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

Abstract

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.

LINE-1 methylation status in prostate cancer and non-neoplastic tissue adjacent to tumor in association with mortality

“…From previous studies we had qualitative information on promoter hypermethylation of adenomatous polyposis coli (APC) and glutathione S-transferase 1 (GSTP1) in the tumor tissue and in the NTAT. 13,32 We also had stored (at ¡20 C) DNA extracted from the tumor tissue (for all patients) and from NTAT (for 91 patients) as well as stored (at -80 C) bisulfite-modified DNA from NTAT (for 49 patients). For 17 patients, stored DNA (modified or not) from NTAT was not available.…”

“…A detailed description of the 2 cohorts has been published previously. 13 Briefly, for all 459 patients we collected demographic and clinical information (age, residence, source of prostatic tumor tissue-biopsy, radical prostatectomy or transurethral resection of the prostate, and tumor grade) from the pathology reports and traced the corresponding blocks of formalin fixed tumor tissue. All diagnostic slides were traced and reviewed by an uropathologist to assign a uniform Gleason score.…”

“…We adjusted for gene-specific methylation as it has been suggested that global hypomethylation may coexist with gene-specific hypermethylation, and the latter has been associated with mortality from prostate cancer. 13 Additional analyses were performed stratifying by source of tumor tissue and Gleason score (<8, 8).…”

“…[7][8][9] In prostate cancer, hypermethylation of several genes has been associated with tumor aggressiveness in terms of clinical-pathological characteristics, biochemical recurrence, and/or mortality from prostate cancer. [10][11][12][13][14][15][16] Global hypomethylation, which may cause reactivation of the transcription of oncogenes and transposable elements and increases chromosomal instability and loss of imprinting, 17,18 has been less extensively investigated. We have recently conducted a systematic review of studies on prostatic tumor global hypomethylation and prostate cancer progression: 19 although studies were heterogeneous and mostly based on a limited sample size, global hypomethylation was reported to be associated with high Gleason score, advanced tumor stage, high pre-operative PSA, and presence of metastasis.…”

“…The study is nested in cohorts of prostate cancer patients that we have previously studied to assess the role of gene-specific promoter hypermethylation in prostate cancer progression. 13,32 Results Selected characteristics of the 157 study patients are reported in Table 1. Most of the patients (82%) were diagnosed in the 1990s and the source of tissue was equally distributed among biopsy (34.4%), transurethral resection of the prostate (TURP) (34.4%), and radical prostatectomy (31.2%).…”