Background: Chronic lymphocytic leukemia (CLL) is the most common leukemia in the Western world. Shorter mean telomere length in leukemic cells has been associated with more aggressive disease. Germline polymorphisms in telomere maintenance genes affect telomere length and may contribute to CLL susceptibility.
Methods: We collected genome-wide data from two groups of patients with CLL (N = 273) and two control populations (N = 5,725). In ancestry-adjusted case–control comparisons, we analyzed eight SNPs in genes definitively associated with inter-individual variation in leukocyte telomere length (LTL) in prior genome-wide association studies: ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208, and RTEL1.
Results: Three of the eight LTL-associated SNPs were associated with CLL risk at P < 0.05, including those near: TERC [OR, 1.46; 95% confidence interval (CI), 1.15–1.86; P = 1.8 × 10−3], TERT (OR = 1.23; 95% CI, 1.02–1.48; P = 0.030), and OBFC1 (OR, 1.36; 95% CI, 1.08–1.71; P = 9.6 × 10−3). Using a weighted linear combination of the eight LTL-associated SNPs, we observed that CLL patients were predisposed to longer LTL than controls in both case–control sets (P = 9.4 × 10−4 and 0.032, respectively). CLL risk increased monotonically with increasing quintiles of the weighted linear combination.
Conclusions: Genetic variants in TERC, TERT, and OBFC1 are associated with both longer LTL and increased CLL risk. Because the human CST complex competes with shelterin for telomeric DNA, future work should explore the role of OBFC1 and other CST complex genes in leukemogenesis.
Impact: A genetic predisposition to longer telomere length is associated with an increased risk of CLL, suggesting that the role of telomere length in CLL etiology may be distinct from its role in disease progression. Cancer Epidemiol Biomarkers Prev; 25(7); 1043–9. ©2016 AACR.
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Note: Supplementary data for this article are available at Cancer Epidemiology, Biomarkers & Prevention Online (http://cebp.aacrjournals.org/).
ENGAGE Consortium Telomere Group: Full lists of members and affiliations appear in the Supplementary Note.
M.R. Wrensch, J.L. Wiemels, and K.M. Walsh codirected this work.
- Received January 19, 2016.
- Revision received March 29, 2016.
- Accepted March 31, 2016.
- ©2016 American Association for Cancer Research.