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Carcinogenesis. 2016 Jan;37(1):96-105. doi: 10.1093/carcin/bgv165. Epub 2015 Nov 20.

Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci.

Author information

1
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada.
2
Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada.
3
Department of Community and Family Medicine , Center for Genomic Medicine , Geisel School of Medicine , Dartmouth College , Lebanon , NH 03766 , USA.
4
International Agency for Research on Cancer , Lyon, CEDEX 08, 69372 , France.
5
Human Genetics Foundation (HuGeF), 10126 Torino, Italy.
6
Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, Norfolk Place, London W2 1PG, UK.
7
Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands.
8
Department of Gastroenterology and Hepatology, University Medical Centre, 3584 CX Utrecht, The Netherlands.
9
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London SW7 2AZ, UK.
10
Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur 50603, Malaysia.
11
INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Lifestyle, Genes and Health: Integrative Trans-Generational Epidemiology, 94805 Villejuif, France.
12
Université Paris Sud, UMRS 1018 94805, Villejuif, France.
13
Institut Gustave Roussy F-94805, Villejuif, France.
14
Department of Radiation Sciences , Umeå University , Umeå SE-901 87 , Sweden.
15
Public Health Directorate Asturias , CP 33006 Oviedo , Spain.
16
Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori , 20133 Milano , Italy.
17
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford , Oxford OX3 7LF , UK.
18
Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, 9037 Tromsø, Norway.
19
Department of Research, Cancer Registry of Norway, 0379 Oslo, Norway.
20
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm SE-171 77, Sweden.
21
Genetic Epidemiology Group, Folkhälsan Research Center, Helsinki FI-00014, Finland.
22
University of Hawaii Cancer Center , Honolulu, HI 96813 , USA.
23
Fred Hutchinson Cancer Research Center , Seattle , WA 98109 , USA.
24
Departments of Environmental Health and Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA.
25
Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
26
Departments of Environmental Health and Epidemiology, Harvard School of Public Health , Boston, MA 02115 , USA.
27
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
28
Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston , MA 02115 , USA.
29
Departments of Biostatistics and Epidemiology, Harvard School of Public Health , Boston , MA 02115 , USA.
30
Russian Cancer Research Center , Moscow 115478 , Russia.
31
Roy Castle Lung Cancer Research Programme , University of Liverpool Cancer Research Centre Institute of Translational Medicine , University of Liverpool , Liverpool L69 3BX , UK.
32
Division of Cancer Epidemiology and Genetics , National Cancer Institute , National Institutes of Health , Department of Health and Human Services , Bethesda , MD 20892 , USA.
33
Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne 3004, Australia.
34
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne 3010, Australia.
35
Department of Epidemiology and Preventive Medicine, Monash University, Melbourne 3004, Australia.
36
Ontario Cancer Institute, Princess Margaret Cancer Center, Toronto, Ontario M5G 0A3, Canada.
37
Public Health Ontario, Toronto, Ontario M5G 1V2, Canada, and.
38
Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital , Toronto , Ontario M5T 3L9 , Canada.
39
Genome Technologies, Ontario Institute for Cancer Research , Toronto , Ontario M5G 0A3 , Canada.

Abstract

Chromosome 5p15.33 has been identified as a lung cancer susceptibility locus, however the underlying causal mechanisms were not fully elucidated. Previous fine-mapping studies of this locus have relied on imputation or investigated a small number of known, common variants. This study represents a significant advance over previous research by investigating a large number of novel, rare variants, as well as their underlying mechanisms through telomere length. Variants for this fine-mapping study were identified through a targeted deep sequencing (average depth of coverage greater than 4000×) of 576 individuals. Subsequently, 4652 SNPs, including 1108 novel SNPs, were genotyped in 5164 cases and 5716 controls of European ancestry. After adjusting for known risk loci, rs2736100 and rs401681, we identified a new, independent lung cancer susceptibility variant in LPCAT1: rs139852726 (OR = 0.46, P = 4.73×10(-9)), and three new adenocarcinoma risk variants in TERT: rs61748181 (OR = 0.53, P = 2.64×10(-6)), rs112290073 (OR = 1.85, P = 1.27×10(-5)), rs138895564 (OR = 2.16, P = 2.06×10(-5); among young cases, OR = 3.77, P = 8.41×10(-4)). In addition, we found that rs139852726 (P = 1.44×10(-3)) was associated with telomere length in a sample of 922 healthy individuals. The gene-based SKAT-O analysis implicated TERT as the most relevant gene in the 5p15.33 region for adenocarcinoma (P = 7.84×10(-7)) and lung cancer (P = 2.37×10(-5)) risk. In this largest fine-mapping study to investigate a large number of rare and novel variants within 5p15.33, we identified novel lung and adenocarcinoma susceptibility loci with large effects and provided support for the role of telomere length as the potential underlying mechanism.

PMID:
26590902
PMCID:
PMC4715236
DOI:
10.1093/carcin/bgv165
[Indexed for MEDLINE]
Free PMC Article

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