Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma

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

doi:10.1016/j.celrep.2016.03.075

Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma

Cell Rep. 2016 Apr 26;15(4):857-865. doi: 10.1016/j.celrep.2016.03.075. Epub 2016 Apr 14.

Authors

Marios Giannakis¹, Xinmeng Jasmine Mu¹, Sachet A Shukla², Zhi Rong Qian³, Ofir Cohen², Reiko Nishihara⁴, Samira Bahl⁵, Yin Cao⁶, Ali Amin-Mansour², Mai Yamauchi³, Yasutaka Sukawa⁷, Chip Stewart⁵, Mara Rosenberg⁵, Kosuke Mima³, Kentaro Inamura³, Katsuhiko Nosho⁸, Jonathan A Nowak⁹, Michael S Lawrence⁵, Edward L Giovannucci¹⁰, Andrew T Chan¹¹, Kimmie Ng¹², Jeffrey A Meyerhardt¹², Eliezer M Van Allen¹, Gad Getz¹³, Stacey B Gabriel⁵, Eric S Lander¹⁴, Catherine J Wu¹, Charles S Fuchs¹⁵, Shuji Ogino¹⁶, Levi A Garraway¹⁷

Affiliations

¹ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
² Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
³ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
⁴ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
⁵ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
⁶ Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
⁷ Department of Gastroenterology and Hepatology, Division of Internal Medicine, School of Medicine, Keio University, Tokyo 108-8345, Japan.
⁸ Department of Gastroenterology, Rheumatology and Clinical Immunology, Sapporo Medical University School of Medicine, Sapporo 060-8543, Japan.
⁹ Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹⁰ Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹¹ Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹² Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹³ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02114, USA.
¹⁴ Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA; Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA; Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA.
¹⁵ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
¹⁶ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA; Division of MPE Molecular Pathological Epidemiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA. Electronic address: shuji_ogino@dfci.harvard.edu.
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA; Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. Electronic address: levi_garraway@dfci.harvard.edu.

Abstract

Large-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.

Abstract

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