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Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development
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Abstract
Yafang Li1, Xiangjun Xiao1, Yohan Bossé2, Olga Gorlova3, Ivan Gorlov3, Younghun Han1, Jinyoung Byun1, Natasha Leighl4, Jakob S. Johansen5, Matt Barnett6, Chu Chen6, Gary Goodman7, Angela Cox8, Fiona Taylor8, Penella Woll8, H. Erich Wichmann9, Judith Manz9, Thomas Muley10, Angela Risch11,12,13, Albert Rosenberger14, Jiali Han15, Katherine Siminovitch16, Susanne M. Arnold17, Eric B. Haura18, Ciprian Bolca19, Ivana Holcatova20, Vladimir Janout20, Milica Kontic21, Jolanta Lissowska22, Anush Mukeria23, Simona Ognjanovic24, Tadeusz M. Orlowski25, Ghislaine Scelo26, Beata Swiatkowska27, David Zaridze23, Per Bakke28, Vidar Skaug29, Shanbeh Zienolddiny29, Eric J. Duell30, Lesley M. Butler31, Richard Houlston32, María Soler Artigas33,34, Kjell Grankvist35, Mikael Johansson36, Frances A. Shepherd37, Michael W. Marcus38, Hans Brunnström39, Jonas Manjer40, Olle Melander40, David C. Muller41, Kim Overvad42, Antonia Trichopoulou43, Rosario Tumino44, Geoffrey Liu45, Stig E. Bojesen46,47,48, Xifeng Wu49, Loic Le Marchand50, Demetrios Albanes51, Heike Bickeböller14, Melinda C. Aldrich52, William S. Bush53, Adonina Tardon54, Gad Rennert55, M. Dawn Teare56, John K. Field38, Lambertus A. Kiemeney57, Philip Lazarus58, Aage Haugen59, Stephen Lam60, Matthew B. Schabath61, Angeline S. Andrew62, Pier Alberto Bertazzi63,64, Angela C. Pesatori64, David C. Christiani65, Neil Caporaso51, Mattias Johansson45, James D. McKay45, Paul Brennan45, Rayjean J. Hung26 and Christopher I. Amos66
1 Baylor College of Medicine, Houston, TX, USA
2 Laval University, Quebec, QC, Canada
3 Department of Biomedical Data Science, Dartmouth College, Hanover, NH, USA
4 University Health Network, The Princess Margaret Cancer Centre, Toronto, CA, USA
5 Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark
6 Fred Hutchinson Cancer Research Center, Seattle, WA, USA
7 Swedish Medical Group, Seattle, WA, USA
8 Department of Oncology, University of Sheffield, Sheffield, UK
9 Research Unit of Molecular Epidemiology, Institute of Epidemiology II, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
10 Thoraxklinik at University Hospital Heidelberg, Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany
11 Translational Lung Research Center Heidelberg (TLRC-H), Heidelberg, Germany
12 German Center for Lung Research (DKFZ), Heidelberg, Germany
13 University of Salzburg and Cancer Cluster, Salzburg, Austria
14 Department of Genetic Epidemiology, University Medical Center, Georg-August-University Göttingen, Göttingen, Germany
15 Indiana University, Bloomington, IN, USA
16 University of Toronto, Toronto, ON, Canada
17 University of Kentucky, Markey Cancer Center, Lexington, KY, USA
18 Department of Thoracic Oncology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
19 Institute of Pneumology “Marius Nasta”, Bucharest, Romania
20 Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic
21 Clinical Center of Serbia, School of Medicine, University of Belgrade, Belgrade, Serbia
22 M. Sklodowska-Curie Cancer Center, Institute of Oncology, Warsaw, Poland
23 Department of Epidemiology and Prevention, N.N. Blokhin Russian Cancer Research Center, Moscow, Russian Federation
24 International Organization for Cancer Prevention and Research, Belgrade, Serbia
25 Department of Surgery, National Tuberculosis and Lung Diseases Research Institute, Warsaw, Poland
26 International Agency for Research on Cancer, World Health Organization, Lyon, France
27 Nofer Institute of Occupational Medicine, Department of Environmental Epidemiology, Lodz, Poland
28 Department of Clinical Science, University of Bergen, Bergen, Norway
29 National Institute of Occupational Health, Oslo, Norway
30 Unit of Nutrition and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), Barcelona, Spain
31 University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA
32 The Institute of Cancer Research, London, UK
33 Department of Health Sciences, Genetic Epidemiology Group, University of Leicester, Leicester, UK
34 National Institute for Health Research (NIHR) Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK
35 Department of Medical Biosciences, Umeå University, Umeå, Sweden
36 Department of Radiation Sciences, Umeå University, Umeå, Sweden
37 Princess Margaret Cancer Centre, Toronto, ON, Canada
38 Institute of Translational Medicine, University of Liverpool, Liverpool, UK
39 Department of Pathology, Lund University, Lund, Sweden
40 Faculty of Medicine, Lund University, Lund, Sweden
41 School of Public Health, St. Mary’s Campus, Imperial College London, London, UK
42 Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark
43 Hellenic Health Foundation, Athens, Greece
44 Molecular and Nutritional Epidemiology Unit CSPO (Cancer Research and Prevention Centre), Scientific Institute of Tuscany, Florence, Italy
45 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, University of Toronto, Toronto, Canada
46 Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Denmark
47 Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
48 Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark
49 Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
50 Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA
51 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
52 Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA
53 Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA
54 IUOPA, University of Oviedo and CIBERESP, Faculty of Medicine, Campus del Cristo s/n, Oviedo, Spain
55 Clalit National Cancer Control Center at Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
56 School of Health and Related Research, University of Sheffield, Sheffield, UK
57 Radboud University Medical Center, Nijmegen, The Netherlands
58 Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, USA
59 National Institute of Occupational Health, Oslo, Norway
60 British Columbia Cancer Agency, Vancouver, Canada
61 Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
62 Department of Epidemiology, Geisel School of Medicine, Hanover, NH, USA
63 Department of Preventive Medicine, IRCCS Foundation Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy
64 Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
65 Department of Epidemiology, Program in Molecular and Genetic Epidemiology Harvard School of Public Health, Boston, MA, USA
66 Biomedical Data Science Department, Dartmouth College, Hanover, NH, USA
Correspondence to:
Christopher I. Amos, email: [email protected]
Keywords: epistasis; lung cancer; oncogenesis; functional annotation
Received: October 27, 2018 Accepted: January 22, 2019 Published: March 05, 2019
Abstract
The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterationsand tumorigenesis is triggered by complex networks of involved genes rather than independent actions. To explore the epistasis existing among oncogenesis-related genes in lung cancer development, we conducted pairwise genetic interaction analyses among 35,031 SNPs from 2027 oncogenesis-related genes. The genotypes from three independent genome-wide association studies including a total of 24,037 lung cancer patients and 20,401 healthy controls with Caucasian ancestry were analyzed in the study. Using a two-stage study design including discovery and replication studies, and stringent Bonferroni correction for multiple statistical analysis, we identified significant genetic interactions between SNPs in RGL1:RAD51B (OR=0.44, p value=3.27x10-11 in overall lung cancer and OR=0.41, p value=9.71x10-11 in non-small cell lung cancer), SYNE1:RNF43 (OR=0.73, p value=1.01x10-12 in adenocarcinoma) and FHIT:TSPAN8 (OR=1.82, p value=7.62x10-11 in squamous cell carcinoma) in our analysis. None of these genes have been identified from previous main effect association studies in lung cancer. Further eQTL gene expression analysis in lung tissues provided information supporting the functional role of the identified epistasis in lung tumorigenesis. Gene set enrichment analysis revealed potential pathways and gene networks underlying molecular mechanisms in overall lung cancer as well as histology subtypes development. Our results provide evidence that genetic interactions between oncogenesis-related genes play an important role in lung tumorigenesis and epistasis analysis, combined with functional annotation, provides a valuable tool for uncovering functional novel susceptibility genes that contribute to lung cancer development by interacting with other modifier genes.
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