Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 139, Issue 12, Pages 2655-2670Publisher
WILEY
DOI: 10.1002/ijc.30288
Keywords
telomere structure; telomere maintenance; cancer risk; GWAS; meta-analysis; lung cancer; breast cancer; ovarian cancer; prostate cancer; colorectal cancer
Categories
Funding
- National Institutes of Health (NIH), National Cancer Institute (NCI) [R01 CA151989]
- European Community's Seventh Framework Programme [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]
- National Institutes of Health [CA128978]
- Post-Cancer GWAS initiative [1U19 CA148537, 1U19 CA148065, 1U19 CA148112]
- Department of Defense [W81XWH-10-1-0341]
- Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer
- Komen Foundation for the Cure
- Breast Cancer Research Foundation
- Ovarian Cancer Research Fund
- US NCI GAME-ON Post-GWAS Initiative [U19-CA148112]
- TRICL (Transdisciplinary Research for Cancer of Lung): NIH [U19 CA148127-01]
- Canadian Cancer Society Research Institute [020214]
- DRIVE (Discovery, Biology, and Risk of Inherited Variants in Breast Cancer): NIH [U19 CA148065]
- CORECT (ColoRectal Transdisciplinary Study): NIH [U19 CA148107, R01 CA81488, P30 CA014089]
- ELLIPSE (ELLIPSE, Elucidating Loci in Prostate Cancer Susceptibility)
- GAMEON U19 initiative for prostate cancer (ELLIPSE) [U19 CA148537]
- FOCI (Transdisciplinary Cancer Genetic Association and Interacting Studies) [NIH U19 CA148112-01, R01-CA122443, P50-CA136393, P30-CA15083]
- Cancer Research UK [C490/A8339, C490/A16561, C490/A10119, C490/A10124]
- GECCO: NCI, NIH, U.S. Department of Health and Human Services (DHHS) [U01 CA137088, R01 CA059045]
- ASTERISK: a Hospital Clinical Research Program (PHRC)
- Regional Council of Pays de la Loire
- Groupement des Entreprises Francaises dans la Lutte contre le Cancer (GEFLUC)
- Association Anne de Bretagne Genetique
- Ligue Regionale Contre le Cancer (LRCC)
- COLO23: NIH [R01 CA60987]
- DACHS: German Research Council (Deutsche Forschungsgemeinschaft) [BR 1704/6-1, BR 1704/6-3, BR 1704/6-4, CH 117/1-1]
- German Federal Ministry of Education and Research [01KH0404, 01ER0814]
- NIH [R01 CA48998, P01 CA 055075, UM1 CA167552, R01 137178, R01 CA151993, P50 CA127003, UM1 CA186107, R01 CA137178, P01 CA87969, R01 CA042182]
- MEC: NIH [R37 CA54281, P01 CA033619, R01 CA63464]
- Ontario Registry for Studies of Familial Colorectal Cancer (OFCCR: NIH) [U01 CA074783]
- Ontario Research Fund
- Canadian Institutes of Health Research
- Ontario Institute for Cancer Research (OFCCR)
- Ontario Ministry of Research and Innovation
- PLCO: Intramural Research Program of the Division of Cancer Epidemiology and Genetics
- Division of Cancer Prevention, NCI, NIH, DHHS
- Cancer Genetic Markers of Susceptibility (CGEMS) Prostate Cancer GWAS
- Nat Genet
- Colon CGEMS pancreatic cancer scan (PanScan)
- NIH, Genes, Environment and Health Initiative (GEI) [Z01 CP 010200, NIH U01 HG004446, NIH GEI U01 HG 004438]
- GENEVA Coordinating Center
- Johns Hopkins University Center for Inherited Disease Research
- PMH: NIH [R01 CA076366]
- VITAL: NIH [K05 CA154337]
- WHI: National Heart, Lung, and Blood Institute, NIH, DHHS (The WHI program) [HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100003C, HHSN268201100004C, HHSN271201100004C]
- MD Anderson: NCI [NIH K07CA160753]
- Cancer Research UK [16561, 15007, 17528] Funding Source: researchfish
- Cancer Research UK
- The Francis Crick Institute [10124, 10119] Funding Source: researchfish
Ask authors/readers for more resources
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 X 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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