Telomere Dysfunction in Peripheral Lymphocytes as a Potential Predisposition Factor for Renal Cancer

Purpose: Genetic integrity is maintained in part by the architecture of telomeres. We previously developed a laser scanning cytometry based quantitative fluorescence in situ hybridization assay to assess telomere length in peripheral blood lymphocytes. In this study we modified the assay by incorporating 9 control cell lines to normalize telomere length. Materials and Methods: We applied this assay to 65 patients with renal cell carcinoma, and 65 age, sex and ethnicity matched controls. For each subject we measured telomere length in CD4⁺ T cells, CD8⁺ T cells and overall peripheral blood lymphocytes. Results: For cases vs controls mean normalized telomere length ± SD was 0.84 ± 0.15 vs 0.95 ± 0.18 for CD4⁺ T cells, 0.80 ± 0.21 vs 0.95 ± 0.22 for CD8⁺ T cells and 0.88 ± 0.25 vs 0.99 ± 0.22 for overall peripheral blood lymphocytes (each p <0.05). After adjustment for patient age, sex, ethnicity and smoking status, and using 75% of telomere length in controls as a cutoff point, short telomere length in CD4⁺ T cells was associated with a significantly increased risk of renal cell carcinoma (OR 3.08, 95% CI 1.14-8.34). Compared to individuals within the highest quartile of telomere length the OR for those within the 3rd, 2nd and 1st quartiles was 1.81 (95% CI 0.54-6.08), 2.15 (95% CI 0.67-6.91) and 5.41 (95% CI 1.78-16.4), respectively (p for trend <0.01). Similar trends were observed in CD8⁺ T cells and overall peripheral blood lymphocytes. In controls there was no significant difference among the telomere lengths of CD4⁺ T cells, CD8⁺ T cells and overall PBLs. Conclusions: Our data argue against the possibility that telomere length difference between cancer cases and controls may be due to the variations of lymphocyte subpopulation or clonal expansion. Our data strongly support the hypothesis that telomere shortening in peripheral blood lymphocytes is a genetic predisposing factor for cancer.