Molecular evidence supporting the precursor nature of atypical adenomatous hyperplasia of the prostate

Abstract

Atypical adenomatous hyperplasia (AAH) of the prostate is characterized by lobular proliferation of closely packed small acini. It is hypothesized that AAH is a precursor lesion for low‐grade prostate cancer arising from the transition zone. Telomere dysfunction is common during malignant transformation of epithelia. In this study, we investigate telomere shortening in AAH (n = 93), high‐grade prostatic intraepithelial neoplasia (HGPIN) ( n = 68), and prostatic adenocarcinoma (PCA) ( n = 70) using quantitative fluorescence in situ hybridization. Twenty percent (19 of 93) of AAH specimens, 68% (46 of 68) of HGPIN, and 83% (58 of 70) of PCA showed significant telomere shortening. Thirty‐two percent of AAH lesions had α‐methylacyl‐CoA racemase (AMACR) expression, a sensitive and specific marker for HGPIN and PCA. AMACR expression in AAH was seen more frequently in AAH foci with telomere shortening or coexisting PCA. Our findings indicate that a subset of AAH lesions have telomere shortening and AMACR expression, suggesting that these foci may be precursors for PCA.

An overview of the role of telomeres and telomerase in pre‑neoplastic lesions (Review)

“…TLs of these lesions differed significantly when compared with one another and the normal tissue (P<0.001). These findings, along with AMACR expression, suggest the premalignant nature of AAH and its role in prostate cancer development (71). Lastly, TL in BPH is associated with race, as African American males have been shown to exhibit significantly shorter telomeres compared to Caucasian males; longer telomeres have also been found to be associated with an increased risk of cancer (72).…”

“…This characteristic is also shared by PIN, but not by BPH, as Southern blot analysis has revealed that normal epithelium and BPH have similar average TLs (6.6 and 6.4 kb, respectively) (70). Using Q-FISH assay, Cheng et al (71) compared TLs between normal epithelium, AAH, high-grade PIN and prostatic adenocarcinoma (PCA). Shortened telomeres were present in 20% of AAH, 68% of high-grade PIN and 83% of PCA samples.…”

TERT promoter mutations and methylation for telomerase activation in urothelial carcinomas: New mechanistic insights and clinical significance

“…Two hotspot mutations occur at the proximal region of the TERT promoter (−124 and −146 bp from the ATG) with a cytidine-tothymidine (C>T) dipyrimidine transition, which are called as C228T (-124C>T) and C250T (-146C>T), respectively (31,32). Across UC subtypes, the frequency of TERT promoter mutations is different, varying from less than 20% in UCU, 45% in UCRPs, to ~85% in UCBs (28,(34)(35)(36)(37)(38)(39)(40)(41)(42)(43)(44)(45)(46)(47)(48)(49). The C228T mutation is predominant and the presence of C228T and C250T is mutually exclusive, indicating a functional redundancy of these two mutations (Figure 2).…”

Histopathology of Prostate Cancer and its Precursors

“…AAH can be difficult to distinguish from low-grade prostatic adenocarcinoma. Very few clinical follow-up studies, even when based on image analysis and molecular investigation, 10,11 have linked this disorder to PCa. Such a link might be difficult to establish if only a small subset of AAH has a premalignant potential.…”