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

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. ChanKimmie 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

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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.

Original language	English
Pages (from-to)	857-865
Number of pages	9
Journal	Cell Reports
Volume	15
Issue number	4
DOIs	https://doi.org/10.1016/j.celrep.2016.03.075
State	Published - Apr 26 2016

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Giannakis, M., Mu, X. J., Shukla, S. A., Qian, Z. R., Cohen, O., Nishihara, R., Bahl, S., Cao, Y., Amin-Mansour, A., Yamauchi, M., Sukawa, Y., Stewart, C., Rosenberg, M., Mima, K., Inamura, K., Nosho, K., Nowak, J. A., Lawrence, M. S., Giovannucci, E. L., ... Garraway, L. A. (2016). Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma. Cell Reports, 15(4), 857-865. https://doi.org/10.1016/j.celrep.2016.03.075

@article{1f63b072ce8f4115aa888efc36eef775,

title = "Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma",

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.",

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

note = "Publisher Copyright: {\textcopyright} 2016 The Authors.",

year = "2016",

month = apr,

day = "26",

doi = "10.1016/j.celrep.2016.03.075",

language = "English",

volume = "15",

pages = "857--865",

journal = "Cell Reports",

issn = "2211-1247",

number = "4",

}

Giannakis, M, Mu, XJ, Shukla, SA, Qian, ZR, Cohen, O, Nishihara, R, Bahl, S, Cao, Y, Amin-Mansour, A, Yamauchi, M, Sukawa, Y, Stewart, C, Rosenberg, M, Mima, K, Inamura, K, Nosho, K, Nowak, JA, Lawrence, MS, Giovannucci, EL, Chan, AT, Ng, K, Meyerhardt, JA, Van Allen, EM, Getz, G, Gabriel, SB, Lander, ES, Wu, CJ, Fuchs, CS, Ogino, S & Garraway, LA 2016, 'Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma', Cell Reports, vol. 15, no. 4, pp. 857-865. https://doi.org/10.1016/j.celrep.2016.03.075

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.

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.

UR - http://www.scopus.com/inward/record.url?scp=84963553379&partnerID=8YFLogxK

U2 - 10.1016/j.celrep.2016.03.075

DO - 10.1016/j.celrep.2016.03.075

M3 - Article

C2 - 27149842

AN - SCOPUS:84963553379

SN - 2211-1247

VL - 15

SP - 857

EP - 865

JO - Cell Reports

JF - Cell Reports

IS - 4

ER -

Genomic Correlates of Immune-Cell Infiltrates in Colorectal Carcinoma

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