Originally published as JCO Early Release 10.1200/JCO.2008.18.2485 on May 26 2009

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Promoter Methylation in APC, RUNX3, and GSTP1 and Mortality in Prostate Cancer Patients

From the Cancer Epidemiology Unit, Center for Experimental Research and Medical Sciences and Center for Oncologic Prevention Piemonte, University of Turin; Department of Pathology, Molinette Hospital, Turin, Italy; and Clinical Epidemiology Unit, Karolinska Institutet, Stockholm, Sweden.

Corresponding author: Lorenzo Richiardi, MD, PhD, Cancer Epidemiology Unit, University of Turin, Via Santena 7, 10126 Turin, Italy; e-mail: lorenzo.richiardi{at}unito.it.

Purpose There is a need to better understand prostate cancer progression and identify new prognostic markers for this tumor. We investigated the association between promoter methylation in a priori selected genes and survival in two independent large series of prostate cancer patients.

Methods We followed up with two cohorts of patients (216 patients diagnosed in 1982 to 1988 and 243 patients diagnosed in 1993 to 1996) diagnosed at one hospital pathology ward in Turin, Italy. DNA was obtained from paraffin-embedded tumor tissues and evaluated for promoter methylation status in glutathione S-transferase (GSTP1), adenomatous polyposis coli (APC), and runt-related transcription factor 3 (RUNX3).

Results The two cohorts had different prevalences of methylation in APC (P = .047), GSTP1 (P = .002), and RUNX3 (P < .001). Methylation in APC was associated with an increased risk of prostate cancer–specific mortality (hazard ratio [HR] = 1.42; 95% CI, 0.98 to 2.07 in the 1980s cohort; HR = 1.57; 95% CI, 0.95 to 2.62 in the 1990s cohort; HR = 1.49; 95% CI, 1.11 to 2.00 in the two cohorts combined). In subgroup analyses, the HRs were higher among patients with a Gleason score less than 8 (HR = 1.52; 95% CI, 0.85 to 2.73 in the 1980s cohort; HR = 2.09; 95% CI, 1.02 to 4.28 in the 1990s cohort). Methylation in RUNX3 was associated with prostate cancer mortality only in the 1990s cohort, and methylation in GSTP1 did not predict mortality in either cohort.

Conclusion The pattern of hypermethylation may have changed after the introduction of prostate-specific antigen testing in the beginning of the 1990s. Promoter methylation in APC was identified as a marker for prostate cancer progression.

Supported in part by the Italian Association for Cancer Research; the Compagnia San Paolo/FIRMS; the Piedmont Region; the Italian Ministry of University; and by the Master in Epidemiology, University of Turin, and San Paolo Foundation (L.V.).

Presented in part at the 98th Annual Meeting of the American Association for Cancer Research, April 14-18, 2007, Los Angeles, CA; and the XXXI Annual Meeting of the Italian Association for Epidemiology, Marina di Ostuni (Brindisi), Italy, October 17-19, 2007.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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