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

      Campa, Daniele; Matarazzi, Martina; Greenhalf, William; Bijlsma, Maarten; Saum, Kai-Uwe; Pasquali, Claudio; van Laarhoven, Hanneke; Szentesi, Andrea; Federici, Francesca; Vodicka, Pavel; Funel, Niccola; Pezzilli, Raffaele; Bueno-de-Mesquita, H Bas; Vodickova, Ludmila; Basso, Daniela; Obazee, Ofure; Hackert, Thilo; Soucek, Pavel; Cuk, Katarina; Kaiser, Jörg; Sperti, Cosimo; Lovecek, Martin; Capurso, Gabriele; Mohelnikova-Duchonova, Beatrice; Khaw, Kay-Tee; König, Anna-Katharina; Kupcinskas, Juozas; Kaaks, Rudolf; Bambi, Franco; Archibugi, Livia; Mambrini, Andrea; Cavestro, Giulia Martina; Landi, Stefano; Hegyi, Péter; Izbicki, Jakob R; Gioffreda, Domenica; Zambon, Carlo Federico; Tavano, Francesca; Talar-Wojnarowska, Renata; Jamroziak, Krzysztof; Key, Timothy J; Fave, Gianfranco Delle; Strobel, Oliver; Jonaitis, Laimas; Andriulli, Angelo; Lawlor, Rita T; Pirozzi, Felice; Katzke, Verena; Valsuani, Chiara; Vashist, Yogesh K; Brenner, Hermann; Canzian, Federico (2018-10-16)
      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.