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Carcinogenesis. 2018 Mar 8;39(3):336-346. doi: 10.1093/carcin/bgx113.

Genome-wide interaction study of smoking behavior and non-small cell lung cancer risk in Caucasian population.

Author information

1
Biomedical Data Science Department, Dartmouth College, Hanover, NH, USA.
2
Department of Medicine, The Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.
3
Department of Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen University, Herlev, Denmark.
4
Public Health Sciences Division, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
5
Public Health Sciences Division, Cancer Prevention Program, Swedish Medical Center, Seattle, WA, USA.
6
Department of Oncology, University of Sheffield, Sheffield UK.
7
Institute of Epidemiology, Helmholtz Centre Munich, Neuherberg, Germany.
8
Biobank and Tumor Documentation, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany.
9
Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
10
Cancer Center Cluster Salzburg at PLUS, Department of Molecular Biology, University of Salzburg, Salzburg, Austria.
11
Department of Genetic Epidemiology, Medical School, Georg-August University of Göttingen, Göttingen, Germany.
12
Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
13
Department of Thoracic Oncology, H. Lee Moffitt Cancer Center, Tampa, FL, USA.
14
Thoracic Surgery Division, "Marius Nasta" National Institute of Pneumology, Bucure?ti, Romania.
15
Faculty of Medicine, University of Ostrava, Ostrava, Czech Republic.
16
Internal Medicine, School of Medicine, Clinical Center of Serbia, University of Belgrade, Belgrade, Serbia.
17
Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center, Institute of Oncology, Warsaw, Pol.
18
Department of Epidemiology and Prevention, Russian N.N. Blokhin Cancer Research Centre, Moscow, Russia.
19
International Organization for Cancer Prevention and Research, Belgrade, Serbia.
20
Department of Thoracic Surgery, National Institute of Tuberculosis and Lung Diseases, Warsaw, Pol.
21
International Agency for Research on Cancer (IARC), Genetic Epidemiology Group, Lyon, France.
22
Department of Environmental Epidemiology, Nofer Institute of Occupational Medicine, Lódz, Pol.
23
Department of Clinical Science, University of Bergen, Bergen, Norway.
24
Department of Toxicology, National Institute of Occupational Health, Oslo, Norway.
25
Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology (ICO-IDIBELL), Hospitalet de Llobregat, Barcelona, Spain.
26
University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA.
27
The Institute of Cancer Research, London, UK.
28
Department of Health Sciences, Genetic Epidemiology Group, University of Leicester, Leicester, UK.
29
Genetic Epidemiology Group, Department of Health Sciences, Leicester Respiratory Biomedical Research Unit, Glenfield Hospital, Leicester, UK.
30
Department of Medical Biosciences, Umeå University, Umeå, Sweden.
31
Department of Radiation Sciences, Umeå University, Umeå, Sweden.
32
Medical Oncology Toronto, Princess Margaret Hospital, Toronto, ON, Canada.
33
Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK.
34
Department of Clinical Sciences, Lund University, Lund, Sweden.
35
Department of Internal Medicine, Skåne University Hospital, Malmö, Sweden.
36
Department of Epidemiology and Biostatistics, Imperial College London, St Mary's Campus, London, UK.
37
Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus C, Denmark.
38
Department of Hygiene and Epidemiology, Medical School, University of Athens, Athens, Greece.
39
Molecular and Nutritional Epidemiology Unit, CSPO (Cancer Research and Prevention Centre), Scientific Institute of Tuscany, Florence, Italy.
40
Princess Margaret Cancer Centre, Toronto, ON M5G, Canada.
41
Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Copenhagen, Denmark.
42
Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
43
Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen, Denmark.
44
Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
45
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, USA.
46
Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, MD, USA.
47
Department of Genetic Epidemiology, University Medical Center, Georg-August University Göttingen, Göttingen, Germany.
48
Department of Thoracic Surgery, Division of Epidemiology, Vanderbilt University Medical Center, Nashville, TN, USA.
49
Department of Epidemiology and Biostatistics, School of Medicine, Case Western Reserve University, Cleveland, OH, USA.
50
Medicina, IUOPA-Universidad de Oviedo, Oviedo, Spain.
51
Technion Faculty of Medicine, Clalit National Cancer Control Center, Carmel Medical Center, Haifa, Israel.
52
Genetic Epidemiology, School of Health and Related Research, University of Sheffield, Sheffield, UK.
53
Institute of Translational Medicine, University of Liverpool, Liverpool, UK.
54
Department for Health Evidence, Radboud University Medical Center, Nijmegen EZ, Netherlands.
55
Department of Pharmaceutical Sciences, College of Pharmacy, Washington State University, Spokane, WA, USA.
56
Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
57
Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.
58
Department of Epidemiology, Norris Cotton Cancer Center, Dartmouth College, Hanover, NH, USA.
59
Department of Preventive Medicine, IRCCS Foundation Cà Granda Ospedale, Maggiore Policlinico, University of Milan, Milan, Italy.
60
Department of Clinical Sciences and Community Health-DISCCO, University of Milan, Milan, Italy.
61
Department of Epidemiology, Harvard School of Public Health, Boston, MA, USA.
62
International Agency for Research on Cancer, World Health Organization, Lyon, France.
63
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada.

Abstract

Non-small cell lung cancer is the most common type of lung cancer. Both environmental and genetic risk factors contribute to lung carcinogenesis. We conducted a genome-wide interaction analysis between single nucleotide polymorphisms (SNPs) and smoking status (never- versus ever-smokers) in a European-descent population. We adopted a two-step analysis strategy in the discovery stage: we first conducted a case-only interaction analysis to assess the relationship between SNPs and smoking behavior using 13336 non-small cell lung cancer cases. Candidate SNPs with P-value <0.001 were further analyzed using a standard case-control interaction analysis including 13970 controls. The significant SNPs with P-value <3.5 × 10-5 (correcting for multiple tests) from the case-control analysis in the discovery stage were further validated using an independent replication dataset comprising 5377 controls and 3054 non-small cell lung cancer cases. We further stratified the analysis by histological subtypes. Two novel SNPs, rs6441286 and rs17723637, were identified for overall lung cancer risk. The interaction odds ratio and meta-analysis P-value for these two SNPs were 1.24 with 6.96 × 10-7 and 1.37 with 3.49 × 10-7, respectively. In addition, interaction of smoking with rs4751674 was identified in squamous cell lung carcinoma with an odds ratio of 0.58 and P-value of 8.12 × 10-7. This study is by far the largest genome-wide SNP-smoking interaction analysis reported for lung cancer. The three identified novel SNPs provide potential candidate biomarkers for lung cancer risk screening and intervention. The results from our study reinforce that gene-smoking interactions play important roles in the etiology of lung cancer and account for part of the missing heritability of this disease.

PMID:
29059373
DOI:
10.1093/carcin/bgx113

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