016 Conquer Cancer Foundation ASCO Young Investigator Award. T.J. Hudson and S.H. Zaidi were supported by the Ontario Institute for Cancer Research, through generous support from the Ontario Ministry of Research and Innovation. B.B. Nadel was supported by the Biomedical Big Data training grant from the NIH-NLM National Cancer Institute; PHS grant number 5T32LM012424-03. D.J. Mon-toya was supported by NIAMS 3P50AR063020-03S1. W.M. Grady was supported by R.A.C.E. Charities and the Gensch family, STTR Translational Research grant. This research was supported by funds from the Parker Institute for Cancer Immunotherapy (PICI), grant number 20163828.",
year = "2018",
month = jun,
doi = "10.1158/2159-8290.CD-17-1327",
language = "English (US)",
volume = "8",
pages = "730--749",
journal = "Cancer Discovery",
issn = "2159-8274",
publisher = "American Association for Cancer Research Inc.",
number = "6",
}