Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region

Rayjean J Hung, Margaret R Spitz, Richard S Houlston, Ann G Schwartz, John K Field, Jun Ying, Yafang Li, Younghun Han, Xuemei Ji, Wei Chen, Xifeng Wu, Ivan P Gorlov, Jie Na, Mariza de Andrade, Geoffrey Liu, Yonathan Brhane, Nancy Diao, Angela Wenzlaff, Michael P A Davies, Triantafillos LiloglouMaria Timofeeva, Thomas Muley, Hedy Rennert, Walid Saliba, Bríd M Ryan, Elise Bowman, Juan-Miguel Barros-Dios, Mónica Pérez-Ríos, Hal Morgenstern, Shanbeh Zienolddiny, Vidar Skaug, Donatella Ugolini, Stefano Bonassi, Erik H F M van der Heijden, Adonina Tardon, Stig E Bojesen, Maria Teresa Landi, Mattias Johansson, Heike Bickeböller, Susanne Arnold, Loic Le Marchand, Olle Melander, Angeline Andrew, Kjell Grankvist, Neil Caporaso, M Dawn Teare, Matthew B Schabath, Melinda C Aldrich, Lambertus A Kiemeney, H-Erich Wichmann

Research output: Contribution to journalArticle (journal)peer-review

25 Citations (Scopus)


INTRODUCTION: Inherited susceptibility to lung cancer risk in never-smokers is poorly understood. The major reason for this gap in knowledge is that this disease is relatively uncommon (except in Asians), making it difficult to assemble an adequate study sample. In this study we conducted a genome-wide association study on the largest, to date, set of European-descent never-smokers with lung cancer.

METHODS: We conducted a two-phase (discovery and replication) genome-wide association study in never-smokers of European descent. We further augmented the sample by performing a meta-analysis with never-smokers from the recent OncoArray study, which resulted in a total of 3636 cases and 6295 controls. We also compare our findings with those in smokers with lung cancer.

RESULTS: We detected three genome-wide statistically significant single nucleotide polymorphisms rs31490 (odds ratio [OR]: 0.769, 95% confidence interval [CI]: 0.722-0.820; p value 5.31 × 10-16), rs380286 (OR: 0.770, 95% CI: 0.723-0.820; p value 4.32 × 10-16), and rs4975616 (OR: 0.778, 95% CI: 0.730-0.829; p value 1.04 × 10-14). All three mapped to Chromosome 5 CLPTM1L-TERT region, previously shown to be associated with lung cancer risk in smokers and in never-smoker Asian women, and risk of other cancers including breast, ovarian, colorectal, and prostate.

CONCLUSIONS: We found that genetic susceptibility to lung cancer in never-smokers is associated to genetic variants with pan-cancer risk effects. The comparison with smokers shows that top variants previously shown to be associated with lung cancer risk only confer risk in the presence of tobacco exposure, underscoring the importance of gene-environment interactions in the etiology of this disease.

Original languageEnglish
Pages (from-to)1360-1369
Number of pages10
JournalJournal of Thoracic Oncology
Issue number8
Publication statusPublished - 1 Aug 2019


  • Case-Control Studies
  • Chromosomes, Human, Pair 5
  • Europe/epidemiology
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genome-Wide Association Study/methods
  • Genotyping Techniques/methods
  • Humans
  • Lung Neoplasms/epidemiology
  • Membrane Proteins/genetics
  • Middle Aged
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Telomerase/genetics


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