Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.

Autor:	Kar SP; Medical Research Council Integrative Epidemiology Unit, University of Bristol, Bristol, UK.; Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK., Considine DPC; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Tyrer JP; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK., Plummer JT; 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., Chen S; 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., Dezem FS; 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., Barbeira AN; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA., Rajagopal PS; Section of Hematology/Oncology, Department of Medicine, University of Chicago, Chicago, IL, USA., Rosenow WT; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA., Moreno F; Department of Oncology, Hospital Clínico San Carlos, Madrid, Spain., Bodelon C; Divison of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA., Chang-Claude J; 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., Chenevix-Trench G; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia., deFazio A; 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., Dörk T; Gynaecology Research Unit, Hannover Medical School, Hannover, Germany., Ekici AB; Institute of Human Genetics, University Hospital Erlangen, Erlangen, Germany.; Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen, Erlangen, Germany., Ewing A; 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., Fountzilas G; Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece., Goode EL; Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA., Hartman M; 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., Heitz F; 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., Hillemanns P; Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany., Høgdall E; 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., Høgdall CK; The Juliane Marie Centre, Department of Gynecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark., Huzarski T; 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., Jensen A; Department of Lifestyle, Reproduction, and Cancer, Danish Cancer Society Research Center, Copenhagen, Denmark., Karlan BY; David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA., Khusnutdinova E; 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., Kiemeney LA; Radboud Institute for Health Sciences, Radboud University Medical Center, Nijmegen, the Netherlands., Kjaer SK; Department of Virus, Lifestyle, and Genes, Danish Cancer Society Research Center, Copenhagen, Denmark.; Department of Gynaecology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark., Klapdor R; Department of Gynecology and Obstetrics, Hannover Medical School, Hannover, Germany., Köbel M; Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, AB, Canada., Li J; 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., Liebrich C; Department of Obstetrics and Gynecology, Klinikum Wolfsburg, Wolfsburg, Germany., May T; Division of Gynecologic Oncology, University Health Network, Princess Margaret Hospital, Toronto, ON, Canada., Olsson H; Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden., Permuth JB; Departments of Cancer Epidemiology and Gastrointestinal Oncology, Moffitt Cancer Center and Research Institute, Tampa, FL, USA., Peterlongo P; Genome Diagnostics Program, IFOM-The FIRC Institute of Molecular Oncology, Milan, Italy., Radice P; Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy., Ramus SJ; 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., Riggan MJ; Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA., Risch HA; Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA., Saloustros E; Department of Oncology, University Hospital of Larissa, Larissa, Greece., Simard J; Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada., Szafron LM; Maria Sklodowska-Curie National Research Institute of Oncology, Warsaw, Poland., Titus L; Muskie School of Public Service, University of Southern Maine, Portland, ME, USA., Thompson CL; Department of Nutrition, Case Western Reserve University, Cleveland, OH, USA., Vierkant RA; Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA., Winham SJ; Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA., Zheng W; Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA., Doherty JA; Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA., Berchuck A; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, NC, USA., Lawrenson K; 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., Im HK; Section of Genetic Medicine, Department of Medicine, University of Chicago, Chicago, IL, USA., Manichaikul AW; Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA.; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA., Pharoah PDP; 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., Gayther SA; Center for Bioinformatics and Functional Genomics, Department of Biomedical Science, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Schildkraut JM; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA.
Jazyk:	angličtina
Zdroj:	HGG advances [HGG Adv] 2021 Jul 08; Vol. 2 (3). Date of Electronic Publication: 2021 Jun 16.
DOI:	10.1016/j.xhgg.2021.100042
Abstrakt:	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 < 0.05 that were >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. Competing Interests: Declaration of interests The authors declare no competing interests.
Databáze:	MEDLINE
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