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

Accepted version
Peer-reviewed

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Article

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Authors

Karami, Sara 
Han, Younghun 
Pande, Mala 
Cheng, Iona 
Rudd, James 

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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Keywords

GWAS, breast cancer, cancer risk, colorectal cancer, lung cancer, meta-analysis, ovarian cancer, prostate cancer, telomere maintenance, telomere structure, Alleles, Case-Control Studies, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Linkage Disequilibrium, Neoplasms, Odds Ratio, Polymorphism, Single Nucleotide, Risk, Telomerase, Telomere, Telomere Homeostasis, White People

Journal Title

Int J Cancer

Conference Name

Journal ISSN

0020-7136
1097-0215

Volume Title

Publisher

Wiley
Sponsorship
Cancer Research Uk (None)
National Institutes of Health (NIH) (via H Lee Moffitt Cancer Center & Research Institute) (SUBAWARD # 10-15915-01-03-G2)
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148537)
National Cancer Institute (U19CA148065)
Cancer Research Uk (None)
Cancer Research Uk (None)
Cancer Research UK (A12014)
Cancer Research UK (A10118)
Funding for the iCOGS infrastructure came from: the European Community’s Seventh Framework Programme under grant agreement n° 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 – the GAME-ON initiative), the Department of Defense (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund.