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
et al (show 42 more authors) (2019) Genetic determinants of telomere length and risk of pancreatic cancer: A PANDoRA study. INTERNATIONAL JOURNAL OF CANCER, 144 (6). pp. 1275-1283.

[thumbnail of IJC-18-1121.R2_PANDoRA_teloscore.pdf] 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<sup>-10</sup> ) and a novel one with the NAF1-rs7675998 SNP (OR = 0.80; 95%CI 0.73-0.88; p = 1.87 × 10<sup>-6</sup> , p<sub>trend</sub> = 3.27 × 10<sup>-7</sup> ). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p = 2.98 × 10<sup>-9</sup> for highest vs. lowest quintile; p = 1.82 × 10<sup>-10</sup> 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:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3028959