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dc.contributor.authorZhang, Chenanen
dc.contributor.authorDoherty, Jennifer Aen
dc.contributor.authorBurgess, Stephenen
dc.contributor.authorHung, Rayjean Jen
dc.contributor.authorLindström, Saraen
dc.contributor.authorKraft, Peteren
dc.contributor.authorGong, Jianen
dc.contributor.authorAmos, Christopheren
dc.contributor.authorSellers, Thomas Aen
dc.contributor.authorMonteiro, Alvaro NAen
dc.contributor.authorChenevix-Trench, Georgiaen
dc.contributor.authorBickeböller, Heikeen
dc.contributor.authorRisch, Angelaen
dc.contributor.authorBrennan, Paulen
dc.contributor.authorMcKay, Jamesen
dc.contributor.authorHoulston, Richarden
dc.contributor.authorLandi, Maria Teresaen
dc.contributor.authorTimofeeva, Mariaen
dc.contributor.authorWang, Yufeien
dc.contributor.authorHeinrich, Joachimen
dc.contributor.authorKote-Jarai, Zsofiaen
dc.contributor.authorEeles, Rosalind Aen
dc.contributor.authorMuir, Kenen
dc.contributor.authorWiklund, Fredriken
dc.contributor.authorGrönberg, Henriken
dc.contributor.authorBerndt, Sonja Ien
dc.contributor.authorChanock, Stephen Jen
dc.contributor.authorSchumacher, Fredricken
dc.contributor.authorHaiman, Christopher Aen
dc.contributor.authorHenderson, Brian Een
dc.contributor.authorAmin, Al Olama Alien
dc.contributor.authorAndrulis, Irene Len
dc.contributor.authorHopper, John Len
dc.contributor.authorChang-Claude, Jennyen
dc.contributor.authorJohn, Esther Men
dc.contributor.authorMalone, Kathleen Een
dc.contributor.authorGammon, Marilie Den
dc.contributor.authorUrsin, Giskeen
dc.contributor.authorWhittemore, Alice Sen
dc.contributor.authorHunter, David Jen
dc.contributor.authorGruber, Stephen Ben
dc.contributor.authorKnight, Julia Aen
dc.contributor.authorHou, Lifangen
dc.contributor.authorLe, Marchand Loicen
dc.contributor.authorNewcomb, Polly Aen
dc.contributor.authorHudson, Thomas Jen
dc.contributor.authorChan, Andrew Ten
dc.contributor.authorLi, Lien
dc.contributor.authorWoods, Michael Oen
dc.contributor.authorAhsan, Habibulen
dc.contributor.authorPierce, Brandon Len
dc.identifier.citationZhang et al. Human Molecular Genetics (2015) Vol. 24 Issue 18, pp. 5356-5366. doi: 10.1093/hmg/ddv252en
dc.description.abstractEpidemiological studies have reported inconsistent associations between telomere length (TL) and risk for various cancers. These inconsistencies are likely attributable, in part, to biases that arise due to post-diagnostic and post-treatment TL measurement. To avoid such biases, we used a Mendelian randomization approach and estimated associations between nine TL-associated SNPs and risk for five common cancer types (breast, lung, colorectal, ovarian and prostate cancer, including subtypes) using data on 51,725 cases and 62,035 controls. We then used an inverse-variance weighted average of the SNP-specific associations to estimate the association between a genetic score representing long TL and cancer risk. The long TL genetic score was significantly associated with increased risk of lung adenocarcinoma (P=6.3x10−15), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P=6.6x10−6). Under Mendelian randomization assumptions, the association estimate (odds ratio (OR)=2.78) is interpreted as the OR for lung adenocarcinoma corresponding to a 1000 base pair increase in TL. The weighted TL SNP score was not associated with other cancer types or subtypes. Our finding that genetic determinants of long TL increase lung adenocarcinoma risk avoids issues with reverse causality and residual confounding that arise in observational studies of TL and disease risk. Under Mendelian randomization assumptions, our finding suggests that longer TL increases lung adenocarcinoma risk. However, caution regarding this causal interpretation is warranted in light of the potential issue of pleiotropy, and a more general interpretation is that SNPs influencing telomere biology are also implicated in lung adenocarcinoma risk.
dc.description.sponsorshipThis work was supported by the Genetic Associations and Mechanisms in Oncology Network, GAMEON: Discovery, Biology, and Risk of Inherited Variants in Breast Cancer, DRIVE, PI: D. Hunter (grant number U19 CA148065); Colorectal Transdisciplinary Study, CORECT, PI: S. Gruber (grant number U19 CA148107); Transdisciplinary Research in Cancer of the Lung, TRICL, PI: C. Amos (grant number U19 CA148127); Follow-up of ovarian cancer genetic association and interaction studies, FOCI, PI: T. Sellers (grant number U19 CA148112); Elucidating Loci Involved in Prostate Cancer Susceptibility, ELLIPSE, PI: B. Henderson (grant number U19 CA148537); Genetics and Epidemiology of Colorectal Cancer Consortium, GECCO: National Cancer Institute, National Institutes of Health, U.S. Department of Health and Human Services (grant numbers U01 CA137088, R01 CA059045); National Institute of Health, National Institute on Aging (T32AG000243; P30AG012857) to CZ; Cancer Research Foundation Young Investigator Award to BLP; The Wellcome Trust (grant number 100114) to SB; The NHMRC Senior Principal Research Fellow to GCT.
dc.publisherOxford University Press
dc.rightsAttribution 2.0 UK: England & Wales
dc.titleGenetic determinants of telomere length and risk of common cancers: a Mendelian randomization studyen
dc.description.versionThis is the final version of the article. It first appeared from Oxford University Press via  en
prism.publicationNameHuman Molecular Geneticsen
dc.rioxxterms.funderWellcome Trust
dc.rioxxterms.projectidU01 CA137088
dc.rioxxterms.projectidR01 CA059045
dc.contributor.orcidBurgess, Stephen [0000-0001-5365-8760]
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idNational Cancer Institute (NCI) (U19CA148537)
pubs.funder-project-idNational Cancer Institute (NCI) (U19CA148065)
pubs.funder-project-idMRC (MR/L003120/1)
pubs.funder-project-idWellcome Trust (100114/Z/12/Z)
pubs.funder-project-idBritish Heart Foundation (RG/08/014/24067)

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Attribution 2.0 UK: England & Wales
Except where otherwise noted, this item's licence is described as Attribution 2.0 UK: England & Wales