Journal
HUMAN MOLECULAR GENETICS
Volume 24, Issue 18, Pages 5356-5366Publisher
OXFORD UNIV PRESS
DOI: 10.1093/hmg/ddv252
Keywords
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Funding
- Genetic Associations and Mechanisms in Oncology Network, GAME-ON: Discovery, Biology, and Risk of Inherited Variants in Breast Cancer, DRIVE [U19 CA148065]
- Colorectal Transdisciplinary Study, CORECT [U19 CA148107]
- Transdisciplinary Research in Cancer of the Lung, TRICL [U19 CA148127]
- Follow-up of ovarian cancer genetic association and interaction studies, FOCI [U19 CA148112]
- Elucidating Loci Involved in Prostate Cancer Susceptibility, ELLIPSE [U19 CA148537]
- Genetics and Epidemiology of Colorectal Cancer Consortium, GECCO: National Cancer Institute, National Institutes of Health, US Department of Health and Human Services [U01 CA137088, R01 CA059045]
- National Institute of Health, National Institute on Aging [T32AG000243, P30AG012857]
- Cancer Research Foundation Young Investigator Award [R01 ES020506, U01 HG007601]
- Wellcome Trust [100114]
- NHMRC
- University of Cambridge (COAF Open Access block grant)
- MRC [MR/L003120/1] Funding Source: UKRI
- British Heart Foundation [RG/08/014/24067] Funding Source: researchfish
- Cancer Research UK [15007, 17528] Funding Source: researchfish
- Medical Research Council [MR/L003120/1] Funding Source: researchfish
- National Institute for Health Research [NF-SI-0512-10165] Funding Source: researchfish
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Epidemiological 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 = 6.3 x 10(-15)), even after exclusion of a SNP residing in a known lung cancer susceptibility region (TERT-CLPTM1L) P = 6.6 x 10(-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 bp 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.
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