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

D Campa, M Matarazzi, W Greenhalf, M Bijlsma, KU Saum, C Pasquali, H van Laarhoven, A Szentesi, F Federici, P Vodicka, N Funel, R Pezzilli, HB Bueno-de-Mesquita, L Vodickova, D Basso, O Obazee, T Hackert, P Soucek, K Cuk, J KaiserC Sperti, M Lovecek, G Capurso, B Mohelnikova-Duchonova, KT Khaw, AK König, J Kupcinskas, R Kaaks, F Bambi, L Archibugi, A Mambrini, GM Cavestro, S Landi, P Hegyi, JR Izbicki, D Gioffreda, CF Zambon, F Tavano, R Talar-Wojnarowska, K Jamroziak, TJ Key, G Delle Fave, O Strobel, L Jonaitis, A Andriulli, RT Lawlor, F Pirozzi, V Katzke, C Valsuani, YK Vashist, H Brenner, F Canzian

Research output: Contribution to journalArticle

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. © 2018 UICC
Original languageEnglish
Pages (from-to)1275-1283
Number of pages9
JournalInt. J. Cancer
Volume144
Issue number6
DOIs
Publication statusPublished - 2019

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    Campa, D., Matarazzi, M., Greenhalf, W., Bijlsma, M., Saum, KU., Pasquali, C., van Laarhoven, H., Szentesi, A., Federici, F., Vodicka, P., Funel, N., Pezzilli, R., Bueno-de-Mesquita, HB., Vodickova, L., Basso, D., Obazee, O., Hackert, T., Soucek, P., Cuk, K., ... Canzian, F. (2019). Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study: International Journal of Cancer. Int. J. Cancer, 144(6), 1275-1283. https://doi.org/10.1002/ijc.31928