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Oncotarget. 2019 Mar 5;10(19):1760-1774. doi: 10.18632/oncotarget.26678. eCollection 2019 Mar 5.

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

Author information

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
British Columbia Cancer Agency, Vancouver, Canada.
60
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
61
Department of Epidemiology, Geisel School of Medicine, Hanover, NH, USA.
62
Department of Preventive Medicine, IRCCS Foundation Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy.
63
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy.
64
Department of Epidemiology, Program in Molecular and Genetic Epidemiology Harvard School of Public Health, Boston, MA, USA.
65
Biomedical Data Science Department, Dartmouth College, Hanover, NH, USA.

Abstract

The development of cancer is driven by the accumulation of many oncogenesis-related genetic alterations and 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.

KEYWORDS:

epistasis; functional annotation; lung cancer; oncogenesis

Conflict of interest statement

CONFLICTS OF INTEREST The authors whose names are listed above certify that they have NO affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.

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