3βHSD1 immunohistochemistry and HSD3B1 genotype in prostate cancer.

277 Background: 3β-hydroxysteroid dehydrogenase (3βHSD1), encoded by HSD3B1, catalyzes intratumoral androgen synthesis from adrenal precursors. The HSD3B1(1245A>C) germline variant encodes a more stable enzyme that promotes increased DHT synthesis and more rapid clinical progression in men treated with androgen deprivation therapy (ADT). 3βHSD1 localization and expression in prostate tissue has not been rigorously characterized. We hypothesized that HSD3B1 homozygous variant genotype is associated with elevated 3βHSD1 immunoreactivity compared with wild-type (WT) genotype. Methods: In a pilot study, HSD3B1 genotypes were obtained from prostatectomy tissues of 30 patients with prostate cancer (10 WT, 10 heterozygous, and 10 homozygous variant). Following prostatectomy, tumor tissue with adjacent benign prostate was formalin-fixed and paraffin-embedded. Immunostaining for 3βHSD1 using a validated mouse monoclonal antibody was performed. Human placenta was used as a positive control. Immunostaining patterns and histology was qualitatively assessed by a GU pathologist. Immunoreactivity was quantitatively assessed using ImagePro7. Results: Qualitative IHC scoring localizes 3βHSD1 to epithelial cells in prostatic glands and urothelium, with faint muscle and stromal staining. 3βHSD1 was immunoreactive in 100% of prostates in both benign and malignant regions. When stratified by HSD3B1 genotype, the mean density/intensity was significantly greater for HSD3B1 homozygous variant prostate (670.10u) compared to heterozygous (174.69u) and WT (176.19u) (p=0.044). (Density/Intensity) per square micron demonstrated higher mean values for homozygous variant (35.79)> heterozygous (28.67) >WT (22.56) (p=0.52). Conclusions: These pilot data demonstrate differential tissue expression of 3βHSD1 according to HSD3B1 genotype: importantly, homozygous variant HSD3B1 (1245A>C) specimen showed the most robust 3βHSD1 expression compared to heterozygous and WT prostates. These results explore the potential for 3βHSD1 as a prostate biomarker to predict aggressive disease.