Germline genetic contribution to the immune landscape of cancer

Rosalyn W Sayaman; Mohamad Saad; Vésteinn Thorsson; Donglei Hu; Wouter Hendrickx; Jessica Roelands; Eduard Porta-Pardo; Younes Mokrab; Farshad Farshidfar; Tomas Kirchhoff; Randy F Sweis; Oliver F Bathe; Carolina Heimann; Michael J Campbell; Cynthia Stretch; Scott Huntsman; Rebecca E Graff; Najeeb Syed; Laszlo Radvanyi; Simon Shelley; Denise Wolf; Francesco M Marincola; Michele Ceccarelli; Jérôme Galon; Elad Ziv; Davide Bedognetti

doi:10.1016/j.immuni.2021.01.011

Germline genetic contribution to the immune landscape of cancer

Immunity. 2021 Feb 9;54(2):367-386.e8. doi: 10.1016/j.immuni.2021.01.011.

Authors

Rosalyn W Sayaman¹, Mohamad Saad², Vésteinn Thorsson³, Donglei Hu⁴, Wouter Hendrickx⁵, Jessica Roelands⁶, Eduard Porta-Pardo⁷, Younes Mokrab⁸, Farshad Farshidfar⁹, Tomas Kirchhoff¹⁰, Randy F Sweis¹¹, Oliver F Bathe¹², Carolina Heimann³, Michael J Campbell¹³, Cynthia Stretch¹⁴, Scott Huntsman⁴, Rebecca E Graff¹⁵, Najeeb Syed¹⁶, Laszlo Radvanyi¹⁷, Simon Shelley¹⁸, Denise Wolf¹⁹, Francesco M Marincola²⁰, Michele Ceccarelli²¹, Jérôme Galon²², Elad Ziv²³, Davide Bedognetti²⁴

Affiliations

¹ Department of Population Sciences, Beckman Research Institute, City of Hope Comprehensive Cancer Center, Duarte, CA 91010, USA; Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA; Biological Sciences and Engineering Division, Lawrence Berkeley National Laboratory, Berkeley, CA 94720, USA. Electronic address: rwsayaman@gmail.com.
² Qatar Computing Research Institute, Hamad Bin Khalifa University, Doha, Qatar; Neuroscience Research Center, Faculty of Medical Sciences, Lebanese University, Beirut, Lebanon.
³ Institute for Systems Biology, Seattle, WA 98109, USA.
⁴ Department of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
⁵ Research Branch, Sidra Medicine, PO Box 26999 Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar.
⁶ Research Branch, Sidra Medicine, PO Box 26999 Doha, Qatar; Department of Surgery, Leiden University Medical Center, 2333 ZA Leiden, the Netherlands.
⁷ Barcelona Supercomputing Center (BSC); Josep Carreras Leukaemia Research Institute (IJC), Badalona, 08034 Barcelona, Catalonia, Spain.
⁸ Research Branch, Sidra Medicine, PO Box 26999 Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar; Weill Cornell Medicine, Doha, Qatar.
⁹ Department of Oncology, University of Calgary, Alberta AB T2N 4N1, Canada; Arnie Charbonneau Cancer Institute, Calgary, Alberta AB T2N 4N1, Canada; Department of Biomedical Data Science and Institute for Stem Cell Biology and Regenerative Medicine, School of Medicine, Stanford University, Stanford, CA 94305, USA; Tenaya Therapeutics, South San Francisco, CA 94080, USA.
¹⁰ Perlmutter Cancer Center, New York University School of Medicine, New York University Langone Health, New York, NY 10016, USA.
¹¹ Department of Medicine, Section of Hematology/Oncology, Committee on Clinical Pharmacology and Pharmacogenomics, Committee on Immunology, University of Chicago, Chicago, IL 60637, USA.
¹² Department of Oncology, University of Calgary, Alberta AB T2N 4N1, Canada; Arnie Charbonneau Cancer Institute, Calgary, Alberta AB T2N 4N1, Canada; Department of Surgery, University of Calgary, Calgary, Alberta AB T2N 4N1, Canada.
¹³ Department of Surgery, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁴ Department of Oncology, University of Calgary, Alberta AB T2N 4N1, Canada; Arnie Charbonneau Cancer Institute, Calgary, Alberta AB T2N 4N1, Canada.
¹⁵ Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA 94143, USA.
¹⁶ Research Branch, Sidra Medicine, PO Box 26999 Doha, Qatar; Department of Science and Technology, University of Sannio, 82100 Benevento, Italy.
¹⁷ Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada.
¹⁸ Department of Research and Development, Leukemia Therapeutics, LLC, Hull, MA 02045, USA.
¹⁹ Department of Laboratory Medicine, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA.
²⁰ Refuge Biotechnologies Inc., Menlo Park, CA 94025, USA.
²¹ Department of Electrical Engineering and Information Technology, University of Naples "Federico II," 80128 Naples, Italy; Istituto di Ricerche Genetiche "G. Salvatore," Biogem s.c.ar.l., 83031 Ariano Irpino, Italy.
²² INSERM, Laboratory of Integrative Cancer Immunology, Equipe Labellisée Ligue Contre Le Cancer, Centre de Recherche de Cordeliers, Université de Paris, Sorbonne Université, Paris, France.
²³ Department of Medicine, Institute for Human Genetics, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: elad.ziv@ucsf.edu.
²⁴ Research Branch, Sidra Medicine, PO Box 26999 Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar; Department of Internal Medicine and Medical Specialties (Di.M.I.), University of Genoa, 16132 Genoa, Italy. Electronic address: dbedognetti@sidra.org.

Abstract

Understanding the contribution of the host's genetic background to cancer immunity may lead to improved stratification for immunotherapy and to the identification of novel therapeutic targets. We investigated the effect of common and rare germline variants on 139 well-defined immune traits in ∼9000 cancer patients enrolled in TCGA. High heritability was observed for estimates of NK cell and T cell subset infiltration and for interferon signaling. Common variants of IFIH1, TMEM173 (STING1), and TMEM108 were associated with differential interferon signaling and variants mapping to RBL1 correlated with T cell subset abundance. Pathogenic or likely pathogenic variants in BRCA1 and in genes involved in telomere stabilization and Wnt-β-catenin also acted as immune modulators. Our findings provide evidence for the impact of germline genetics on the composition and functional orientation of the tumor immune microenvironment. The curated datasets, variants, and genes identified provide a resource toward further understanding of tumor-immune interactions.

Keywords: Cancer immunotherapy; GWAS; Immune subtypes; TCGA; cancer immune landscape; cancer immunity; germline genetics; heritability; iATLAS; rare variant analysis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Databases, Genetic
Female
Gene Expression Regulation, Neoplastic
Genes, BRCA1
Genome-Wide Association Study
Germ-Line Mutation / genetics*
Humans
Immunotherapy / methods*
Interferons / metabolism
Killer Cells, Natural / immunology*
Lymphocytes, Tumor-Infiltrating / immunology*
Male
Middle Aged
Neoplasms / genetics
Neoplasms / immunology*
Quantitative Trait, Heritable
Retinoblastoma-Like Protein p107 / genetics
Signal Transduction / genetics
T-Lymphocytes / immunology*
Wnt Proteins / genetics
Wnt Proteins / metabolism
beta Catenin / genetics
beta Catenin / metabolism

Substances

Retinoblastoma-Like Protein p107
Wnt Proteins
beta Catenin
Interferons

Abstract

Publication types

MeSH terms

Substances

Grants and funding