Overexpression of the cell cycle inhibitor p16(INK4A) in high-grade prostatic intraepithelial neoplasia predicts early relapse in prostate cancer patients

Prostate cancer (PC) is the most commonly diagnosed male cancer in industri alized societies. No molecular markers of PC progression or outcome with pr oven clinical utility have been described, Because the loss of normal cell cycle control is an early event in the evolution of cancer, we sought to de termine whether changes in expression of the cyclin-dependent kinase inhibi tor, p16(INK4A), predicted outcome in this disease. We screened a cohort of 206 patients with clinically localized PC treated with radical prostatecto my for overexpression of the INK4A gene, the product of which inactivates t he G(1)-phase cyclin dependent kinases, Cdk4 and Cdk6. p16(INK4A) protein e xpression was evaluated by immunohistochemistry in areas of high-grade intr aepithelial neoplasia (HGPIN), a precursor to invasive disease, and of canc er in the same specimen, Data were evaluated for disease relapse using the Kaplan-Meier method and in a Cox proportional hazards model by assessing p1 6(INK4A) status in areas of HGPIN and canter with other variables of known clinical relevance, Overexpression of p16(INK4A) in HGPIN and cancer was co rrelated,vith, but independent of, pathological stage and was associated wi th early relapse in PC patients treated with radical prostatectomy (log-ran k test, P < 0.001), In a multivariate model adjusted for Gleason grade, pre treatment prostate-specific antigen levels, pathological stage, and margin status, overexpression of p16(INK4A) in HGPIN was an independent predictor of disease relapse and increased the risk of recurrence 2.24-fold (95% conf idence interval, 1.28-3.93), These data provide the first evidence for a pr ognostic marker in HGPIN. The clinical utility of p16(INK4A) status in stra tifying patients for aggressive treatment very early in the disease process , potentially several years prior to the onset of invasive disease, require s further investigation.