Identification of shared and unique susceptibility pathways among cancers of the lung, breast, and prostate from genome-wide association studies and tissue-specific protein interactions.
Results from genome-wide association studies (GWAS) have indicated that strong single-gene effects are the exception, not the rule, for most diseases. We assessed the joint effects of germline genetic variations through a pathway-based approach that considers the tissue-specific contexts of GWAS findings. From GWAS meta-analyses of lung cancer (12 160 cases/16 838 controls), breast cancer (15 748 cases/18 084 controls) and prostate cancer (14 160 cases/12 724 controls) in individuals of European ancestry, we determined the tissue-specific interaction networks of proteins expressed from genes that are likely to be affected by disease-associated variants. Reactome pathways exhibiting enrichment of proteins from each network were compared across the cancers. Our results show that pathways associated with all three cancers tend to be broad cellular processes required for growth and survival. Significant examples include the nerve growth factor (P = 7.86 × 10(-33)), epidermal growth factor (P = 1.18 × 10(-31)) and fibroblast growth factor (P = 2.47 × 10(-31)) signaling pathways. However, within these shared pathways, the genes that influence risk largely differ by cancer. Pathways found to be unique for a single cancer focus on more specific cellular functions, such as interleukin signaling in lung cancer (P = 1.69 × 10(-15)), apoptosis initiation by Bad in breast cancer (P = 3.14 × 10(-9)) and cellular responses to hypoxia in prostate cancer (P = 2.14 × 10(-9)). We present the largest comparative cross-cancer pathway analysis of GWAS to date. Our approach can also be applied to the study of inherited mechanisms underlying risk across multiple diseases in general.
Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
David C
DC
Qian
Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Jinyoung
J
Byun
Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.
Younghun
Y
Han
Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA 19104, USA.
Casey S
CS
Greene
Department of Molecular and Clinical Cancer Medicine, University of Liverpool Cancer Research Centre, Liverpool L69 3GA, UK.
John K
JK
Field
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
Rayjean J
RJ
Hung
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
Yonathan
Y
Brhane
Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada.
John R
JR
Mclaughlin
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
Gordon
G
Fehringer
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Maria Teresa
MT
Landi
Department of Genetic Epidemiology, University Medical Centre Göttingen, 37099 Göttingen, Germany.
Albert
A
Rosenberger
Department of Genetic Epidemiology, University Medical Centre Göttingen, 37099 Göttingen, Germany.
Heike
H
Bickeböller
Division of Hematology and Oncology, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
Jyoti
J
Malhotra
Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, 69120 Heidelberg, Germany.
Angela
A
Risch
Institute of Epidemiology I, German Research Center for Environmental Health, 85764 Neuherberg, Germany.
Joachim
J
Heinrich
Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA 02115, USA.
David J
DJ
Hunter
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Brian E
BE
Henderson
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Christopher A
CA
Haiman
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
Fredrick R
FR
Schumacher
Department of Cancer Genetics, Institute of Cancer Research, London SW7 3RP, UK and.
Rosalind A
RA
Eeles
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
Douglas F
DF
Easton
National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Daniela
D
Seminara
Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA, christopher.i.amos@dartmouth.edu.
Christopher I
CI
Amos
D001943:Breast Neoplasms / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics