Telomere Variability Is Common in Neoplastic Urothelium and Associated Morphologically Normal Urothelium
DE Hansel, Y Konishi, AK Meeker. The Cleveland Clinic, Cleveland, OH; The Johns Hopkins Hospital, Baltimore, MD
Background: Telomeres are situated at the ends of chromosomes and serve to prevent aberrant chromosomal fusions and to regulate cellular senescence. Variable telomere lengths, including both abnormally short and long telomeres, have been reported in pre-invasive and invasive carcinomas and have been proposed to contribute to the genetic instability characteristic of these lesions. Urothelial carcinomas (UCCs) generally arise from well-characterized precursor lesions and are often multifocal in nature. In order to determine the role of telomere variability in UCC, we examined not only invasive carcinoma and flat urothelial carcinoma in situ (CIS), but also in adjacent morphologically normal urothelium.
Design: Telomere lengths were quantitatively assessed by the Telomere-Immunostaining Fluorescence in Situ Hybridization (TELI-FISH) technique followed by use of a custom software plugin (http://bui2.win.ad.jhu.edu/telometer/) written for the open source image analysis software program ImageJ (http://rsbweb.nih.gov/ij/). Fifteen to twenty nuclei from stromal cells and accompanying normal or lesional tissue were quantified.
Results: We examined 10 invasive UCCs, 5 matched CIS cases, 10 matched morphologically normal urothelium adjacent to UCC, and 5 cases of normal urothelium from patients with no precedent or subsequent urothelial malignancy. True normal urothelium demonstrated an average telomere length of 0.73 relative to stroma, whereas urothelium adjacent to UCC or CIS demonstrated markedly shortened telomere lengths in 3 cases (30%) of 0.35, 0.37 and 0.41. Shortened telomeres were also present in 3/5 CIS lesions (range 0.2 to 0.41) and 5/10 invasive UCCs (range 0.18 to 0.55). In contrast, 2 cases of invasive UCC demonstrated increased telomere lengths relative to associated normal stroma. The remainder of cases (1 CIS, 3 invasive UCCs) demonstrated telomere lengths within the range of normal stroma.
Conclusions: Telomere variability, predominantly telomere shortening, commonly occurs in pre-invasive and invasive UCC, supporting an early pathogenic role of telomere dysfunction in bladder cancer. Importantly, a subset of morphologically normal urothelium adjacent to in situ and invasive UCC also demonstrated shortened telomeres, suggesting telomere dysfunction as a potential key step in the earliest neoplastic transformation of the urothelium, prior to morphologically identifiable changes.
Category: Genitourinary (including renal tumors)
Tuesday, March 10, 2009 1:00 PM
Poster Session IV # 148, Tuesday Afternoon