Leukocyte telomere length and its interaction with germline variation in telomere-related genes in relation to pancreatic adenocarcinoma risk

Background: Leukocyte telomere length (LTL) has been associated with risk of multiple cancers, but its association with pancreatic ductal adenocarcinoma (PDAC) is unclear. We therefore investigated the association between peripheral blood LTL and PDAC risk, and examined effect modification by candidate SNPs previously reported to be associated with variation in LTL. Methods: A case–control study of 1,460 PDAC cases and 1,459 frequency-matched controls was performed using biospecimens and data from the Mayo Clinic Biospecimen Resource for Pancreas Research. Quantitative PCR was used to measure LTL and categorized into tertiles based on sex-specific control distribution. Eleven telomere-related SNPs also were genotyped. Logistic regression was used to calculate ORs and 95% confidence intervals (CI). Results: Shorter peripheral blood LTL was associated with a higher risk of PDAC (OR_T1vsT3 ¼ 1.26, 95% CI ¼ 1.03–1.54, P_trend ¼ 0.02; OR_continuous ¼ 1.14, 95% CI ¼ 1.02–1.28), but the association was restricted to cases with treatment-nave blood samples (OR_T1vsT3 ¼ 1.51, 95% CI ¼ 1.16–1.96, P_trend ¼ 0.002; OR_continuous ¼ 1.25, 95% CI ¼ 1.08–1.45) and not cases whose blood samples were collected after initiation of cancer therapy (OR_T1vsT3 ¼ 1.10, 95% CI ¼ 0.87–1.39, P_trend ¼ 0.42; OR_continuous ¼ 1.08, 95% CI ¼ 0.94–1.23). Three SNPs (TERC-rs10936599, ACYP2-rs11125529, and TERC-rs1317082) were each associated with interindividual variation in LTL among controls, but there was no evidence of effect modification by these SNPs. Conclusions: Treatment-nave short LTL is associated with a higher risk of PDAC, and the association does not differ by germline variation in the candidate telomere-related SNPs examined. Impact: Peripheral blood LTL might serve as a molecular marker for risk modeling to identify persons at high risk of PDAC.