ABSTRACT
In DNA from prostate tumors, methylation patterns in gene promoter regions can be a biomarker for disease progression. It remains unclear whether methylation patterns in benign prostate tissue--prior to malignant transformation--may provide similar prognostic information. To determine whether early methylation events predict prostate cancer outcomes, we evaluated histologically benign prostate specimens from 353 men who eventually developed prostate cancer and received "definitive" treatment [radical prostatectomy (58%) or radiation therapy (42%)]. Cases were drawn from a large hospital-based cohort of men with benign prostate biopsy specimens collected between 1990 and 2002. Risk of disease progression associated with methylation was estimated using time-to-event analyses. Average follow-up was over 5 years; biochemical recurrence (BCR) occurred in 91 cases (26%). In White men, methylation of the APC gene was associated with increased risk of BCR, even after adjusting for standard clinical risk factors for prostate cancer progression (adjusted hazard ratio (aHR) = 2.26; 95%CI 1.23-4.16). APC methylation was most strongly associated with a significant increased risk of BCR in White men with low prostate specific antigen at cohort entry (HR = 3.66; 95%CI 1.51-8.85). In additional stratified analyses, we found that methylation of the RARB gene significantly increased risk of BCR in African American cases who demonstrated methylation of at least one of the other four genes under study (HR = 3.80; 95%CI 1.07-13.53). These findings may have implications in the early identification of aggressive prostate cancer as well as reducing unnecessary medical procedures and emotional distress for men who present with markers of indolent disease.
Subject(s)
Carcinogenesis/genetics , DNA Methylation , Prostatic Hyperplasia/genetics , Prostatic Neoplasms/genetics , Aged , Cohort Studies , Disease Progression , Gene Expression Regulation, Neoplastic , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Proportional Hazards Models , Prostate/pathology , Prostatic Hyperplasia/pathology , Risk , Sequence Analysis, DNAABSTRACT
PURPOSE: Gene promoter hypermethylation may be useful as a biomarker for cancer risk in histopathologically benign prostate specimens. MATERIALS AND METHODS: We performed a nested case-control study of gene promoter methylation status for 5 genes (APC, RARB, CCND2, RASSF1 and MGMT) measured in benign biopsy specimens from 511 prostate cancer case-control pairs. We estimated the overall and race stratified risk of subsequent prostate cancer associated with methylation status. RESULTS: On race stratified analysis RARB methylation was associated with a higher cancer risk in black American men (OR 2.18, 95% CI 1.39-3.44). APC methylation was associated with an increased risk of high grade tumors (OR 2.43, 95% CI 1.20-4.90), which was higher in black than in white men (OR 3.21 vs 2.04). In cases RARB and APC gene methylation in benign prostate samples persisted in matched malignant specimens. In black cases the combined risk associated with RARB and APC methylation (OR 3.04, 95% CI 1.44-6.42) was greater than the individual risk of each gene and significantly different from that in white cases (OR 1.14, 95% CI 0.56-2.30). CONCLUSIONS: RARB gene methylation in histopathologically benign prostate samples was associated with a statistically significant increased risk of subsequent prostate cancer in black men. Methylation data on additional genes may improve risk stratification and clinical decision making algorithms for cancer screening and diagnosis.
Subject(s)
Black or African American/genetics , DNA Methylation/genetics , Genetic Predisposition to Disease/epidemiology , Prostatic Neoplasms/ethnology , Prostatic Neoplasms/genetics , Receptors, Retinoic Acid/genetics , Age Distribution , Aged , Biopsy, Needle , Case-Control Studies , Confidence Intervals , Gene Expression Regulation, Neoplastic , Humans , Immunohistochemistry , Incidence , Male , Middle Aged , Neoplasm Invasiveness/pathology , Neoplasm Staging , Odds Ratio , Prognosis , Promoter Regions, Genetic , Prostatic Neoplasms/pathology , Reference Values , Retrospective Studies , Risk Assessment , White People/geneticsABSTRACT
Polycyclic aromatic hydrocarbon (PAH)-DNA adducts may induce mutations that contribute to carcinogenesis. We evaluated potential associations between smoking and polymorphisms in PAH metabolism [CYP1A1 Ile 462Val, CYP1B1 Ala 119Ser and Leu 432Val, microsomal epoxide hydrolase (mEH) Tyr 113His and His139Arg, CYP3A4 A(-392)G] and conjugation [glutathione S-transferase (GST) M1 null deletion, GSTP1 Ile 105Val] genes and PAH-DNA adduct levels (measured by immunohistochemistry) in tumor and nontumor prostate cells in 400 prostate cancer cases. Although no statistically significant associations were observed in the total sample, stratification by ethnicity revealed that Caucasian ever smokers compared with nonsmokers had higher adduct levels in tumor cells (mean staining intensity in absorbance units +/- SE, 0.1748 +/- 0.0052 versus 0.1507 +/- 0.0070; P = 0.006), and Caucasians carrying two mEH 139Arg compared with two 139His alleles had lower adducts in tumor (0.1320 +/- 0.0129 versus 0.1714 +/- 0.0059; P = 0.006) and nontumor (0.1856 +/- 0.0184 versus 0.2291 +/- 0.0085; P = 0.03) cells. African Americans with two CYP1B1 432Val compared with two 432Ile alleles had lower adducts in tumor cells (0.1600 +/- 0.0060 versus 0.1970 +/- 0.0153; P = 0.03). After adjusting for smoking status, carrying the putative "high-risk" genotype combination, the faster metabolism of PAH-epoxides to PAH-diol-epoxides (CYP1B1 432Val/Val and mEH 139Arg/Arg) with lower PAH-diol-epoxide conjugation (GSTP1 (105)Ile/Ile), was associated with increased adducts only in Caucasian nontumor cells (0.2363 +/- 0.0132 versus 0.1920 +/- 0.0157; P= 0.05). We present evidence, for the first time in human prostate that the association between smoking and PAH-DNA adducts differs by race and is modified by common genetic variants.
