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 Liloglou; Maria 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

doi:10.1016/j.jtho.2019.04.008

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

Medical School

Research output: Contribution to journal › Article (journal) › peer-review

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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.

Original language	English
Pages (from-to)	1360-1369
Number of pages	10
Journal	Journal of Thoracic Oncology
Volume	14
Issue number	8
DOIs	https://doi.org/10.1016/j.jtho.2019.04.008
Publication status	Published - 1 Aug 2019

Keywords

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

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jtho.2019.04.008

Cite this

Hung, R. J., Spitz, M. R., Houlston, R. S., Schwartz, A. G., Field, J. K., Ying, J., Li, Y., Han, Y., Ji, X., Chen, W., Wu, X., Gorlov, I. P., Na, J., de Andrade, M., Liu, G., Brhane, Y., Diao, N., Wenzlaff, A., Davies, M. P. A., ... Wichmann, H.-E. (2019). Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region. Journal of Thoracic Oncology, 14(8), 1360-1369. https://doi.org/10.1016/j.jtho.2019.04.008

@article{58a1cca9a0ac4b1ead0a3551eec09fa9,

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

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 = "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",

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

year = "2019",

month = aug,

day = "1",

doi = "10.1016/j.jtho.2019.04.008",

language = "English",

volume = "14",

pages = "1360--1369",

journal = "Journal of Thoracic Oncology",

issn = "1556-0864",

publisher = "International Association for the Study of Lung Cancer",

number = "8",

}

Hung, RJ, Spitz, MR, Houlston, RS, Schwartz, AG, Field, JK, Ying, J, Li, Y, Han, Y, Ji, X, Chen, W, Wu, X, Gorlov, IP, Na, J, de Andrade, M, Liu, G, Brhane, Y, Diao, N, Wenzlaff, A, Davies, MPA, Liloglou, T, Timofeeva, M, Muley, T, Rennert, H, Saliba, W, Ryan, BM, Bowman, E, Barros-Dios, J-M, Pérez-Ríos, M, Morgenstern, H, Zienolddiny, S, Skaug, V, Ugolini, D, Bonassi, S, van der Heijden, EHFM, Tardon, A, Bojesen, SE, Landi, MT, Johansson, M, Bickeböller, H, Arnold, S, Le Marchand, L, Melander, O, Andrew, A, Grankvist, K, Caporaso, N, Teare, MD, Schabath, MB, Aldrich, MC, Kiemeney, LA & Wichmann, H-E 2019, 'Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region', Journal of Thoracic Oncology, vol. 14, no. 8, pp. 1360-1369. https://doi.org/10.1016/j.jtho.2019.04.008

TY - JOUR

T1 - Lung Cancer Risk in Never-Smokers of European Descent is Associated With Genetic Variation in the 5p15.33 TERT-CLPTM1Ll Region

AU - Hung, Rayjean J

AU - Spitz, Margaret R

AU - Houlston, Richard S

AU - Schwartz, Ann G

AU - Field, John K

AU - Ying, Jun

AU - Li, Yafang

AU - Han, Younghun

AU - Ji, Xuemei

AU - Chen, Wei

AU - Wu, Xifeng

AU - Gorlov, Ivan P

AU - Na, Jie

AU - de Andrade, Mariza

AU - Liu, Geoffrey

AU - Brhane, Yonathan

AU - Diao, Nancy

AU - Wenzlaff, Angela

AU - Davies, Michael P A

AU - Liloglou, Triantafillos

AU - Timofeeva, Maria

AU - Muley, Thomas

AU - Rennert, Hedy

AU - Saliba, Walid

AU - Ryan, Bríd M

AU - Bowman, Elise

AU - Barros-Dios, Juan-Miguel

AU - Pérez-Ríos, Mónica

AU - Morgenstern, Hal

AU - Zienolddiny, Shanbeh

AU - Skaug, Vidar

AU - Ugolini, Donatella

AU - Bonassi, Stefano

AU - van der Heijden, Erik H F M

AU - Tardon, Adonina

AU - Bojesen, Stig E

AU - Landi, Maria Teresa

AU - Johansson, Mattias

AU - Bickeböller, Heike

AU - Arnold, Susanne

AU - Le Marchand, Loic

AU - Melander, Olle

AU - Andrew, Angeline

AU - Grankvist, Kjell

AU - Caporaso, Neil

AU - Teare, M Dawn

AU - Schabath, Matthew B

AU - Aldrich, Melinda C

AU - Kiemeney, Lambertus A

AU - Wichmann, H-Erich

PY - 2019/8/1

Y1 - 2019/8/1

N2 - 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.

AB - 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.

KW - Case-Control Studies

KW - Chromosomes, Human, Pair 5

KW - Europe/epidemiology

KW - Female

KW - Genetic Predisposition to Disease

KW - Genetic Variation

KW - Genome-Wide Association Study/methods

KW - Genotyping Techniques/methods

KW - Humans

KW - Lung Neoplasms/epidemiology

KW - Membrane Proteins/genetics

KW - Middle Aged

KW - Polymorphism, Single Nucleotide

KW - Risk Factors

KW - Telomerase/genetics

U2 - 10.1016/j.jtho.2019.04.008

DO - 10.1016/j.jtho.2019.04.008

M3 - Article (journal)

C2 - 31009812

SN - 1556-0864

VL - 14

SP - 1360

EP - 1369

JO - Journal of Thoracic Oncology

JF - Journal of Thoracic Oncology

IS - 8

ER -

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

Abstract

Keywords

UN SDGs

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