title: Telomere attrition in isolated high-grade prostatic intraepithelial neoplasia and surrounding stroma is predictive of prostate cancer.
abstract: The causes of early genomic events underlying the development of prostate cancer (CaP) remain unclear. The onset of chromosomal instability is likely to facilitate the formation of crucial genomic aberrations both in the precursor lesion high-grade prostatic intraepithelial neoplasia (HPIN) and in CaP. Instability generated by telomere attrition is one potential mechanism that could initiate chromosomal rearrangements. In this study, normalized telomere length variation was examined in a cohort of 68 men without CaP who had HPIN only on prostatic biopsies. Multiple significant associations between telomere attrition and eventual diagnosis of CaP in the HPIN and in the surrounding stroma were found. Kaplan-Meier analysis of telomere length demonstrated a significantly increased risk for the development of cancer with short telomeres in the surrounding stroma [P = .035; hazard ratio (HR) = 2.12; 95% confidence interval (95% CI) = 0.231-0.956], and a trend for HPIN itself (P = .126; HR = 1.72; 95% CI = 0.287-1.168). Cox regression analysis also demonstrated significance between the time from the original biopsy to the diagnosis of cancer and telomere length in HPIN and in the surrounding stroma. These analyses showed significance, both alone and in combination with baseline prostate-specific antigen, and lend support to the hypothesis that telomere attrition in prostatic preneoplasia may be fundamental to the generation of chromosomal instability and to the emergence of CaP.
authors.affiliation: Department of Medical Biophysics, University of Toronto, Toronto, Canada.
authors.forename: Anthony Michael
authors.initials: AM
authors.lastname: Joshua
authors.forename: Bisera
authors.initials: B
authors.lastname: Vukovic
authors.forename: Ilan
authors.initials: I
authors.lastname: Braude
authors.forename: Sundus
authors.initials: S
authors.lastname: Hussein
authors.forename: Maria
authors.initials: M
authors.lastname: Zielenska
authors.forename: John
authors.initials: J
authors.lastname: Srigley
authors.forename: Andrew
authors.initials: A
authors.lastname: Evans
authors.forename: Jeremy Andrew
authors.initials: JA
authors.lastname: Squire
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D043171:Chromosomal Instability; D004249:DNA Damage; D005453:Fluorescence; D006801:Humans; D008297:Male; D008875:Middle Aged; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics* / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D012044:Regression Analysis; D016615:Telomere