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Telomere structure and maintenance gene variants and risk of five cancer types.

About this Publication
Title
Telomere structure and maintenance gene variants and risk of five cancer types.
Pubmed ID
27459707 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Int. J. Cancer. 2016 Dec; Volume 139 (Issue 12): Pages 2655-2670
Authors
Karami S, Han Y, Pande M, Cheng I, Rudd J, Pierce BL, Nutter EL, Schumacher FR, Kote-Jarai Z, Lindstrom S, Witte JS, Fang S, Han J, Kraft P, Hunter DJ, Song F, Hung RJ, McKay J, Gruber SB, Chanock SJ, ...show more Risch A, Shen H, Haiman CA, Boardman L, Ulrich CM, Casey G, Peters U, Amin Al Olama A, Berchuck A, Berndt SI, Bezieau S, Brennan P, Brenner H, Brinton L, Caporaso N, Chan AT, Chang-Claude J, Christiani DC, Cunningham JM, Easton D, Eeles RA, Eisen T, Gala M, Gallinger SJ, Gayther SA, Goode EL, Grönberg H, Henderson BE, Houlston R, Joshi AD, Küry S, Landi MT, Le Marchand L, Muir K, Newcomb PA, Permuth-Wey J, Pharoah P, Phelan C, Potter JD, Ramus SJ, Risch H, Schildkraut J, Slattery ML, Song H, Wentzensen N, White E, Wiklund F, Zanke BW, Sellers TA, Zheng W, Chatterjee N, Amos CI, Doherty JA, GECCO and the GAME-ON Network: CORECT, DRIVE, ELLIPSE, FOCI, and TRICL
Affiliations
  • Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH.
  • The Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH.
  • Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, TX.
  • Cancer Prevention Institute of California, Fremont, CA; Stanford Cancer Institute, Stanford, CA.
  • Departments of Public Health Sciences and Human Genetics and Comprehensive Cancer Center, The University of Chicago, Chicago, IL.
  • Department of Preventive Medicine, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA.
  • Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, United Kingdom.
  • Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. School of Public Health, Boston, MA.
  • Division of Genetic and Cancer Epidemiology, Department of Epidemiology and Biostatistics and Institute of Human Genetics, University of California, San Francisco, CA.
  • Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.
...show more
  • Department of Epidemiology, Fairbanks School of Public Health, Simon Cancer Center, Indiana University, Indianapolis, IN.
  • Department of Epidemiology and Biostatistics, Harvard School of Public Health, Boston, MA.
  • Department of Epidemiology and Biostatistics, Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Centre of Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.
  • Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada.
  • Genetic Cancer Susceptibility Group, Genetic Epidemiology Group International Agency for Research on Cancer (IARC), Lyon, France.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD.
  • Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center (DKFZ), Heidelberg, Germany; Translational Lung Research Center Heidelberg (TLRC-H), Member of the German Center for Lung Research (DZL), Heidelberg, Germany.
  • Department of Epidemiology and Biostatistics, Collaborative Innovation Center for Cancer Medicine, Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, School of Public Health, Nanjing Medical University, Nanjing, People's Republic of China.
  • Mayo Clinic, Rochester, MN.
  • Huntsman Cancer Institute, Salt Lake City, UT.
  • Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA.
  • Department of Public Health and Primary Care, Center for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.
  • Department of Obstetrics and Gynecology, Duke University, Durham, NC.
  • Service de Génétique Médicale, CHU Nantes, Nantes, France.
  • Klinische Epidemiologie und Alternsforschung, Deutsches Krebsforschungszentrum, Heidelberg, Germany.
  • Division of Gastroenterology, Massachusetts General Hospital, Boston, MA.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
  • Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge, United Kingdom.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden.
  • The Institute of Cancer Research, London, United Kingdom.
  • Division of Epidemiology, University of Hawaii Cancer Center, Honolulu, HI.
  • Warwick Medical School, University of Warwick, Coventry, United Kingdom.
  • H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL.
  • Department of Oncology, University of Cambridge, Cambridge, United Kingdom.
  • Yale School of Public Health, New Haven, CT.
  • University of Virginia, Charlottesville, VA.
  • Division of Hematology, The University of Ottawa, Ottawa Hospital Research Institute, Ottawa, ON.
  • Vanderbilt Epidemiology Center and Division of Epidemiology, Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN.
  • Department of Epidemiology, Geisel School of Medicine at Dartmouth, Lebanon, NH. Jennifer.A.Doherty@Dartmouth.edu.
Abstract

Telomeres cap chromosome ends, protecting them from degradation, double-strand breaks, and end-to-end fusions. Telomeres are maintained by telomerase, a reverse transcriptase encoded by TERT, and an RNA template encoded by TERC. Loci in the TERT and adjoining CLPTM1L region are associated with risk of multiple cancers. We therefore investigated associations between variants in 22 telomere structure and maintenance gene regions and colorectal, breast, prostate, ovarian, and lung cancer risk. We performed subset-based meta-analyses of 204,993 directly-measured and imputed SNPs among 61,851 cancer cases and 74,457 controls of European descent. Independent associations for SNP minor alleles were identified using sequential conditional analysis (with gene-level p value cutoffs ≤3.08 × 10-5 ). Of the thirteen independent SNPs observed to be associated with cancer risk, novel findings were observed for seven loci. Across the DCLRE1B region, rs974494 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Across the TERC region, rs75316749 was positively associated with colorectal, breast, ovarian, and lung cancers. Across the DCLRE1B region, rs974404 and rs12144215 were inversely associated with prostate and lung cancers, and colorectal, breast, and prostate cancers, respectively. Near POT1, rs116895242 was inversely associated with colorectal, ovarian, and lung cancers, and RTEL1 rs34978822 was inversely associated with prostate and lung cancers. The complex association patterns in telomere-related genes across cancer types may provide insight into mechanisms through which telomere dysfunction in different tissues influences cancer risk.

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