Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study
Language English Country United States Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
Grant support
16491
Cancer Research UK - United Kingdom
MR/N003284/1
Medical Research Council - United Kingdom
G1000143
Medical Research Council - United Kingdom
14136
Cancer Research UK - United Kingdom
G0401527
Medical Research Council - United Kingdom
PubMed
30325019
DOI
10.1002/ijc.31928
Knihovny.cz E-resources
- Keywords
- Mendelian randomization, association, genetic polymorphisms, lymphocyte telomere length, pancreatic ductal adenocarcinoma,
- MeSH
- Genome-Wide Association Study MeSH
- Carcinoma, Pancreatic Ductal genetics MeSH
- Polymorphism, Single Nucleotide MeSH
- Middle Aged MeSH
- Humans MeSH
- Lymphocytes metabolism MeSH
- Pancreatic Neoplasms genetics MeSH
- Ribonucleoproteins genetics MeSH
- Aged MeSH
- Case-Control Studies MeSH
- Telomerase genetics metabolism MeSH
- Telomere metabolism MeSH
- Telomere Shortening genetics MeSH
- Check Tag
- Middle Aged MeSH
- Humans MeSH
- Male MeSH
- Aged MeSH
- Female MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Geographicals
- Europe MeSH
- Names of Substances
- NAF1 protein, human MeSH Browser
- Ribonucleoproteins MeSH
- Telomerase MeSH
- TERT protein, human MeSH Browser
Telomere deregulation is a hallmark of cancer. Telomere length measured in lymphocytes (LTL) has been shown to be a risk marker for several cancers. For pancreatic ductal adenocarcinoma (PDAC) consensus is lacking whether risk is associated with long or short telomeres. Mendelian randomization approaches have shown that a score built from SNPs associated with LTL could be used as a robust risk marker. We explored this approach in a large scale study within the PANcreatic Disease ReseArch (PANDoRA) consortium. We analyzed 10 SNPs (ZNF676-rs409627, TERT-rs2736100, CTC1-rs3027234, DHX35-rs6028466, PXK-rs6772228, NAF1-rs7675998, ZNF208-rs8105767, OBFC1-rs9420907, ACYP2-rs11125529 and TERC-rs10936599) alone and combined in a LTL genetic score ("teloscore", which explains 2.2% of the telomere variability) in relation to PDAC risk in 2,374 cases and 4,326 controls. We identified several associations with PDAC risk, among which the strongest were with the TERT-rs2736100 SNP (OR = 1.54; 95%CI 1.35-1.76; p = 1.54 × 10-10 ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10-6 , ptrend = 3.27 × 10-7 ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10-9 for highest vs. lowest quintile; p = 1.82 × 10-10 as a continuous variable). In conclusion, we present a novel genome-wide candidate SNP for PDAC risk (TERT-rs2736100), a completely new signal (NAF1-rs7675998) approaching genome-wide significance and we report a strong association between the teloscore and risk of pancreatic cancer, suggesting that telomeres are a potential risk factor for pancreatic cancer.
1st Department of Medicine University of Szeged Szeged Hungary
ARC NET University and Hospital Trust of Verona Verona Italy
Biomedical Center Faculty of Medicine in Pilsen Charles University Pilsen Czech Republic
Blood Transfusion Service Azienda Ospedaliero Universitaria Meyer Florence Italy
Department for Determinants of Chronic Diseases Bilthoven The Netherlands
Department of Biology University of Pisa Pisa Italy
Department of Digestive Tract Diseases Medical University of Lodz Lodz Poland
Department of Gastroenterology and Hepatology University Medical Centre Utrecht The Netherlands
Department of Gastroenterology Lithuanian University of Health Sciences Kaunas Lithuania
Department of Laboratory Medicine University Hospital of Padova Padua Italy
Department of Surgery Unit of Experimental Surgical Pathology University of Pisa Pisa Italy
Digestive and Liver Disease Unit S Andrea Hospital 'Sapienza' University Rome Italy
Division of Abdominal Surgery IRCCS Ospedale Casa Sollievo Sofferenza San Giovanni Rotondo Italy
Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany
Division of Preventive Oncology German Cancer Research Center Heidelberg Germany
Genomic Epidemiology Group German Cancer Research Center Heidelberg Germany
German Cancer Consortium Heidelberg Germany
Institute for Translational Medicine University of Pécs Pécs Hungary
Institute of Hematology and Transfusion Medicine Warsaw Poland
Medical Oncology Academic Medical Centre Amsterdam The Netherlands
MTA SZTE Momentum Translational Gastroenterology Research Group Szeged Hungary
Pancreas Unit Department of Digestive System Sant'Orsola Malpighi Hospital Bologna Italy
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