Epigenetic events highlight the challenge of validating prognostic biomarkers during the clinical and biologic evolution of prostate cancer.

The association of molecular events with prostate cancer behavior presents dual opportunities for increased molecular insight and improved care. The promise of molecular oncology relies on the belief that optimal clinical care will result from a comprehensive understanding of the molecular pathogenesis of cancer and the specific genetic events present within an individual’s tumor. In this issue of Journal of Clinical Oncology, Richiardi et al have associated methylation of APC with poor prognosis in two independent cohorts of prostate cancer patients. The strong association between epigenetic silencing of APC and poor prognosis additionally supports a role for WNT/ -catenin signaling in aggressive prostate cancer and introduces a novel prognostic biomarker with which clinicians may be able to better anticipate prostate cancer behavior. Epigenetic silencing of targeted genes is one of the earliest molecular alterations commonly found in prostate neoplasia. Methylation of the CpG-enriched promoter region of GSTP1 has been recognized for more than a decade as a frequent, early event with potential as a diagnostic biomarker. More comprehensive screens of promoter methylation patterns demonstrate consistent changes associated with the development and progression of prostate cancer and, in the first publication from the Cancer Genome Atlas Project supported by the National Human Genome Research Institute of the National Institutes of Health, epigenetic silencing was complementary to genetic loss in activating critical signaling pathways. Thus, epigenetic control of gene expression is fundamental to cancer biology; as a result, assays for epigenetic alterations have the potential to become accurate diagnostic, prognostic, and predictive biomarkers. Richiardi et al report on a retrospective analysis of promoter methylation of three genes, GSTP1, RUNX3, and APC, in two cohorts of patients with prostate cancer from Turin, Italy. Men were diagnosed with prostate cancer after biopsy of the prostate, transurethral resection of the prostate, or radical prostatectomy, and each had available paraffin-embedded tumor tissue and long-term follow-up. The first cohort was comprised of specimens collected in the 1980s, before widespread use of prostate-specific antigen (PSA) screening (n 216; 1982 to 1988), and the second cohort included specimens collected in the 1990s (n 243; 1993 to 1996) after the adoption of PSA screening. Promoter methylation of the APC gene was associated with increased risk of prostate cancer–specific mortality in both cohorts (1980s hazard ratio [HR], 1.42; 95% CI, 0.98 to 2.07; 1990s cohort HR, 1.57; 95% CI, 0.95 to 2.62; combined HR, 1.49; 95% CI, 1.11 to 2.00). Promoter methylation of GSTP1 had no association with disease-specific mortality in either cohort, and promoter methylation of GATA2 was associated with increased prostate cancer–specific mortality in the earlier cohort (odds ratio [OR], 2.17; 95% CI, 1.48 to 3.18) but not in the more contemporary cohort. When evaluated as single events, the degree of risk associated with promoter methylation for APC or GATA2 was less than that for high-grade tumors (Gleason sum 8; 1980s cohort OR, 2.17; 95% CI, 1.48 to 3.18; 1990s cohort OR, 3.27; 95% CI, 2.00 to 5.37). However, there was a progressive increase in prostate cancer mortality risk as the number of genes with methylated promoters increased (no methylated promoters HR, 0.80; 95% CI, 0.31 to 2.08; one methylated promoter HR, 1.00 [reference]; two methylated promoters HR, 1.53; 95% CI, 1.24 to 3.15; three methylated promoters HR, 1.97; 95% CI 1.24 to 3.15; P for trend .002). This study underscores the potential role for epigenetic biomarkers and highlights the challenges in validating molecular biomarkers while the natural history of prostate cancer is evolving. A substantial body of research focuses on the role for GSTP1 as a tissue-, blood-, urine-, and semen-based biomarker. Although GSTP1 promoter methylation occurs with greater frequency in malignant epithelial cells, it is commonly observed in premalignant prostate epithelial cells and has relatively limited utility as a tissue-based diagnostic biomarker for prostate cancer. However, GSTP1 promoter methylation in cell-free serum DNA and in urine may be more specific for prostate cancer and eventually may be helpful for diagnosis. As a prognostic biomarker, conflicting reports focus on GSTP1 promoter methylation; some find a positive association with risk of recurrence after radical prostatectomy, and others find no association. In the current report, Richiardi et al found no association between GSTP1 promoter methylation and the robust prognostic outcome of prostate cancer–specific mortality. Overall, GSTP1 promoter methylation may have a future role as a biomarker, but its diagnostic or prognostic potential when used as a single molecular event appears quite limited. A critical and as yet unresolved question raised by studies that focused on epigenetic changes in prostate cancer is whether a general hypermethylation phenotype is more important than the decreased expression of the specific genes targeted. Although GSTP1 is commonly targeted for promoter methylation, GSTP1/P2 knockout mice do not develop cancers at increased rates, either as an individual event or when crossed with a p53-null background, although they JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 19 JULY 1 2009