Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma

Marios Giannakis,Katsuhiko Nosho,Reiko Nishihara,Samira Bahl,Kimmie Ng,Kentaro Inamura,Mara Rosenberg,Gad Getz,Chip Stewart,Yin Cao,Yasutaka Sukawa,Shuji Ogino,Mai Yamauchi,Ofir Cohen,Kosuke Mima,Sachet A Shukla ,Michael S Lawrence ,Jeffrey A Meyerhardt ,Stacey Gabriel ,Zhi Rong Qian ,Ali Amin‐Mansour ,Eric S Lander ,Jonathan A Nowak ,Catherine J Wu ,Andrew T Chan ,Edward Giovannucci ,Xinmeng Jasmine Mu ,Charles S Fuchs ,Eliezer M Van Allen ,Levi A Garraway

doi:10.1016/j.celrep.2016.03.075

Abstract

SummaryLarge-scale genomic characterization of tumors from prospective cohort studies may yield new insights into cancer pathogenesis. We performed whole-exome sequencing of 619 incident colorectal cancers (CRCs) and integrated the results with tumor immunity, pathology, and survival data. We identified recurrently mutated genes in CRC, such as BCL9L, RBM10, CTCF, and KLF5, that were not previously appreciated in this disease. Furthermore, we investigated the genomic correlates of immune-cell infiltration and found that higher neoantigen load was positively associated with overall lymphocytic infiltration, tumor-infiltrating lymphocytes (TILs), memory T cells, and CRC-specific survival. The association with TILs was evident even within microsatellite-stable tumors. We also found positive selection of mutations in HLA genes and other components of the antigen-processing machinery in TIL-rich tumors. These results may inform immunotherapeutic approaches in CRC. More generally, this study demonstrates a framework for future integrative molecular epidemiology research in colorectal and other malignancies.

Highlights

Large-scale cancer sequencing efforts have advanced our understanding of the genomic landscape of many malignancies (Garraway and Lander, 2013)
We identified significantly mutated genes that were previously unthe Nurses’ Health Study (NHS), involving 121,701 women appreciated in this disease and linked tumor neoantigen loads who were followed since 1976, and the Health Professionals and other immune-related genomic aberrations to immune-cell
In 488 non-hypermutated tumors, we found 90 significantly mutated genes that include most genes observed in the Cancer Genome Atlas Network (2012) analysis of colorectal cancers (CRCs), as well as RNF43, which we described to be frequently mutated in this disease (Giannakis et al, 2014)

Summary

Graphical Abstract

Through whole-exome sequencing of annotated colorectal tumors, Giannakis et al identify additional colorectal cancer driver genes and correlate high neoantigen load with increased lymphocytic infiltration and improved survival. They find positive selection for HLA mutations in immune-cellinfiltrated tumors. These results may inform immunotherapeutic approaches in colorectal cancer. 2016, Cell Reports 15, 857–865 April 26, 2016 a 2016 The Authors.

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EXPERIMENTAL PROCEDURES