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J Thorac Oncol. 2019 Apr 19. pii: S1556-0864(19)30289-8. doi: 10.1016/j.jtho.2019.04.008. [Epub ahead of print]

Lung Cancer Risk in Never Smokers of European Descent is Associated with Genetic Variation in the 5P15.33 TERT-CLPTM1L Region.

Author information

1
Lunenfeld-Tanenbaum Research Institute, Sinai Health System, 60 Murray Street, Toronto, ON M5T 3L9, Canada.
2
Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
3
Institute of Cancer Research, 123 Old Brompton Road, London, SW7 3RP, UK.
4
Wayne State University, 4100 John R, Detroit, MI 48201, USA.
5
University of Liverpool, The Wiliam Duncan Building, 6 West Derby Street , Liverpool, L69 3BX, UK.
6
University of Texas McGovern Medical School, 6431 Fannin Street, Houston, TX 77030, USA.
7
Geisel School of Medicine at Dartmouth, 1 Medical Center Dr, Lebanon, NH 03756, USA.
8
The University of Texas, MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.
9
Mayo Clinic, 200 First Street SW , Rochester, MN 55905, USA.
10
Princess Margaret Cancer Center, Room 7 - 207, 610 University Avenue, Toronto, ON M5G 2M9, Canada.
11
Harvard T.H. Chan School of Public Health, 665 Huntington Ave, Boston, MA 2115, USA.
12
German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; University of Edinburgh, 4th Floor MRC-HGU, Crewe Road, Edinburgh, EH4 2XU, UK.
13
German Center for Lung Research, Im Neuenheimer Feld 110, Heidelberg, 69120, Germany; University Hospital Heidelberg, Im Neuenheimer Feld 110, Heidelberg, 69120, Germany.
14
Technion-Israel Institute of Technology, 7 Michal St, Haifa, 3436212, Israel.
15
Centre for Cancer Research, NCI, 37 Convent Dr, Bethesda, MD 20892, USA.
16
University of Santiago de Compostela, Praza do Obradoiro, 0, Santiago de Compostela, A Coruña 15705, Spain.
17
Medical School, University of Michigan, 1301 Catherine Road, Ann Arbor, MI 48109, USA.
18
National Institute of Occupational Health (STAMI), Gydas vei 8, Oslo, 0033, Norway.
19
University of Genoa, L.go R. Benzi, 10, Genoa, 16132, Italy.
20
San Raffaele University, Via di Val Cannuta, 247, Rome, 00166, Italy; San Raffaele Pisana - Scientific Hospitalization and Care Insitution, Via di Val Cannuta, 247, Rome, 00166, Italy.
21
Radboud University Medical Center, P.O.Box 9101, 6500 HB , Nijmegen, 614, The Netherlands.
22
University of Oviedo and CIBERESP, Campus del Cristo s/n, Oviedo, 33006, Spain.
23
Copenhagen University Hospital, Herlev Ringvej 75, 2730 Herlev, Blegdamsvej 3, Copenhagen, 2200, Denmark.
24
National Cancer Institute, 37 Convent Dr, Bethesda, MD 20892, USA.
25
International Agency for Research on Cancer, 150 Cours Albert Thomas, Lyon, 69372 CEDEX 08, France.
26
University Medical Center Goettingen, Humboldtallee 32, Goettingen, 37073, Germany.
27
University of Kentucky, First Floor, 800 Rose Street, Lexington, KY 40508, USA.
28
University of Hawaii Cancer Center, 701 Ilalo Street , Honolulu, HI 96813, USA.
29
Lund University, Box 117, Lund, 221 00, Sweden.
30
Dartmouth-Hitchcock Medical Center, 1 Medical Center Drive, Lebanon, NH 03756, USA.
31
Umeå University, By 6M van 2, Sjukhusomradet, Umeå, 901 85, Sweden.
32
University of Sheffield, 30 Regent Street, Sheffield, S1 4DA, UK.
33
H. Lee Moffitt Cancer Center and Research Institute, 12902, Magnolia Drive, Tampa, FL 33612, USA.
34
Vanderbilt University Medical Center, 609 Oxford House, Nashville, TN 37232, USA.
35
Helmholtz Zentrum Munchen, German Research Center for Environmental Health (GmbH), Ingolstadter Landstr. 1, Neuherberg, Bavaria 85764, Germany.
36
Washington State University, PBS 431 PO Box 1495, Spokane, WA 99210, USA.
37
University of Colorado, 13001 E. 17th Place, Campus Box C290, Aurora, CO 80045, USA.
38
San Raffaele Pisana - Scientific Hospitalization and Care Insitution, Via di Val Cannuta, 247, Rome, 00166, Italy.
39
University of California - Los Angeles, 650 Charles E. Young Dr. South, Los Angeles, CA 90095, USA.
40
German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany.
41
Memorial Sloan Kettering Cancer Center, 1275 York Ave, Box 353, New York, NY 10065, USA.
42
German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, 69120, Germany; University of Salzburg, Billrothstrasse 11, Salzburg, 5020, Austria; Cancer Cluster Salzburg, Müllner Hauptstraße 48 , Salzburg, 5020, Austria.
43
Mayo Clinic, 13400 E. Shea Blvd, Scottsdale, AZ 85259, USA.
44
Geisel School of Medicine at Dartmouth, 1 Medical Center Dr, Lebanon, NH 03756, USA. Electronic address: olga.y.gorlova@dartmouth.edu.

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 (GWAS) on the largest, to date, set of European-descent never smokers with lung cancer.

METHODS:

We conducted a two-phase (discovery and replication) GWAS 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 3,636 cases and 6,295 controls. We also compare our findings with those in smokers with lung cancer.

RESULTS:

We detected three genome-wide statistically significant SNPs rs31490 (OR 0.769, 95% confidence interval (CI) [0.722-0.820], p-value 5.31x10-16), rs380286 (OR 0.770, 95% CI [0.723-0.820], p-value 4.32x10-16), and rs4975616 (OR 0.778, 95% CI [0.730-0.829], p-value 1.04x10-14). 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.

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