Overexpression of the cyclin-dependent kinase inhibitor p16 is associated with tumor recurrence in human prostate cancer

The INK4A gene maps to the 9p21 region and was initially described [M. Serrano et al., Nature (Lond.), 366: 704-707, 1993; A. Kamb et at, Science (Washington DC), 264: 436-440, 1994] as encoding a 148-amino-acid protein termed p16, The p16 protein associates exclusively with Cdk4 and Cdk6, inhibiting their complexation with D-type cyclins and the consequent phosphorylation of pRb, This contributes to cell cycle arrest. The purpose of the present study was to evaluate patterns of p16 expression in a well-characterized cohort of prostatic adenocarcinomas while exploring potential associations between alterations of p16 and clinicopathological variables. Normal and malignant tissues from 88 patients with prostate carcinoma were examined. In situ hybridization and immunohistochemistry assays were used to determine the status of the INK4A exon 1 alpha transcripts and levels of p16 protein, respectively. Associations between altered patterns of expression and clinico-pathological variables, including pretreatment prostate-specific antigen (PSA) level, Gleason grade, pathological stage, and hormonal status, were evaluated using the Mantel-Haenszel chi(2) test. Biochemical (PSA) relapse after surgery was evaluated using the Kaplan-Meier method and the log-rank test. Levels of p16 expression and INK4A exon Icu transcripts in normal prostate and benign hyperplastic tissues were undetectable. However, p16 nuclear overexpression was observed in 38 (43%) prostate carcinomas, whereas the remaining 50 (57%) cases showed undetectable p16 levels. Overexpression of p16 protein was found to correlate with increased INK4A exon 1 alpha transcripts. Moreover, p16 overexpression was associated with a higher pretreatment PSA level (P = 0.018), the use of neoadjuvant androgen ablation (P = 0.001), and a sooner time to PSA relapse after radical prostatectomy (P = 0.002). These data suggest that p16 overexpression is associated with tumor recurrence and a poor clinical course in patients with prostate cancer.