Potential Prognostic Value Of Telomere Lengths In Prostate Cancer

Telomere shortening has been found to be predictive of poor prognosis in several cancers, including those of the lung, endometrium, breast, and neuroblastoma (65-68). A potential link between telomere length and prostate cancer prognosis was first reported by Donaldson et al., using a slot blot method devised by Bryant et al., which measures relative telomeric DNA content as a surrogate for telomere length (69). In this retrospective case-control study, both lack of biochemical recurrence and overall survival were statistically significantly correlated with tumor telomere length as measured by this assay. Specifically, all seven prostatectomy patients whose tumor telomeric DNA contents were less than that of control samples (placenta) showed evidence of biochemical recurrence (elevated prostate-specific antigen [PSA] levels) within 10 years after surgery (70). Of nine patients with short tumor telomeres, seven died within 10 years, in contrast to 100% 10-year survival for patients with normal-to-long tumor telomeres; these patients also showed no evidence of disease recurrence. Potential drawbacks of this study include a small sample size (18 cases; only 7 of 9 men in the short telomere category underwent surgery), and the fact that it was not known whether the deaths observed were specifically caused by prostate cancer.

In a more recent retrospective study using 77 prostatectomy samples and a more sensitive chemi-luminescent slot blot assay, Fordyce et al. reported that less-than-normal telomere content in primary prostate cancers was associated with recurrence, independent of patient age, pathologic grade (Gleason sum), and regional lymph node status (71). The magnitude of the relative hazard for disease recurrence associated with low telomere content was on par with that of Gleason grade and nodal status. Interestingly, a positive correlation was found between the telomere content of the tumor and that of the surrounding normal-appearing prostate tissue within the same prostatectomy samples. An association was also found between telomere content of the normal-appearing prostate tissues and 72-month recurrence-free survival. The authors postulated that telomere loss in morphologically normal tissue may represent areas at heightened risk of experiencing genetic instability. This is reminiscent of the so-called "field effect" phenomenon that has long been discussed in the cancer literature (72-75). The authors further proposed that cancers arising in such areas may show greater genotypic and phenotypic heterogeneity, and, thus, be more prone to behave aggressively because of a greater level of CIN caused by short telomeres (71).

Fig. 2. Telomere shortening occurs early in prostate tumorigenesis and is limited to luminal epithelial cells. Image analysis was used to quantify telomere lengths in specific prostatic cell types within histologically normal tissue (upper left) and prostatic intraepithelial neoplasia (PIN) lesions. Each point plotted represents the telomere content of an individual cell. Note that telomere shortening is pronounced in the luminal epithelial cells in the three PIN lesions (77).

Fig. 2. Telomere shortening occurs early in prostate tumorigenesis and is limited to luminal epithelial cells. Image analysis was used to quantify telomere lengths in specific prostatic cell types within histologically normal tissue (upper left) and prostatic intraepithelial neoplasia (PIN) lesions. Each point plotted represents the telomere content of an individual cell. Note that telomere shortening is pronounced in the luminal epithelial cells in the three PIN lesions (77).

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