Susceptibility and Prevention A Prospective Study of Telomere Length Measured by Monochrome Multiplex Quantitative PCR and Risk of Non-Hodgkin Lymphoma

Purpose: Telomere length plays an important role in the maintenance of chromosomal stability and in tumorigenesis. We hypothesized that telomere length in peripheral WBC DNA obtained from healthy individuals would be a predictor of future risk of developing non-Hodgkin lymphoma. Experimental Design: Using a new assay to measure relative telomere length, monochrome multiplex quantitative PCR, which strongly correlates with telomere length measured by Southern blot (Spearman r = 0.91, P < 0.0001) and has high precision (coefficient of variation = 7%), we compared telomere length in peripheral WBC DNA in 107 incident male non-Hodgkin lymphoma cases and 107 matched controls within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Results: Median (10th, 90th percentile) telomere length was 1.10 (0.79, 1.43) in cases and 1.02 (0.78, 1.26) in controls (P = 0.0017, Wilcoxon sign test). There was a strong dose-response relationship between quartiles of telomere length and risk of nonHodgkin lymphoma overall [odds ratios (95% confidence intervals) by quartile: 1.0; 1.1 (0.4-2.7); 1.8 (0.7-4.9); and 3.6 (1.4-8.9); P trend = 0.003], and this association was similar across the most common non-Hodgkin lymphoma subtypes present in this study. Conclusion: These results suggest that longer telomere length may be a potential predictor for future risk of non-Hodgkin lymphoma. (Clin Cancer Res 2009;15(23):7429–33) Telomeres are complexes of tandem repeats of the sequence TTAGGG that cap chromosomes. They are essential for protecting chromosomal integrity (1), and shorten after every cell division. Short telomere length can cause genomic instability, which is associated with the initiation and progression of human cancers (2). At the same time, many incipient tumors can terminate their own growth by shortening their telomeres sufficiently to trigger replicative senescence or apoptosis (3). However, if sufficient numbers of mutations that promote growth and block cell senescence and apoptotic pathways accumulate in a cell before its telomeres shorten enough to trigger senescence or apoptosis and protect it from cancer, then unlimited proliferation may ensue. It follows that in some cell types, under some circumstances, long telomeres may actually increase the risk of cancer, by allowing more time and more cell divisions during which the cell can accumulate oncogenic mutations. Most epidemiologic studies have reported that relatively shorter telomere length measured in peripheral WBC and in some instances buccal cells is associated with increased risk of cancer (4–10). In contrast, some recent reports have suggested that longer telomere length may be associated with increased risk of certain tumors, such as breast cancer and melanoma (11, 12). Most studies have used a case-control design (4–8), with several more recent reports using a prospective cohort design (9–11). Given that peripheral WBC contain lymphocyte subsets that derive from lymphocytic stem cells and immunologically active tissue, we hypothesized that telomere length in peripheral WBC DNA might be particularly informative with regard to risk of developing non-Hodgkin lymphoma. To avoid potential disease bias, we carried out our study within a prospective cohort, the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study (13). In addition, we applied a modification of the original PCR-based assay developed by Cawthon (14), referred to as monochrome multiplex quantitative PCR (15), which has high assay precision and is highly correlated (Spearman r = 0.91, P < 0.0001) with the Southern blot method of measuring telomere length. Authors' Affiliations: Division of Cancer Epidemiology and Genetics, NCI, NIH, DHHS, Bethesda, Maryland; Department of Human Genetics, University of Utah, Salt Lake City, Utah; Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland; and Cancer Research Center of Hawaii, Honolulu, Hawaii Received 4/3/09; revised 7/29/09; accepted 8/3/09; published OnlineFirst 11/24/09. Grant support: Intramural funds from the National Cancer Institute. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: D. Albanes and N. Rothman contributed equally to this work. Requests for reprints: Qing Lan, Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, DHHS, MSC 7240, 6120 Executive Boulevard, EPS 8109, Bethesda, MD 20892-7240. Phone: 301-435-4706; Fax: 301-402-1819; E-mail: qingl@mail.nih. gov. F 2009 American Association for Cancer Research. doi:10.1158/1078-0432.CCR-09-0845 7429 Clin Cancer Res 2009;15(23) December 1, 2009 www.aacrjournals. org Published Online First on November 24, 2009 as 10.1158/1078-0432.CCR-09-0845 Research. on July 15, 2017. © 2009 American Association for Cancer clincancerres.aacrjournals. org Downloaded from Published OnlineFirst November 24, 2009; DOI: 10.1158/1078-0432.CCR-09-0845