TY - JOUR
T1 - Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma
AU - Giannakis, Marios
AU - Mu, Xinmeng Jasmine
AU - Shukla, Sachet A.
AU - Qian, Zhi Rong
AU - Cohen, Ofir
AU - Nishihara, Reiko
AU - Bahl, Samira
AU - Cao, Yin
AU - Amin-Mansour, Ali
AU - Yamauchi, Mai
AU - Sukawa, Yasutaka
AU - Stewart, Chip
AU - Rosenberg, Mara
AU - Mima, Kosuke
AU - Inamura, Kentaro
AU - Nosho, Katsuhiko
AU - Nowak, Jonathan A.
AU - Lawrence, Michael S.
AU - Giovannucci, Edward L.
AU - Chan, Andrew T.
AU - Ng, Kimmie
AU - Meyerhardt, Jeffrey A.
AU - Van Allen, Eliezer M.
AU - Getz, Gad
AU - Gabriel, Stacey B.
AU - Lander, Eric S.
AU - Wu, Catherine J.
AU - Fuchs, Charles S.
AU - Ogino, Shuji
AU - Garraway, Levi A.
N1 - Funding Information:
We thank N. Gupta, E. Nickerson, and S. Seepo for additional project management and the Broad Sequencing platform, as well as Xin Jin, Julian Hess, Diana Miao, Yohei Masugi, and Pavan Bachireddy for helpful discussions. We thank the participants and staff of the NHS and the HPFS for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, 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 conducted with the support of a KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH, Award KL2 TR001100; M.G.). This work was also supported by the Dana-Farber Cancer Institute Leadership Council (M.G.), the 2014 Colon Cancer Alliance-AACR Fellowship for Biomarker Research Grant Number 14-40-40-GIAN (M.G.), the Perry S. Levy Endowed Fellowship (M.G.), the BroadNext10 (E.M.V.A.) and BroadIgnite (E.M.V.A.) grants, the Project P Fund (C.S.F.), the Blavatnik Family Foundation (C.J.W.), and the Friends of the Dana-Farber Cancer Institute (S.O.), as well as NIH grants U54 HG003067 (E.S.L., S.B.G.), K07 CA190673 (R.N.), K07 CA148894 (Ki.N.), K24 DK098311 (A.T.C.), R01 CA137178 (A.T.C.), R01 CA155010 (C.J.W.), P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552, R01 CA151993 (S.O.), R35 CA197735 (S.O.), R01 CA118553 (C.S.F.), R01 CA168141 (C.S.F.), and P50 CA127003 (M.G., L.A.G., C.S.F.).
Funding Information:
We thank N. Gupta, E. Nickerson, and S. Seepo for additional project management and the Broad Sequencing platform, as well as Xin Jin, Julian Hess, Diana Miao, Yohei Masugi, and Pavan Bachireddy for helpful discussions. We thank the participants and staff of the NHS and the HPFS for their valuable contributions, as well as the following state cancer registries for their help: AL, AZ, AR, CA, CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, 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 conducted with the support of a KL2/Catalyst Medical Research Investigator Training award from Harvard Catalyst/The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH, Award KL2 TR001100; M.G.). This work was also supported by the Dana-Farber Cancer Institute Leadership Council (M.G.), the 2014 Colon Cancer Alliance-AACR Fellowship for Biomarker Research Grant Number 14-40-40-GIAN (M.G.), the Perry S. Levy Endowed Fellowship (M.G.), the BroadNext10 (E.M.V.A.) and BroadIgnite (E.M.V.A.) grants, the Project P Fund (C.S.F.), the Blavatnik Family Foundation (C.J.W.), and the Friends of the Dana-Farber Cancer Institute (S.O.), as well as NIH grants U54 HG003067 (E.S.L., S.B.G.), K07 CA190673 (R.N.), K07 CA148894 (Ki.N.), K24 DK098311 (A.T.C.), R01 CA137178 (A.T.C.), R01 CA155010 (C.J.W.), P01 CA87969, UM1 CA186107, P01 CA55075, UM1 CA167552, R01 CA151993 (S.O.), R35 CA197735 (S.O.), R01 CA118553 (C.S.F.), R01 CA168141 (C.S.F.), and P50 CA127003 (M.G., L.A.G., C.S.F.).
Publisher Copyright:
© 2016 The Authors.
PY - 2016/4/26
Y1 - 2016/4/26
N2 - 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.
AB - 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.
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U2 - 10.1016/j.celrep.2016.03.075
DO - 10.1016/j.celrep.2016.03.075
M3 - Article
AN - SCOPUS:84963553379
SN - 2211-1247
VL - 15
SP - 857
EP - 865
JO - Cell Reports
JF - Cell Reports
IS - 4
ER -
