Objective Telomere shortening occurs as an early event in pancreatic tumorigenesis, and genetic variants at the telomerase reverse transcriptase (TERT) gene region have been associated with pancreatic cancer risk. However, it is unknown whether prediagnostic leucocyte telomere length is associated with subsequent risk of pancreatic cancer.
Design We measured prediagnostic leucocyte telomere length in 386 pancreatic cancer cases and 896 matched controls from five prospective US cohorts. ORs and 95% CIs were calculated using conditional logistic regression. Matching factors included year of birth, cohort (which also matches on sex), smoking status, fasting status and month/year of blood collection. We additionally examined single-nucleotide polymorphisms (SNPs) at the TERT region in relation to pancreatic cancer risk and leucocyte telomere length using logistic and linear regression, respectively.
Results Shorter prediagnostic leucocyte telomere length was associated with higher risk of pancreatic cancer (comparing extreme quintiles of telomere length, OR 1.72; 95% CI 1.07 to 2.78; ptrend=0.048). Results remained unchanged after adjustment for diabetes, body mass index and physical activity. Three SNPs at TERT (linkage disequilibrium r2<0.25) were associated with pancreatic cancer risk, including rs401681 (per minor allele OR 1.33; 95% CI 1.12 to 1.59; p=0.002), rs2736100 (per minor allele OR 1.36; 95% CI 1.13 to 1.63; p=0.001) and rs2736098 (per minor allele OR 0.75; 95% CI 0.63 to 0.90; p=0.002). The minor allele for rs401681 was associated with shorter telomere length (p=0.023).
Conclusions Prediagnostic leucocyte telomere length and genetic variants at the TERT gene region were associated with risk of pancreatic cancer.
- PANCREATIC CANCER
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Contributors YB had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: YB, BMW. Acquisition of data: PK, JEB, BBC, JMG, JAEM, TER, HDS, MJS, CSF, IDV, LTA, BMW. Analysis and interpretation of data: YB, JP, CY, MZ, PK, AB, VM-O, ZRQ, JEB, BBC, JMG, ELG, JAEM, KN, SO, TER, HDS, MJS, CSF, IDV, LTA, BMW. Drafting of the manuscript: YB, BMW. Critical revision of the manuscript for important intellectual content: YB, JP, CY, MZ, PK, AB, VM-O, ZRQ, JEB, BBC, JMG, ELG, JAEM, KN, SO, TER, HDS, MJS, CSF, IDV, LTA, BMW. Statistical analysis: YB. Obtained funding: CF, BMW. Administrative, technical, or material support: JP, CY, MZ. Study supervision: BMW.
Funding NHS is supported by NIH grants UM1 CA186107, P01 CA87969 and R01 CA49449. HPFS is supported by NIH grant UM1 CA167552. PHS is supported by NIH grants CA 97193, CA 34944, CA 40360, HL 26490 and HL 34595. The WHI programme is funded by the NIH through contracts N01WH22110, 24152, 32100-2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. WHS is supported by NIH grants CA047988, HL043851 and HL080467. Additional support from KL2/Catalyst Medical Research Investigator Training award (an appointed KL2 award) from Harvard Catalyst | The Harvard Clinical and Translational Science Center (National Center for Research Resources and the National Center for Advancing Translational Sciences, NIH KL2 TR001100) to YB; from the Robert T. and Judith B. Hale Fund for Pancreatic Cancer, Perry S. Levy Fund for Gastrointestinal Cancer Research, Pappas Family Research Fund for Pancreatic Cancer, NIH R01 CA124908, and NIH P50 CA127003 to CSF; NIH R35 CA197735 to SO; and from Department of Defense CA130288, Lustgarten Foundation, NIH/NCI K07 CA140790, the Noble Effort Fund, the Peter R. Leavitt Family Fund and Promises for Purple to BMW.
Competing interests None declared.
Patient consent Obtained.
Ethics approval Human Research Committee at the Brigham and Women's Hospital.
Provenance and peer review Not commissioned; externally peer reviewed.