Germline genetic polymorphisms influence tumor gene expression and immune cell infiltration.

Autor:	Lim YW; Department of Cancer Immunology, Genentech, South San Francisco, CA 94080., Chen-Harris H; Department of Cancer Immunology, Genentech, South San Francisco, CA 94080., Mayba O; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080., Lianoglou S; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080., Wuster A; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080.; Department of Human Genetics, Genentech, South San Francisco, CA 94080., Bhangale T; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080.; Department of Human Genetics, Genentech, South San Francisco, CA 94080., Khan Z; Department of Human Genetics, Genentech, South San Francisco, CA 94080., Mariathasan S; Oncology Biomarker Development, Genentech, South San Francisco, CA 94080., Daemen A; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080., Reeder J; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080., Haverty PM; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080., Forrest WF; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080., Brauer M; Department of Bioinformatics and Computational Biology, Genentech, South San Francisco, CA 94080., Mellman I; Department of Cancer Immunology, Genentech, South San Francisco, CA 94080., Albert ML; Department of Cancer Immunology, Genentech, South San Francisco, CA 94080; albert.matthew@gene.com.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Dec 11; Vol. 115 (50), pp. E11701-E11710. Date of Electronic Publication: 2018 Nov 21.
DOI:	10.1073/pnas.1804506115
Abstrakt:	Cancer immunotherapy has emerged as an effective therapy in a variety of cancers. However, a key challenge in the field is that only a subset of patients who receive immunotherapy exhibit durable response. It has been hypothesized that host genetics influences the inherent immune profiles of patients and may underlie their differential response to immunotherapy. Herein, we systematically determined the association of common germline genetic variants with gene expression and immune cell infiltration of the tumor. We identified 64,094 expression quantitative trait loci (eQTLs) that associated with 18,210 genes (eGenes) across 24 human cancers. Overall, eGenes were enriched for their being involved in immune processes, suggesting that expression of immune genes can be shaped by hereditary genetic variants. We identified the endoplasmic reticulum aminopeptidase 2 ( ERAP2 ) gene as a pan-cancer type eGene whose expression levels stratified overall survival in a subset of patients with bladder cancer receiving anti-PD-L1 (atezolizumab) therapy. Finally, we identified 103 gene signature QTLs (gsQTLs) that were associated with predicted immune cell abundance within the tumor microenvironment. Our findings highlight the impact of germline SNPs on cancer-immune phenotypes and response to therapy; and these analyses provide a resource for integration of germline genetics as a component of personalized cancer immunotherapy. Competing Interests: Conflict of interest statement: All authors are employees of Genentech, Inc. (Copyright © 2018 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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