Journal
INTERNATIONAL JOURNAL OF CANCER
Volume 144, Issue 6, Pages 1275-1283Publisher
WILEY
DOI: 10.1002/ijc.31928
Keywords
pancreatic ductal adenocarcinoma; genetic polymorphisms; lymphocyte telomere length; Mendelian randomization; association
Categories
Funding
- Statistics Netherlands
- World Cancer Research Fund
- Dutch ZON
- Dutch Prevention Funds
- LK Research Funds
- Netherlands Cancer Registry
- Dutch Ministry of Public Health, Welfare and Sports
- Ministry of Education Youth and Sports of the Czech Republic [1503, LO1503]
- Czech Ministry of Education [61989592, NPS I LO1304]
- Czech Ministry of Health [16-28375A]
- DKFZ
- MRC [MR/N003284/1] Funding Source: UKRI
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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.
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