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

0495333 - ÚEM 2020 RIV DE eng J - Journal Article
Campa, D. - Matarazzi, M. - Greenhalf, W. - Bijlsma, M. - Saum, K.U. - Pasquali, C. - van Laarhoven, H. - Szentesi, A. - Federici, F. - Vodička, Pavel - Funel, N. - Pezzilli, R. - Bueno-de-Mesquita, H. B. - Vodičková, Ludmila - Basso, D. - Obazee, O. - Hackert, T. - Souček, P. - Cuk, K. - Kaiser, J. - Sperti, C. - Loveček, M. - Capurso, G. - Mohelníková-Duchoňová, B. - Khaw, K. T. - König, A.K. - Kupcinskas, J. - Kaaks, R. - Bambi, F. - Archibugi, L. - Mambrini, A. - Cavestro, G.M. - Landi, S. - Hegyi, P. - Izbicki, J.R. - Gioffreda, D. - Zambon, C.F. - Tavano, F. - Talar-Wojnarowska, R. - Jamroziak, K. - Key, T. J. - Fave, G.D. - Strobel, O. - Jonaitis, L. - Andriulli, A. - Lawlor, R.T. - Pirozzi, F. - Katzke, V. - Valsuani, Ch. - Vashist, Y.K. - Brenner, H. - Canzian, F.
Genetic determinants of telomere length and risk of pancreatic cancer: a PANDoRA study.
International Journal of Cancer. Roč. 144, č. 6 (2019), s. 1275-1283. ISSN 0020-7136. E-ISSN 1097-0215
Institutional support: RVO:68378041
Keywords : pancreatic ductal adenocarcinoma * genetic polymorphisms * lymphocyte telomere length
OECD category: Human genetics
Impact factor: 5.145, year: 2019
Method of publishing: Limited access
https://onlinelibrary.wiley.com/doi/full/10.1002/ijc.31928

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 x 10(-10)) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80, 95%CI 0.73-0.88, p = 1.87 x 10(-6), p(trend) = 3.27 x 10(-7)). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 x 10(-9) for highest vs. lowest quintile, p = 1.82 x 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.
Permanent Link: http://hdl.handle.net/11104/0302810