Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia
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Abstract
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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Longer telomere length is associated with increased risk of B cell lymphoma and chronic lymphocytic leukaemia.
“Another observation in support of the telomere tumour suppressor pathway is that longer telomere length has been associated with an increased risk of B cell lymphoma and chronic lymphocytic leukaemia (CLL)65–67.”
From Telomeres in cancer: tumour suppression and genome instability (2017) · cites this paper as [67]
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Telomeres in cancer: tumour suppression and genome instability
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- Authors
- Ojha, J., Codd, V., Nelson, C. P., Samani, N. J., Smirnov, I. V., Madsen, N. R., Hansen, H. M., de Smith, A. J., Bracci, P. M., Wiencke, J. K., Wrensch, M. R., Wiemels, J. L., & Walsh, K. M.
- Affiliations
- University of California, San Francisco (US)
- University of Leicester (GB)
- 2Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California.
- Corresponding author
- Walsh, Kyle M.
- ORCID
- Venue
- Cancer Epidemiology, Biomarkers & Prevention
- Published
- 2016-06-30
- Volume
- 25
- Issue
- 7
- Pages
- 1043-1049
- ISSN
- 1055-9965 (ISSN-L)
- 1538-7755
- PMC
- PMC5008454
- OpenAlex
- W2370704029
- Cited by
- 71
- References
- 42
- Citations by year
- 2026: 5 · 2024: 7 · 2023: 6 · 2022: 8 · 2021: 9 · 2020: 11 · 2019: 7 · 2018: 10 · 2017: 6 · 2016: 1
- FWCI
- 5.80
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Cancer Epidemiology Biomarkers & Prevention (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Site cant be reached (submittedVersion)
- PuSH - Publication Server of Helmholtz Zentrum München (submittedVersion)
- Funders
- National Human Genome Research Institute (5U54HG003067)
- Blavatnik Family Foundation, NCI (5R21CA115043-2)
- Howard Hughes Medical Institute, and the Damon-Runyon Cancer Research Foundation (CI-38-07)
- NCI (R01CA132780)
- Wellcome Trust (076113 and 085475)
- NIH (R01CA52689, P50CA097257, R01CA126831, R01CA139020)
- The Sontag Foundation
- UCSF Lewis Chair in Brain Tumor Research
- UCSF Robert Magnin Newman Chair in Neuro-Oncology
- European Union Framework 7 ENGAGE Project (HEALTH-F4-2007-201413)
- British Heart Foundation
- Topics
- Health Sciences › Medicine › Genetics › Chronic Lymphocytic Leukemia Research
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Keywords
- chronic lymphocytic leukemia, telomere length, leukocyte telomere length, genetic susceptibility, TERC, telomerase reverse transcriptase, telomere maintenance genes, single nucleotide polymorphisms, shelterin, CST complex, leukemogenesis, disease progression, ACYP2, NAF1, CTC1
- MeSH terms
- Adult, Aged, Female, Humans, Leukocytes, Male, Middle Aged, Risk Factors, Biomarkers, Tumor, Genetic Variation, Leukemia, Lymphocytic, Chronic, B-Cell, Case-Control Studies, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide, Genome-Wide Association Study, Telomere Homeostasis
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