The association between genetic variants in HSD3B1 and clinical management of PCa

Abstract

Androgen is an important factor in the occurrence and progression of prostate cancer. The principal clinical strategy is androgen deprivation therapy (ADT). However, progression to castrate-resistant prostate cancer (CRPC) is almost inevitable to occur after ADT. One of the key mechanisms is the intertumoral synthesis of androgen where 3β-hydroxysteroid dehydrogenase isoenzyme-1 (3βHSD1, encoded by HSD3B1) catalyzes the ratelimiting step. A germline missense-encoding variant of HSD3B1(1245A>C, rs1047303) has been the focus of research because HSD3B1(1245C) works as an adrenal-permissive allele and encodes a more stable enzyme that promotes the synthesis of androgen. Several studies were performed to explore the role of HSD3B1(1245C) in the development of CRPC and the outcome of clinical management. Thus, we searched the published research articles using the keywords "prostate cancer" and "HSD3B1", in PubMed and Embase database. After reviewing the abstracts and full articles, 16 original research articles from 45 search results were finally selected and reviewed. Based on the current evidence, HSD3B1(1245C) is proposed to accelerate ADT resistance and the development of CRPC. It is also associated with a poorer prognosis of PCa treated with ADT. However, due to conflicting results, the association between HSD3B1(1245C) and the effect of next-generation hormone therapy (i.e., abiraterone) for patients with CRPC is not clear enough. In conclusion, HSD3B1(1245C) has value for predicting the outcome of PCa and potential to be involved in therapeutic decision making.

Role of single nucleotide polymorphisms of the HSD3B1 gene (rs6203 and rs33937873) in the prediction of prostate cancer risk

“…In the current study, the suggested polymorphisms, either G313A or C338T, may create a new potential protein with different structure and function which induces cellular carcinogenesis, resistance and apoptosis ( 57 ). Another suggestion is that the two polymorphisms may render HSD3B1 resistant to ubiquitination and proteasomal degradation, leading to a large amount of protein (DHT) accumulation in the cell, causing prostate tissue carcinogenesis as well as resistance to androgen-deprivation therapy in PC recurrence ( 57 – 60 ). The results suggested that these variants of the HSD3B1 steroidogenic enzyme gene could be a powerful new biomarker capable of identifying patients with aggressive disease who warrant early escalated therapy and in clinical management of the disease.…”