Fulltext

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

Kachuri L 1 , Amos CI 2 , McKay JD 3 , Johansson M 3 , Vineis P 4 , Bueno-de-Mesquita HB 5 Show all authors , Boutron-Ruault MC 6 , Johansson M 7 , Quirós JR 8 , Sieri S 9 , Travis RC 10 , Weiderpass E 11 , Le Marchand L 12 , Henderson BE 12 , Wilkens L 12 , Goodman GE 13 , Chen C 13 , Doherty JA 2 , Christiani DC 14 , Wei Y 15 , Su L 15 , Tworoger S 14 , Zhang X 16 , Kraft P 17 , Zaridze D 18 , Field JK 19 , Marcus MW 19 , Davies MPA 19 , Hyde R 19 , Caporaso NE 20 , Landi MT 20 , Severi G 4 , Giles GG 21 , Liu G 22 , McLaughlin JR 1 , Li Y 2 , Xiao X 2 , Fehringer G 23 , Zong X 23 , Denroche RE 24 , Zuzarte PC 24 , McPherson JD 24 , Brennan P 3 , Hung RJ 1

Affiliations 

  • 1 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario M5T 3L9, Canada
  • 2 Department of Community and Family Medicine , Center for Genomic Medicine , Geisel School of Medicine , Dartmouth College , Lebanon , NH 03766 , USA
  • 3 International Agency for Research on Cancer , Lyon, CEDEX 08, 69372 , France
  • 4 Human Genetics Foundation (HuGeF), 10126 Torino, Italy
  • 5 Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3721 MA Bilthoven, The Netherlands
  • 6 INSERM, Centre for Research in Epidemiology and Population Health (CESP), U1018, Lifestyle, Genes and Health: Integrative Trans-Generational Epidemiology, 94805 Villejuif, France
  • 7 Department of Radiation Sciences , Umeå University , Umeå SE-901 87 , Sweden
  • 8 Public Health Directorate Asturias , CP 33006 Oviedo , Spain
  • 9 Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori , 20133 Milano , Italy
  • 10 Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford , Oxford OX3 7LF , UK
  • 11 Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, 9037 Tromsø, Norway
  • 12 University of Hawaii Cancer Center , Honolulu, HI 96813 , USA
  • 13 Fred Hutchinson Cancer Research Center , Seattle , WA 98109 , USA
  • 14 Departments of Environmental Health and Epidemiology, Harvard School of Public Health, Boston, MA 02115, USA
  • 15 Departments of Environmental Health and Epidemiology, Harvard School of Public Health , Boston, MA 02115 , USA
  • 16 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School , Boston , MA 02115 , USA
  • 17 Departments of Biostatistics and Epidemiology, Harvard School of Public Health , Boston , MA 02115 , USA
  • 18 Russian Cancer Research Center , Moscow 115478 , Russia
  • 19 Roy Castle Lung Cancer Research Programme , University of Liverpool Cancer Research Centre Institute of Translational Medicine , University of Liverpool , Liverpool L69 3BX , UK
  • 20 Division of Cancer Epidemiology and Genetics , National Cancer Institute , National Institutes of Health , Department of Health and Human Services , Bethesda , MD 20892 , USA
  • 21 Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne 3004, Australia
  • 22 Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario M5T 3M7, Canada
  • 23 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital , Toronto , Ontario M5T 3L9 , Canada
  • 24 Genome Technologies, Ontario Institute for Cancer Research , Toronto , Ontario M5G 0A3 , Canada
Carcinogenesis, 2016 Jan;37(1):96-105.
PMID: 26590902 DOI: 10.1093/carcin/bgv165

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

MeSH terms
Similar publications