Telomere Length by Tel-PCR in B Cell Malignancies.

Abstract

Previous studies have shown heterogeneity of telomere length among chronic B cell malignancies and within CLL. Longer telomeres are a feature of germinal center-derived tumours and mean telomere length is shorter in unmutated than mutated CLL. The relative contributions of telomere length pre-transformation, germinal centre experience and tumour cell proliferation in determining telomere length remains uncertain. We have used a recently introduced real-time quantitative PCR method to measure the factor by which the ratio of telomere repeat copy number to single gene copy number differs between a sample and that of a reference DNA sample. We compared relative telomere length in 4 types of B cell tumour whose VH genes may be either unmutated or mutated. In 24 cases of mutated CLL mean relative length was 4.24 (range 0.16–24.13) compared to 0.81 (range 0.1–3.1) in 21 cases of unmutated CLL, p= 0.004. However, analysis of 8 mutated and 7 unmutated CLL cases using the poor prognosis Vh3-21 gene showed no significant difference between the two subsets. In non-CLL cases, the mean relative telomere length was 0.7 in 11 cases of B-PLL, 1.9 in 10 cases of MCL and 4.06 (range 0.2–22.7) in 29 cases of SMZL. In the latter 3 disorders there was again no significant difference in mean relative telomere length between mutated and unmutated cases. However, when SMZL patients were divided into 2 groups with relative telomere lengths above or below the median, 11/14 patients with stable disease had long telomeres whereas 10/15 patients with progressive disease had short telomeres, p= 0.025. We then compared 26 cases of stage A, mutated CLL, of whom 13 had stable disease for >10 years and 13 had progressive disease. There was no significant difference in telomere length at presentation between the 2 groups nor on follow up testing of samples from 7 patients from each group with a mean of 92 months between test samples. In contrast, 5 cases with stable, stage A, unmutated CLL for >8years had a longer mean relative telomere length of 2.15 (range 1.29–4.12) than the cohort of 21 unmutated cases with progressive disease described above p=0.002. These data confirm the differences in mean telomere length among different B cell tumours and between mutated and unmutated CLL, but suggest that mutational status per se does not influence telomere length, while in SMZL and unmutated CLL, rate of cell proliferation is reflected in telomere length.