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Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia

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Genetic Variation Associated with Longer Telomere Length Increases Risk of Chronic Lymphocytic Leukemia Published OnlineFirst May 13, 2016; DOI: 10.1158/1055-9965.EPI-15-1329 Research Article Cancer Epidemiology, Biomarkers Genetic Variation Associated with Longer & Prevention Telomere Length Increases Risk of Chronic Lymphocytic Leukemia Juhi Ojha1,2; Veryan Codd3,4, Christopher P. Nelson3,4, and Nilesh J. Samani3,4, on behalf of the ENGAGE Consortium Telomere Group; Ivan V. Smirnov5, Nils R. Madsen1, Helen M. Hansen1, Adam J. de Smith2, Paige M. Bracci2, John K. Wiencke1,6, Margaret R. Wrensch1,6, Joseph L. Wiemels1,2,6, and Kyle M. Walsh1,7 Abstract À Background: Chronic lymphocytic leukemia (CLL) is the most 1.36; 95% CI, 1.08–1.71; P ¼ 9.6 Â 10 3). Using a weighted linear common leukemia in the Western world. Shorter mean telomere combination of the eight LTL-associated SNPs, we observed that length in leukemic cells has been associated with more aggressive CLL patients were predisposed to longer LTL than controls in both À disease. Germline polymorphisms in telomere maintenance genes case–control sets (P ¼ 9.4 Â 10 4 and 0.032, respectively). CLL affect telomere length and may contribute to CLL susceptibility. risk increased monotonically with increasing quintiles of the Methods: We collected genome-wide data from two groups of weighted linear combination. patients with CLL (N ¼ 273) and two control populations (N ¼ Conclusions: Genetic variants in TERC, TERT, and OBFC1 are 5,725). In ancestry-adjusted case–control comparisons, we ana- associated with both longer LTL and increased CLL risk. Because lyzed eight SNPs in genes definitively associated with inter-indi- the human CST complex competes with shelterin for telomeric vidual variation in leukocyte telomere length (LTL) in prior DNA, future work should explore the role of OBFC1 and other CST genome-wide association studies: ACYP2, TERC, NAF1, TERT, complex genes in leukemogenesis. OBFC1, CTC1, ZNF208, and RTEL1. Impact: A genetic predisposition to longer telomere length is Results: Three of the eight LTL-associated SNPs were associated associated with an increased risk of CLL, suggesting that the with CLL risk at P < 0.05, including those near: TERC [OR, 1.46; role of telomere length in CLL etiology may be distinct from its À 95% confidence interval (CI), 1.15–1.86; P ¼ 1.8 Â 10 3], TERT role in disease progression. Cancer Epidemiol Biomarkers Prev; 25(7); (OR ¼ 1.23; 95% CI, 1.02–1.48; P ¼ 0.030), and OBFC1 (OR, 1043–9. Ó2016 AACR. Introduction highly progressive (1). Currently, several prognostic markers including somatic hypermutation in the immunoglobulin Chronic lymphocytic leukemia (CLL) is a highly heteroge- heavy-chain variable region, ZAP70 and CD38 expression, and neous disease with clinical course ranging from indolent to TP53/SF3B1/NOTCH1 mutation status are used in combination to estimate disease prognosis (2). Telomere length is also 1 Division of Neuroepidemiology, Department of Neurological Surgery, associated with CLL progression, where shorter telomere length University of California, San Francisco, San Francisco, California. 2Department of Epidemiology and Biostatistics, University of California, is correlated with advanced disease stages, Richter transforma- San Francisco, San Francisco, California. 3Department of Cardiovascular tion (3), and poor patient prognosis (4). 4 Sciences, University of Leicester, Leicester, United Kingdom. National Telomeres are repetitive DNA sequences that cap and protect Institute for Health Research Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital, Leicester, United Kingdom. 5Depart- chromosomes. Telomeric repeats are lost with each somatic ment of Neurological Surgery, University of California, San Francisco, cellular division and, when depleted, future mitoses result in San Francisco, California. 6Institute for Human Genetics, University of the loss of integral genomic DNA. This induces replicative California, San Francisco, San Francisco, California. 7Program in Neuro- logic Oncology, Helen Diller Family Comprehensive Cancer Center, senescence and apoptosis, limiting the replicative potential of University of California, San Francisco, San Francisco, California. somatic cells (5). If adequate oncogenic mutations are Note: Supplementary data for this article are available at Cancer Epidemiology, acquired before reaching replicative senescence, unlimited Biomarkers & Prevention Online (http://cebp.aacrjournals.org/). proliferation may follow and cancer may result. Thus, long telomeres may increase the risk of cancer by allowing addi- ENGAGE Consortium Telomere Group: Full lists of members and affiliations appear in the Supplementary Note. tional time in which a cell can accumulate mutations before reaching this apoptotic checkpoint (6). Following malignant M.R. Wrensch, J.L. Wiemels, and K.M. Walsh codirected this work. transformation, leukemic cells that proliferate in the absence Corresponding Author: Kyle M. Walsh, University of California San Francisco, of an active mechanism of telomere maintenance (e.g., telo- Box 0520, 1450 3rd Street HD475, San Francisco, CA 94143-0520. Phone: 415- merase reactivation) will continue to experience telomere 476-1627; Fax: 415-502-7411; E-mail: [email protected] depletion (7, 8). In such tumors, short telomere length would doi: 10.1158/1055-9965.EPI-15-1329 be expected to associate with more advanced and/or highly Ó2016 American Association for Cancer Research. proliferative leukemia (9, 10). www.aacrjournals.org 1043 Downloaded from cebp.aacrjournals.org on September 28, 2021. © 2016 American Association for Cancer Research. Published OnlineFirst May 13, 2016; DOI: 10.1158/1055-9965.EPI-15-1329 Ojha et al. Telomere length decreases with age, but can be significantly atic, untreated CLL as defined by NCI 1996 guidelines (20). The different between individuals of the same age due to genetic second group included 101 nonoverlapping CLL patients from and environmental influences (11). Heritable differences in DFCI and 2,603 controls from the Wellcome Trust Case-Control leukocyte telomere length (LTL) are associated with SNPs Consortium (WTCCC; refs. 1, 21). The majority (67%) of DFCI in eight genes involved in telomere maintenance, including cases were chemotherapy-na€ve. Additional case and control data ACYP2, TERC, NAF1, TERT, OBFC1, CTC1, ZNF208,andRTEL1 appear in Supplementary Table S1. (12, 13). Genome-wide association studies (GWAS) indicate that inherited SNPs near the telomerase-component genes Case–control genotyping and quality control TERC and TERT are also associated with increased risk of CLL For ECOG patients, DNA was isolated from peripheral blood, and implicate telomere biology in leukemia predisposition obtained before treatment, and shipped overnight at ambient (14, 15). We therefore hypothesized that inherited variation temperature to a central processing laboratory. Mononuclear cells affecting telomere length may be associated with risk of devel- were isolated using Ficoll density-gradient centrifugation and oping CLL, with the heritable and somatic genetic influences then processed for DNA. All case and control DNA specimens in having a net effect on telomere length in tumors. discovery analyses were genotyped using either the Illumina To determine whether common genetic variants associated HumanCNV370-Duo BeadChip or the Illumina HumanHap550 with inter-individual variation in telomere length confer risk platform. Samples with call rates <95% were excluded from for CLL, we analyzed eight independent SNPs in 273 patients analysis, as were samples with mismatched reported versus gen- with CLL and 5,725 controls. These SNPs have previously been otyped sex. Although all subjects were of self-reported European definitively associated with inter-individual variation in LTL in ancestry, this was validated using principal components analysis a GWAS of 37,684 individuals of European ancestry conducted in Eigenstrat (22). Analyzed SNPs had call rates >98% and Hardy– by the ENGAGE Consortium Telomere Group (12). In addition Weinberg equilibrium P values >0.001 among controls. to single variant analyses, we also constructed a weighted linear For DFCI patients, DNA samples were obtained from normal combination of subject genotype at the eight SNPs to create a tissue via either 5 mm skin punch biopsies or collection of 2 mL of summary score that quantifies genotypic contributions to dif- saliva as a source of normal epithelial cells. DNA specimens were ferences in LTL across patients and controls. Although direct genotyped using the Affymetrix 6.0 genotyping array. Genotype measurement of LTL (e.g., by qPCR) is frequently influenced data for 2,603 European-ancestry control samples genotyped by differing distributions of potential confounders across using the Affymetrix 6.0 genotyping array were downloaded from patients and controls (e.g., age, sex, chemotherapy), SNP gen- the WTCCC (21). Subjects showing evidence of non-European otypes are present since birth and are not confounded by the ancestry, as well as duplicate samples and related subjects (IBD > effect that these variables may have on both telomere length 0.125) were excluded from analyses. Genome-wide SNP data and cancer risk. In addition, although the effect of individual were used to ensure there was no overlap between ECOG patients alleles in telomere maintenance genes may be small, the com- and DFCI patients. SNPs with call rates <98% or HWE P value bined effect of numerous such polymorphisms could poten- <0.001 (among controls) were excluded. tially be quite large and could help identify the
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