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Age and Obesity Promote Methylation and Suppression of 5-Alpha Reductase 2- Implications for Personalized Therapy in BPH
Seth K. Bechis, MD MS, Alexander G. Otsetov, MD, Rongbin Ge, MD PhD, Zongwei Wang, PhD, Mark G. Vangel, PhD, Chin-Lee Wu, MD PhD, Shahin Tabatabaei, MD, Aria F. Olumi, MD.
Massachusetts General Hospital, Boston, MA, USA.
INTRODUCTION:
5α reductase 2 (5AR2) plays a key role in prostate growth and BPH progression. While 5α reductase inhibitors (5ARIs) are a main modality of treatment for men suffering bladder outlet obstruction secondary to BPH, over 30% of men are resistant to the therapeutic effects of 5ARIs. We have previously found that 30% of benign prostate samples do not express 5AR2, suggesting a mechanism for resistance to therapy. In this study we obtained prostate specimens from men undergoing surgical intervention for symptomatic BPH and sought to identify whether 5AR2 expression was linked to methylation of the 5AR2 gene promoter. We also assessed whether previously described clinical variables including age, obesity, cardiac risk factors, and prostate specific antigen (PSA) were associated with 5AR expression.
MATERIALS AND METHODS:
We obtained BPH specimens from patients after surgical resection of the prostate. Immunohistochemistry was used to assess for 5AR2 protein expression. Methylation status of the gene promoter was determined using standard immunoprecipitation-based assays. We conducted univariate and multivariate statistical analyses to seek associations with clinical variables including age, body mass index (BMI), hypertension, hyperlipidemia, diabetes, prostate specific antigen (PSA), and prostate volume.
RESULTS:
A total of 96 samples were included in the analysis. A majority (85%) of men were overweight (BMI 25-29) or obese (BMI≥30), and 80% of men who underwent surgical management of their bladder outlet obstruction were medically treated preoperatively with an α-blocker, 5ARI, or both. BMI and age were significantly correlated with methylation status of the 5AR2 gene promoter (p<0.05), whereas prostate volume, PSA, or use of BPH medication were not. Methylation status was highly correlated with 5AR protein expression (p<0.0001). As expected, prostate volume was associated with age and PSA (p<0.01). Using multivariate linear regression to form a predictive model, both age and BMI significantly predicted methylation status and protein expression (p<0.01).
CONCLUSIONS:
Age and BMI correlate with methylation status of the 5AR2 gene promoter in symptomatic BPH samples. In addition, 5AR2 methylation is highly correlated with absence of protein expression. These results highlight the interplay between age, obesity and gene regulation. Our findings suggest the presence of an epigenetic signature for symptomatic BPH resistant to 5ARIs, which may be important for choosing appropriate treatment options.
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