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Int J Cancer. 2018 Oct 16. doi: 10.1002/ijc.31928. [Epub ahead of print]

Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study.

Author information

1
Department of Biology, University of Pisa, Pisa, Italy.
2
Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.
3
Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom.
4
Medical Oncology, Academic Medical Centre, Amsterdam, The Netherlands.
5
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
6
Pancreatic and Digestive Endocrine Surgery - Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy.
7
Institute for Translational Medicine, University of Pécs, Pécs, Hungary.
8
First Department of Medicine, University of Szeged, Szeged, Hungary.
9
Oncological Department, Azienda USL Toscana Nord Ovest, Oncological Unit of Massa Carrara, Carrara, Italy.
10
Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic.
11
Institute of Biology and Medical Genetics, 1st Medical Faculty, Charles University, Prague, Czech Republic.
12
Biomedical Center, Faculty of Medicine in Pilsen, Charles University, Pilsen, Czech Republic.
13
Department of Surgery, Unit of Experimental Surgical Pathology, University of Pisa, Pisa, Italy.
14
Pancreas Unit, Department of Digestive System, Sant'Orsola-Malpighi Hospital, Bologna, Italy.
15
Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands.
16
Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands.
17
Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, United Kingdom.
18
Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.
19
Department of Laboratory Medicine, University-Hospital of Padova, Padua, Italy.
20
Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany.
21
Third Surgical Clinic - Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padova, Padova, Italy.
22
Department of Surgery I, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Olomouc, Czech Republic.
23
Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University, Rome, Italy.
24
PancreatoBiliary Endoscopy and EUS Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita Salute San Raffaele University, Milan, Italy.
25
Department of Oncology, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
26
University of Cambridge School of Clinical Medicine Clinical Gerontology Unit, Addenbrooke's Hospital, Cambridge, United Kingdom.
27
Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania.
28
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
29
Blood Transfusion Service, Azienda Ospedaliero-Universitaria Meyer, Florence, Italy.
30
Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, San Raffaele Scientific Institute, Milan, Italy.
31
MTA-SZTE Momentum Translational Gastroenterology Research Group, Szeged, Hungary.
32
Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
33
Division of Gastroenterology and Molecular Biology Lab, IRCCS Ospedale Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy.
34
Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland.
35
Institute of Hematology and Transfusion Medicine, Warsaw, Poland.
36
Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom.
37
ARC-NET, University and Hospital Trust of Verona, Verona, Italy.
38
Division of Abdominal Surgery, IRCCS Ospedale Casa Sollievo Sofferenza, San Giovanni Rotondo, Italy.
39
Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.
40
German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.

Abstract

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.

KEYWORDS:

Mendelian randomization; association; genetic polymorphisms; lymphocyte telomere length; pancreatic ductal adenocarcinoma

PMID:
30325019
DOI:
10.1002/ijc.31928

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