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=1.54x10-10) and a novel one with the NAF1-rs7675998 SNP (OR=0.80; 95%CI 0.73-0.88; p=1.87x10-6, ptrend=3.27x10-7). The association of short LTL, measured by the teloscore, with PDAC risk reached genome-wide significance (p=2.98x10-9 for highest vs. lowest quintile; p=1.82x10-10 as a continuous variable).
In conclusion, we present a novel genomewide 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.