Priority Research Papers:

Genetic interaction analysis among oncogenesis-related genes revealed novel genes and networks in lung cancer development

Yafang Li _, Xiangjun Xiao, Yohan Bossé, Olga Gorlova, Ivan Gorlov, Younghun Han, Jinyoung Byun, Natasha Leighl, Jakob S. Johansen, Matt Barnett, Chu Chen, Gary Goodman, Angela Cox, Fiona Taylor, Penella Woll, H.-Erich Wichmann, Judith Manz, Thomas Muley, Angela Risch, Albert Rosenberger, Jiali Han, Katherine Siminovitch, Susanne M. Arnold, Eric B. Haura, Ciprian Bolca, Ivana Holcatova, Vladimir Janout, Milica Kontic, Jolanta Lissowska, Anush Mukeria, Simona Ognjanovic, Tadeusz M. Orlowski, Ghislaine Scelo, Beata Swiatkowska, David Zaridze, Per Bakke, Vidar Skaug, Shanbeh Zienolddiny, Eric J. Duell, Lesley M. Butler, Richard Houlston, María Soler Artigas, Kjell Grankvist, Mikael Johansson, Frances A. Shepherd, Michael W. Marcus, Hans Brunnström, Jonas Manjer, Olle Melander, David C. Muller, Kim Overvad, Antonia Trichopoulou, Rosario Tumino, Geoffrey Liu, Stig E. Liu, Xifeng Wu, Loic Le Marchand, Demetrios Albanes, Heike Bickeböller, Melinda C. Aldrich, William S. Bush, Adonina Tardon, Gad Rennert, M. Dawn Teare, John K. Field, Lambertus A. Kiemeney, Philip Lazarus, Aage Haugen, Stephen Lam, Matthew B. Schabath, Angeline S. Andrew, Pier Alberto Bertazzi, Angela C. Pesatori, David C. Christiani, Neil Caporaso, Mattias Johansson, James D. McKay, Paul Brennan, Rayjean J. Hung and Christopher I. Amos

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Oncotarget. 2019; 10:1760-1774. https://doi.org/10.18632/oncotarget.26678

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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


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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