title: Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis.
abstract: Chromosomal instability appears to be key to the pathogenesis of malignant transformation in human cancers, yet the precise molecular mechanisms underlying chromosomal rearrangements remain largely unknown. Telomeres stabilize and protect the ends of chromosomes, but shorten because of cell division and/or oxidative damage. Critically short telomeres, in the setting of abrogated DNA damage checkpoints, have been shown to cause chromosomal instability in vitro and in animal models, leading to an increased cancer incidence as a result of chromosome fusions, subsequent breakage, and rearrangement. We present results from a quantitative, high-resolution, in situ method for telomere length assessment used to test the hypothesis that telomere shortening is an early contributor to human tumorigenesis. High-grade prostatic intraepithelial neoplasia (HGPIN) is a putative preinvasive precursor of prostatic adenocarcinoma, the most common noncutaneous malignancy in Western men. The telomere lengths of epithelial cells within HGPIN lesions were strikingly shorter than those of adjacent normal appearing epithelial cells in 93% (28 of 30) of lesions examined. This shortening is similar to what has been shown in fully invasive prostate adenocarcinomas. Interestingly, telomere shortening was restricted to the luminal epithelial cells of HGPIN and was not present in the underlying basal epithelial cells; this provides strong evidence that basal cells are most likely not the direct targets of neoplastic transformation. These findings reveal that telomere shortening is a defining somatic DNA alteration characterizing HGPIN. The implications of this are that the earliest phase of human prostate carcinogenesis may proceed as a consequence of chromosomal instability mediated by shortened, dysfunctional telomeres.
authors.affiliation: Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21231, USA.
authors.forename: Alan K
authors.initials: AK
authors.lastname: Meeker
authors.forename: Jessica L
authors.initials: JL
authors.lastname: Hicks
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Platz
authors.forename: Gerrun E
authors.initials: GE
authors.lastname: March
authors.forename: Christina J
authors.initials: CJ
authors.lastname: Bennett
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Delannoy
authors.forename: Angelo M
authors.initials: AM
authors.lastname: De Marzo
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure; D000368:Aged; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics* / Q000648:ultrastructure; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure; D016615:Telomere / Q000235:genetics* / Q000648:ultrastructure