. 2019 Aug;14(8):1360-1369.

doi: 10.1016/j.jtho.2019.04.008. Epub 2019 Apr 19.

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5_p15.33 TERT-CLPTM1Ll Region

Rayjean J Hung¹, Margaret R Spitz², Richard S Houlston³, Ann G Schwartz⁴, John K Field⁵, Jun Ying⁶, Yafang Li², Younghun Han², Xuemei Ji⁷, Wei Chen⁸, Xifeng Wu⁸, Ivan P Gorlov⁷, Jie Na⁹, Mariza de Andrade⁹, Geoffrey Liu¹⁰, Yonathan Brhane¹, Nancy Diao¹¹, Angela Wenzlaff⁴, Michael P A Davies⁵, Triantafillos Liloglou⁵, Maria Timofeeva¹², Thomas Muley¹³, Hedy Rennert¹⁴, Walid Saliba¹⁴, Bríd M Ryan¹⁵, Elise Bowman¹⁵, Juan-Miguel Barros-Dios¹⁶, Mónica Pérez-Ríos¹⁶, Hal Morgenstern¹⁷, Shanbeh Zienolddiny¹⁸, Vidar Skaug¹⁸, Donatella Ugolini¹⁹, Stefano Bonassi²⁰, Erik H F M van der Heijden²¹, Adonina Tardon²², Stig E Bojesen²³, Maria Teresa Landi²⁴, Mattias Johansson²⁵, Heike Bickeböller²⁶, Susanne Arnold²⁷, Loic Le Marchand²⁸, Olle Melander²⁹, Angeline Andrew³⁰, Kjell Grankvist³¹, Neil Caporaso²⁴, M Dawn Teare³², Matthew B Schabath³³, Melinda C Aldrich³⁴, Lambertus A Kiemeney²¹, H-Erich Wichmann³⁵, Philip Lazarus³⁶, Jose Mayordomo³⁷, Monica Neri³⁸, Aage Haugen¹⁸, Zuo-Feng Zhang³⁹, Alberto Ruano-Raviña¹⁶, Hermann Brenner⁴⁰, Curtis C Harris¹⁵, Irene Orlow⁴¹, Gadi Rennert¹⁴, Angela Risch⁴², Paul Brennan²⁵, David C Christiani¹¹, Christopher I Amos², Ping Yang⁴³, Olga Y Gorlova⁴⁴

Affiliations

¹ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
² Baylor College of Medicine, Houston, Texas.
³ Institute of Cancer Research, London, United Kingdom.
⁴ Wayne State University, Detroit, Michigan.
⁵ University of Liverpool, Liverpool, United Kingdom.
⁶ University of Texas McGovern Medical School, Houston, Texas.
⁷ Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
⁸ The University of Texas, MD Anderson Cancer Center, Houston, Texas.
⁹ Mayo Clinic, Rochester, Minnesota.
¹⁰ Princess Margaret Cancer Center, Toronto, Ontario, Canada.
¹¹ Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
¹² German Cancer Research Center (DKFZ), Heidelberg, Germany; University of Edinburgh, Edinburgh, United Kingdom.
¹³ German Center for Lung Research, Heidelberg, Germany; University Hospital Heidelberg, Heidelberg, Germany.
¹⁴ Technion-Israel Institute of Technology, Haifa, Israel.
¹⁵ Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
¹⁶ University of Santiago de Compostela, Praza do Obradoiro, Coruña, Spain.
¹⁷ Medical School, University of Michigan, Ann Arbor, Michigan.
¹⁸ National Institute of Occupational Health (STAMI), Oslo, Norway.
¹⁹ University of Genoa, Genoa, Italy.
²⁰ San Raffaele University, Rome, Italy; San Raffaele Pisana - Scientific Hospitalization and Care Insitution, Rome, Italy.
²¹ Radboud University Medical Center, Nijmegen, Netherlands.
²² University of Oviedo and CIBERESP, Oviedo, Spain.
²³ Copenhagen University Hospital, Copenhagen, Denmark.
²⁴ National Cancer Institute, Bethesda, Maryland.
²⁵ International Agency for Research on Cancer, Lyon, France.
²⁶ University Medical Center Goettingen, Goettingen, Germany.
²⁷ University of Kentucky, Lexington, Kentucky.
²⁸ University of Hawaii Cancer Center, Honolulu, Hawaii.
²⁹ Lund University, Lund, Sweden.
³⁰ Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
³¹ Umeå University, Umeå, Sweden.
³² University of Sheffield, Sheffield, United Kingdom.
³³ H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
³⁴ Vanderbilt University Medical Center, Nashville, Tennessee.
³⁵ Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Bavaria, Germany.
³⁶ Washington State University, Spokane, Washington.
³⁷ University of Colorado, Aurora, Colorado.
³⁸ San Raffaele Pisana - Scientific Hospitalization and Care Insitution, Rome, Italy.
³⁹ University of California - Los Angeles, Los Angeles, California.
⁴⁰ German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴¹ Memorial Sloan Kettering Cancer Center, New York, New York.
⁴² German Cancer Research Center (DKFZ), Heidelberg, Germany; University of Salzburg, Salzburg, Austria; Cancer Cluster Salzburg, Salzburg, Austria.
⁴³ Mayo Clinic, Scottsdale, Arizona.
⁴⁴ Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Electronic address: olga.y.gorlova@dartmouth.edu.

PMID: 31009812
PMCID: PMC6833942
DOI: 10.1016/j.jtho.2019.04.008

Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5_p15.33 TERT-CLPTM1Ll Region

Rayjean J Hung et al. J Thorac Oncol. 2019 Aug.

. 2019 Aug;14(8):1360-1369.

doi: 10.1016/j.jtho.2019.04.008. Epub 2019 Apr 19.

Authors

Affiliations

¹ Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Ontario, Canada.
² Baylor College of Medicine, Houston, Texas.
³ Institute of Cancer Research, London, United Kingdom.
⁴ Wayne State University, Detroit, Michigan.
⁵ University of Liverpool, Liverpool, United Kingdom.
⁶ University of Texas McGovern Medical School, Houston, Texas.
⁷ Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire.
⁸ The University of Texas, MD Anderson Cancer Center, Houston, Texas.
⁹ Mayo Clinic, Rochester, Minnesota.
¹⁰ Princess Margaret Cancer Center, Toronto, Ontario, Canada.
¹¹ Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
¹² German Cancer Research Center (DKFZ), Heidelberg, Germany; University of Edinburgh, Edinburgh, United Kingdom.
¹³ German Center for Lung Research, Heidelberg, Germany; University Hospital Heidelberg, Heidelberg, Germany.
¹⁴ Technion-Israel Institute of Technology, Haifa, Israel.
¹⁵ Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
¹⁶ University of Santiago de Compostela, Praza do Obradoiro, Coruña, Spain.
¹⁷ Medical School, University of Michigan, Ann Arbor, Michigan.
¹⁸ National Institute of Occupational Health (STAMI), Oslo, Norway.
¹⁹ University of Genoa, Genoa, Italy.
²⁰ San Raffaele University, Rome, Italy; San Raffaele Pisana - Scientific Hospitalization and Care Insitution, Rome, Italy.
²¹ Radboud University Medical Center, Nijmegen, Netherlands.
²² University of Oviedo and CIBERESP, Oviedo, Spain.
²³ Copenhagen University Hospital, Copenhagen, Denmark.
²⁴ National Cancer Institute, Bethesda, Maryland.
²⁵ International Agency for Research on Cancer, Lyon, France.
²⁶ University Medical Center Goettingen, Goettingen, Germany.
²⁷ University of Kentucky, Lexington, Kentucky.
²⁸ University of Hawaii Cancer Center, Honolulu, Hawaii.
²⁹ Lund University, Lund, Sweden.
³⁰ Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire.
³¹ Umeå University, Umeå, Sweden.
³² University of Sheffield, Sheffield, United Kingdom.
³³ H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.
³⁴ Vanderbilt University Medical Center, Nashville, Tennessee.
³⁵ Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Bavaria, Germany.
³⁶ Washington State University, Spokane, Washington.
³⁷ University of Colorado, Aurora, Colorado.
³⁸ San Raffaele Pisana - Scientific Hospitalization and Care Insitution, Rome, Italy.
³⁹ University of California - Los Angeles, Los Angeles, California.
⁴⁰ German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁴¹ Memorial Sloan Kettering Cancer Center, New York, New York.
⁴² German Cancer Research Center (DKFZ), Heidelberg, Germany; University of Salzburg, Salzburg, Austria; Cancer Cluster Salzburg, Salzburg, Austria.
⁴³ Mayo Clinic, Scottsdale, Arizona.
⁴⁴ Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire. Electronic address: olga.y.gorlova@dartmouth.edu.

PMID: 31009812
PMCID: PMC6833942
DOI: 10.1016/j.jtho.2019.04.008

Abstract

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.

Keywords: Genetic susceptibility; Genome-wide association study; Lung cancer; Never smokers.

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Conflict of interest statement

The authors declare that none of them has a conflict of interest

Figures

**Figure 1.**
Manhattan plot of the association analysis of lung cancer in European ancestry never smokers performed jointly in the discovery set and the OncoArray samples. The x-axis is chromosomal position, and the y-axis is the statistical significance on a –log₁₀ scale.

**Figure 2.**
Regional association plots for smokers (red line) and never smokers (blue line) in *CLPTM1L-TERT* region (a) and *CHRNA3-5* region (b). The y axis corresponds to –log₁₀P for 650 SNPs in the *CLPTM1L-TERT* region and –log₁₀P for 535 SNPs in *CHRNA3-5* region. To aid visual representation we selected the 10 closest SNP and computed average –log₁₀P- values.

See this image and copyright information in PMC

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Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5_p15.33 TERT-CLPTM1Ll Region

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Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5_p15.33 TERT-CLPTM1Ll Region

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