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Grant Details

Grant Number: 5R01CA151989-04 Interpret this number
Primary Investigator: Doherty, Jennifer
Organization: Fred Hutchinson Cancer Research Center
Project Title: Telomeres and Lung Cancer Incidence and Survival
Fiscal Year: 2014


Abstract

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer incidence and death worldwide. Once diagnosed with lung cancer, only 15% of individuals survive longer than five years. Tobacco-smoking is estimated to be responsible for 85- 90% of lung cancer cases, but fewer than 20% of smokers develop lung cancer, suggesting that other factors may play a predisposing role. Recently, several large-scale genome-wide association studies have reported that SNPs in the telomerase reverse transcriptase (TERT) gene are strongly associated with lung cancer risk. TERT is a telomere maintenance gene, and is often a site of chromosomal abnormalities in lung tumors. Telomeres, located at the ends of chromosomes, protect the genetic integrity of cells. They progressively shorten with every cell division, and after they reach a critically short length, the cell will undergo apoptosis or cellular senescence. Alternatively, critically short telomeres can cause chromosomal instability and fusions, allowing the accumulation of genetic changes in favor of carcinogenesis. While three case-control studies have observed that shorter telomere length was associated with lung cancer risk, longer telomere length (measured prior to lung cancer diagnosis) was associated with increased lung cancer risk in a nested case- control study. Given the discrepant but suggestive findings from these four studies, additional studies are needed to elucidate the role of telomere length in lung cancer development. It is possible that shortening of specific chromosomes is associated with an increased risk of lung cancer, though this has not been studied previously. Also, no studies to date have examined lymphocyte telomere length and lung cancer survival. In a nested case-control study (n=790 cases, 1,558 controls) within the Carotene and Retinol Efficacy Trial, a cohort of heavy smokers with blood samples collected prospectively, we propose to examine: whether global, and chromosome-arm-specific, telomere length measured in samples collected prior to lung cancer diagnosis are associated with lung cancer risk; whether approximately 400 tag and putative functional SNPs in TERT and other telomere maintenance-related genes are associated with lung cancer risk; and whether telomere length and variation in telomere maintenance genes are associated with survival among individuals who develop lung cancer. A large, prospective study among smokers such as the one proposed will provide evidence that will aid in clarifying whether telomere length is associated with lung cancer risk and/or survival. If either global or chromosome-specific telomere length is associated with lung cancer risk, this measurement could possibly be developed to identify a subset of individuals at particularly high risk of lung cancer, among the high-risk population of smokers.



Publications

AHRR methylation in heavy smokers: associations with smoking, lung cancer risk, and lung cancer mortality.
Authors: Grieshober L. , Graw S. , Barnett M.J. , Thornquist M.D. , Goodman G.E. , Chen C. , Koestler D.C. , Marsit C.J. , Doherty J.A. .
Source: BMC cancer, 2020-09-22; 20(1), p. 905.
EPub date: 2020-09-22.
PMID: 32962699
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Protein-altering germline mutations implicate novel genes related to lung cancer development.
Authors: Ji X. , Mukherjee S. , Landi M.T. , Bosse Y. , Joubert P. , Zhu D. , Gorlov I. , Xiao X. , Han Y. , Gorlova O. , et al. .
Source: Nature communications, 2020-05-11; 11(1), p. 2220.
EPub date: 2020-05-11.
PMID: 32393777
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Immune-mediated genetic pathways resulting in pulmonary function impairment increase lung cancer susceptibility.
Authors: Kachuri L. , Johansson M. , Rashkin S.R. , Graff R.E. , Bossé Y. , Manem V. , Caporaso N.E. , Landi M.T. , Christiani D.C. , Vineis P. , et al. .
Source: Nature communications, 2020-01-07; 11(1), p. 27.
EPub date: 2020-01-07.
PMID: 31911640
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Mendelian Randomization and mediation analysis of leukocyte telomere length and risk of lung and head and neck cancers.
Authors: Kachuri L. , Saarela O. , Bojesen S.E. , Davey Smith G. , Liu G. , Landi M.T. , Caporaso N.E. , Christiani D.C. , Johansson M. , Panico S. , et al. .
Source: International journal of epidemiology, 2019-06-01; 48(3), p. 751-766.
PMID: 30059977
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Elevated Platelet Count Appears to Be Causally Associated with Increased Risk of Lung Cancer: A Mendelian Randomization Analysis.
Authors: Zhu Y. , Wei Y. , Zhang R. , Dong X. , Shen S. , Zhao Y. , Bai J. , Albanes D. , Caporaso N.E. , Landi M.T. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2019 05; 28(5), p. 935-942.
EPub date: 2019-01-30.
PMID: 30700444
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Shared heritability and functional enrichment across six solid cancers.
Authors: Jiang X. , Finucane H.K. , Schumacher F.R. , Schmit S.L. , Tyrer J.P. , Han Y. , Michailidou K. , Lesseur C. , Kuchenbaecker K.B. , Dennis J. , et al. .
Source: Nature communications, 2019-01-25; 10(1), p. 431.
EPub date: 2019-01-25.
PMID: 30683880
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Methylation-derived Neutrophil-to-Lymphocyte Ratio and Lung Cancer Risk in Heavy Smokers.
Authors: Grieshober L. , Graw S. , Barnett M.J. , Thornquist M.D. , Goodman G.E. , Chen C. , Koestler D.C. , Marsit C.J. , Doherty J.A. .
Source: Cancer prevention research (Philadelphia, Pa.), 2018 11; 11(11), p. 727-734.
EPub date: 2018-09-25.
PMID: 30254071
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Identification of susceptibility pathways for the role of chromosome 15q25.1 in modifying lung cancer risk.
Authors: Ji X. , Bossé Y. , Landi M.T. , Gui J. , Xiao X. , Qian D. , Joubert P. , Lamontagne M. , Li Y. , Gorlov I. , et al. .
Source: Nature communications, 2018-08-13; 9(1), p. 3221.
EPub date: 2018-08-13.
PMID: 30104567
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Telomere Length and Lung Cancer Mortality among Heavy Smokers.
Authors: Doherty J.A. , Grieshober L. , Houck J.R. , Barnett M.J. , Tapsoba J.D. , Thornquist M. , Wang C.Y. , Goodman G.E. , Chen C. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2018 07; 27(7), p. 829-837.
EPub date: 2018-05-09.
PMID: 29743162
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Large-scale association analysis identifies new lung cancer susceptibility loci and heterogeneity in genetic susceptibility across histological subtypes.
Authors: McKay J.D. , Hung R.J. , Han Y. , Zong X. , Carreras-Torres R. , Christiani D.C. , Caporaso N.E. , Johansson M. , Xiao X. , Li Y. , et al. .
Source: Nature genetics, 2017 Jul; 49(7), p. 1126-1132.
EPub date: 2017-06-12.
PMID: 28604730
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Obesity, metabolic factors and risk of different histological types of lung cancer: A Mendelian randomization study.
Authors: Carreras-Torres R. , Johansson M. , Haycock P.C. , Wade K.H. , Relton C.L. , Martin R.M. , Davey Smith G. , Albanes D. , Aldrich M.C. , Andrew A. , et al. .
Source: PloS one, 2017; 12(6), p. e0177875.
EPub date: 2017-06-08.
PMID: 28594918
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Telomere structure and maintenance gene variants and risk of five cancer types.
Authors: Karami S. , Han Y. , Pande M. , Cheng I. , Rudd J. , Pierce B.L. , Nutter E.L. , Schumacher F.R. , Kote-Jarai Z. , Lindstrom S. , et al. .
Source: International journal of cancer, 2016-12-15; 139(12), p. 2655-2670.
EPub date: 2016-09-08.
PMID: 27459707
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Genetic variant in DNA repair gene GTF2H4 is associated with lung cancer risk: a large-scale analysis of six published GWAS datasets in the TRICL consortium.
Authors: Wang M. , Liu H. , Liu Z. , Yi X. , Bickeboller H. , Hung R.J. , Brennan P. , Landi M.T. , Caporaso N. , Christiani D.C. , et al. .
Source: Carcinogenesis, 2016 09; 37(9), p. 888-896.
EPub date: 2016-06-10.
PMID: 27288692
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A Cross-Cancer Genetic Association Analysis of the DNA Repair and DNA Damage Signaling Pathways for Lung, Ovary, Prostate, Breast, and Colorectal Cancer.
Authors: Scarbrough P.M. , Weber R.P. , Iversen E.S. , Brhane Y. , Amos C.I. , Kraft P. , Hung R.J. , Sellers T.A. , Witte J.S. , Pharoah P. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2016 Jan; 25(1), p. 193-200.
EPub date: 2015-12-04.
PMID: 26637267
Related Citations

Fine mapping of chromosome 5p15.33 based on a targeted deep sequencing and high density genotyping identifies novel lung cancer susceptibility loci.
Authors: Kachuri L. , Amos C.I. , McKay J.D. , Johansson M. , Vineis P. , Bueno-de-Mesquita H.B. , Boutron-Ruault M.C. , Johansson M. , Quirós J.R. , Sieri S. , et al. .
Source: Carcinogenesis, 2016 Jan; 37(1), p. 96-105.
EPub date: 2015-11-20.
PMID: 26590902
Related Citations

Genetic determinants of telomere length and risk of common cancers: a Mendelian randomization study.
Authors: Zhang C. , Doherty J.A. , Burgess S. , Hung R.J. , Lindström S. , Kraft P. , Gong J. , Amos C.I. , Sellers T.A. , Monteiro A.N. , et al. .
Source: Human molecular genetics, 2015-09-15; 24(18), p. 5356-66.
EPub date: 2015-07-02.
PMID: 26138067
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