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

Abstract

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...

Prediagnostic telomere length and risk of B-cell lymphoma-Results from the EPIC cohort study

“…32,33 Moreover, based on animal and in vitro studies, it seems that an early activation of telomerase via exogenous regulators of human telomerase reverse transcriptase, along with an increased lymphocyte growth and a subsequent selection of cells with increased transforming potential may characterize several virus-related lymphoid malignancies. 34 The results of our prospective study and the prospective study by Lan et al 23 are in contrast to results reported from previous case-control studies. A small case-control study that compared TL in nonmalignant peripheral leukocytes from untreated patients who recently developed an aggressive NHL (n 5 40) with TL in granulocytes from healthy individuals (n 5 40) showed an increased risk of NHL for short TL.…”

“…Our findings of BCL are consistent with the study by Lan et al 23 on TL in peripheral WBC DNA of 107 incident male NHL cases and 107 matched controls within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study cohort. Similarly, we found in our study, which was about three times larger than the previous study, an increased risk of all major subtypes of BCL with increasing TL with the subtypes DLBCL and FL reaching statistical significance.…”

“…24 The only prospective study evaluating lymphoma risk in relation to TL 23 suggested that individuals with relatively longer telomeres have an elevated NHL risk which is inconsistent with the results of previous case-control studies. 22,25 As such, the finding in the prospective cohort study deserves further follow-up to see if these findings can be corroborated in an independent study.…”

“…22,23 Interestingly, according to the most recent meta-analysis on TL and cancer, reported results of What's new? Can telomere length affect cancer risk?…”

Leukocyte Telomere Length in Relation to Pancreatic Cancer Risk: A Prospective Study

“…Comparison of geometric mean LTL values at different levels of baseline variables or prospective (the blood was taken before diagnosis, in a cohort study), with the retrospective studies generally showing stronger associations than the prospective studies (12). It is worth emphasizing that in several recent publications, which include prospective studies, longer telomeres were found to be associated with an increase in cancer risk (12,13,(38)(39)(40)(41)(42)(43)(44)(45). For pancreatic cancer, only two studies on the relationship with LTL have been performed so far: one retrospective case-control study, which showed an inverse association between shorter LTL and pancreas cancer risk (14), and one prospective study that showed an association between longer LTL and increased pancreatic cancer risk (13).…”