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

Collapse authors list.
Campa, Daniele, Matarazzi, Martina, Greenhalf, William, Bijlsma, Maarten, Saum, Kai-Uwe, Pasquali, Claudio, van Laarhoven, Hanneke, Szentesi, Andrea, Federici, Francesca, Vodicka, Pavel et al (show 42 more authors) , Funel, Niccola, Pezzilli, Raffaele, Bueno-de-Mesquita, H Bas, Vodickova, Ludmila, Basso, Daniela, Obazee, Ofure, Hackert, Thilo, Soucek, Pavel, Cuk, Katarina, Kaiser, Joerg, Sperti, Cosimo, Lovecek, Martin, Capurso, Gabriele, Mohelnikova-Duchonova, Beatrice, Khaw, Kay-Tee, Koenig, Anna-Katharina, Kupcinskas, Juozas, Kaaks, Rudolf, Bambi, Franco, Archibugi, Livia, Mambrini, Andrea, Cavestro, Giulia Martina, Landi, Stefano, Hegyi, Peter, Izbicki, Jakob R, Gioffreda, Domenica, Zambon, Carlo Federico, Tavano, Francesca, Talar-Wojnarowska, Renata, Jamroziak, Krzysztof, Key, Timothy J, Delle Fave, Gianfranco, Strobel, Oliver, Jonaitis, Laimas, Andriulli, Angelo, Lawlor, Rita T, Pirozzi, Felice, Katzke, Verena, Valsuani, Chiara, Vashist, Yogesh K, Brenner, Hermann and Canzian, Federico (2019) Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study. INTERNATIONAL JOURNAL OF CANCER, 144 (6). pp. 1275-1283.

Text IJC-18-1121.R2_PANDoRA_teloscore.pdf - Author Accepted Manuscript Download (428kB)

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 , p_trend = 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.

Item Type:	Article
Uncontrolled Keywords:	pancreatic ductal adenocarcinoma, genetic polymorphisms, lymphocyte telomere length, Mendelian randomization, association
Depositing User:	Symplectic Admin
Date Deposited:	21 Nov 2018 11:02
Last Modified:	19 Jan 2023 01:12
DOI:	10.1002/ijc.31928
Related URLs:	Author Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3028959