HGG Advances (Jul 2021)
Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer
- Siddhartha P. Kar,
- Daniel P.C. Considine,
- Jonathan P. Tyrer,
- Jasmine T. Plummer,
- Stephanie Chen,
- Felipe S. Dezem,
- Alvaro N. Barbeira,
- Padma S. Rajagopal,
- Will T. Rosenow,
- Fernando Moreno,
- Clara Bodelon,
- Jenny Chang-Claude,
- Georgia Chenevix-Trench,
- Anna deFazio,
- Thilo Dörk,
- Arif B. Ekici,
- Ailith Ewing,
- George Fountzilas,
- Ellen L. Goode,
- Mikael Hartman,
- Florian Heitz,
- Peter Hillemanns,
- Estrid Høgdall,
- Claus K. Høgdall,
- Tomasz Huzarski,
- Allan Jensen,
- Beth Y. Karlan,
- Elza Khusnutdinova,
- Lambertus A. Kiemeney,
- Susanne K. Kjaer,
- Rüdiger Klapdor,
- Martin Köbel,
- Jingmei Li,
- Clemens Liebrich,
- Taymaa May,
- Håkan Olsson,
- Jennifer B. Permuth,
- Paolo Peterlongo,
- Paolo Radice,
- Susan J. Ramus,
- Marjorie J. Riggan,
- Harvey A. Risch,
- Emmanouil Saloustros,
- Jacques Simard,
- Lukasz M. Szafron,
- Linda Titus,
- Cheryl L. Thompson,
- Robert A. Vierkant,
- Stacey J. Winham,
- Wei Zheng,
- Jennifer A. Doherty,
- Andrew Berchuck,
- Kate Lawrenson,
- Hae Kyung Im,
- Ani W. Manichaikul,
- Paul D.P. Pharoah,
- Simon A. Gayther,
- Joellen M. Schildkraut
Affiliations
- Siddhartha P. Kar
- Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK; Corresponding author
- Daniel P.C. Considine
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
- Jonathan P. Tyrer
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
- Jasmine T. Plummer
- Center for Bioinformatics and Functional Genomics, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, USA
- Stephanie Chen
- Center for Bioinformatics and Functional Genomics, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, USA
- Felipe S. Dezem
- Center for Bioinformatics and Functional Genomics, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Department of Biomedical Sciences, Cedars Sinai Medical Center, Los Angeles, CA, USA
- Alvaro N. Barbeira
- Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA
- Padma S. Rajagopal
- Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA
- Will T. Rosenow
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA
- Fernando Moreno
- Department of Oncology, Hospital Clínico San Carlos, Madrid, Spain
- Clara Bodelon
- Divison of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
- Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany; Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany
- Georgia Chenevix-Trench
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
- Anna deFazio
- Centre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney, Sydney, NSW, Australia; Department of Gynaecological Oncology, Westmead Hospital, Sydney, NSW, Australia
- Thilo Dörk
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany
- Arif B. Ekici
- Institute of Human Genetics, University Hospital Erlangen, Erlangen, Germany; Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen, Erlangen, Germany
- Ailith Ewing
- MRC Human Genetics Unit, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK; Cancer Research UK Edinburgh Centre, Institute of Genetics and Cancer, University of Edinburgh, Edinburgh, UK
- George Fountzilas
- Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece
- Ellen L. Goode
- Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA
- Mikael Hartman
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore; Saw Swee Hock School of Public Health, National University of Singapore and National University Health System, Singapore, Singapore
- Florian Heitz
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/Evang., Essen, Germany; Department of Gynecology, Center for Oncologic Surgery, Charité Campus Virchow-Klinikum, Berlin, Germany
- Peter Hillemanns
- Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany
- Estrid Høgdall
- Department of Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Molecular Unit, Department of Pathology, Herlev Hospital, University of Copenhagen, Copenhagen, Denmark
- Claus K. Høgdall
- The Juliane Marie Centre, Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Tomasz Huzarski
- Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland; Department of Genetics and Pathology, University of Zielona Góra, Zielona Góra, Poland
- Allan Jensen
- Department of Lifestyle, Reproduction, and Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark
- Beth Y. Karlan
- David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA
- Elza Khusnutdinova
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia; Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa, Russia
- Lambertus A. Kiemeney
- Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands
- Susanne K. Kjaer
- Department of Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark; Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark
- Rüdiger Klapdor
- Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany
- Martin Köbel
- Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, AB, Canada
- Jingmei Li
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore, Singapore; Genome Institute of Singapore, Human Genetics, Singapore, Singapore
- Clemens Liebrich
- Department of Obstetrics and Gynecology, Klinikum Wolfsburg, Wolfsburg, Germany
- Taymaa May
- Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada
- Håkan Olsson
- Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden
- Jennifer B. Permuth
- Departments of Cancer Epidemiology and Gastrointestinal Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA
- Paolo Peterlongo
- Genome Diagnostics Program, IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy
- Paolo Radice
- Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
- Susan J. Ramus
- School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Sydney, NSW, Australia; Adult Cancer Program, Lowy Cancer Research Centre, University of New South Wales, Sydney, NSW, Australia
- Marjorie J. Riggan
- Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA
- Harvey A. Risch
- Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
- Emmanouil Saloustros
- Department of Oncology, University Hospital of Larissa, Larissa, Greece
- Jacques Simard
- Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada
- Lukasz M. Szafron
- Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland
- Linda Titus
- Muskie School of Public Service, University of Southern Maine, Portland, ME, USA
- Cheryl L. Thompson
- Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA
- Robert A. Vierkant
- Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA
- Stacey J. Winham
- Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA
- Wei Zheng
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA
- Jennifer A. Doherty
- Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA
- Andrew Berchuck
- Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA
- Kate Lawrenson
- Center for Bioinformatics and Functional Genomics, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA, USA; Women’s Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Hae Kyung Im
- Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA
- Ani W. Manichaikul
- Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA
- Paul D.P. Pharoah
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
- Simon A. Gayther
- Center for Bioinformatics and Functional Genomics, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA, USA
- Joellen M. Schildkraut
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA
- Journal volume & issue
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Vol. 2,
no. 3
p. 100042
Abstract
Summary: Familial, sequencing, and genome-wide association studies (GWASs) and genetic correlation analyses have progressively unraveled the shared or pleiotropic germline genetics of breast and ovarian cancer. In this study, we aimed to leverage this shared germline genetics to improve the power of transcriptome-wide association studies (TWASs) to identify candidate breast cancer and ovarian cancer susceptibility genes. We built gene expression prediction models using the PrediXcan method in 681 breast and 295 ovarian tumors from The Cancer Genome Atlas and 211 breast and 99 ovarian normal tissue samples from the Genotype-Tissue Expression project and integrated these with GWAS meta-analysis data from the Breast Cancer Association Consortium (122,977 cases/105,974 controls) and the Ovarian Cancer Association Consortium (22,406 cases/40,941 controls). The integration was achieved through application of a pleiotropy-guided conditional/conjunction false discovery rate (FDR) approach in the setting of a TWASs. This identified 14 candidate breast cancer susceptibility genes spanning 11 genomic regions and 8 candidate ovarian cancer susceptibility genes spanning 5 genomic regions at conjunction FDR 1 Mb away from known breast and/or ovarian cancer susceptibility loci. We also identified 38 candidate breast cancer susceptibility genes and 17 candidate ovarian cancer susceptibility genes at conjunction FDR < 0.05 at known breast and/or ovarian susceptibility loci. The 22 genes identified by our cross-cancer analysis represent promising candidates that further elucidate the role of the transcriptome in mediating germline breast and ovarian cancer risk.
