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Huang et al. J Transl Genet Genom 2021;5:240-9 https://dx.doi.org/10.20517/jtgg.2021.14 Page 246

[19]
Shiota et al. reported a completely opposite conclusion based on a cohort of 99 Japanese patients with
CRPC using abiraterone. Patients carrying variant genotypes (CC or AC) had significantly lower
progression risk (HR = 0.32; P = 0.006) and lower all-cause mortality risk (HR = 0.40; P = 0.04) compared
[33]
with others carrying the AA genotype. Furthermore, Shiota et al. also studied the combinational use of
HSD3B1 and 5α-reductase (encoding by SRD5A2), a key enzyme for conversion of testosterone into DHT.
They showed that HSD3B1 (AA) with variant genotype of SRD5A2 led to the worst response to abiraterone
in the state of CRPC.

In summary, germline variants of HSD3B1 influence the therapeutic effects of patients with CRPC,
especially for abiraterone and enzalutamide. However, there exists a contradiction with regard to the exact
function. Further studies are necessary to figure out the role of HSD3B1.

Potential role of the HSD3B1 in the clinical management of PCa
Based on the published studies, the role of germline HSD3B1(1245C) in PCa is summarized as follows: (1)
in the state of CSPC, HSD3B1(1245C) accelerates resistance to ADT, especially for patients with low-
volume diseases; (2) for the survival outcome of patients with CSPC undergoing ADT, evidence of the
impact of HSD3B1(1245C) is not sufficient; (3) in the state of CRPC, HSD3B1(1245C) affects the efficiency
of clinical management but cannot be a reliable biomarker because of conflicting results; and (4) for the
survival outcome of patients with CRPC, HSD3B1(1245C) probably has a negative effect.

Although how HSD3B1 functions is still not clear, the HSD3B1 genotype can still provide some advice for
clinical management. For patients with advanced PCa receiving ADT, HSD3B1 variant genotypes can
remind physicians to pay more attention to the progression of resistance to ADT. When choosing other
medical therapies, germline variants of HSD3B1 can act as a reference according to current studies.

Additionally, further studies are worth performing to demonstrate the effect of HSD3B1 variants on clinical
management of PCa. In theory, HSD3B1(1245C), as an adrenal-permissive allele, is considered to induce a
switch to a reduced tumor dependence on gonadal androgens and augmented dependence on extragonadal
androgens. According to the study by Khalaf et al. , the treatment effect and survival outcome were more
[31]
favorable in the cohort where ARPIs were used as first-line therapy than other cohorts where previous first-
line therapies were allowed. These two facts suggest that using ARPIs in the state of CSPC might benefit
patients carrying HSD3B1 variants. In recent years, abiraterone with ADT was also shown to improve the
prognosis of CSPC [34,35] . As a result, a predictive role of HSD3B1 variants for abiraterone used in the state of
CSPC is a potential topic of further research.

Besides, some points provide potential directions for future study in order to identify the association
between HSD3B1 and the clinical management of PCa. First, HSD3B1 variants present a significant inter-
ethnic disparity. For example, the frequency of HSD3B1(1245C) is 34% for European, 20% for American,
16% for South Asian, 9% for African, and 8% for East Asian patients . Inter-ethnic disparity may be one of
[36]
the explanations to the opposite outcomes about the effect of HSD3B1(1245C) on abiraterone. Second, loss
of heterozygosity (LOH) is presented in the HSD3B1 gene. Hearn et al. observed that 3 of 11 (27%)
[17]
patients with HSD3B1 (AC) had developed CRPC with LOH of the wild-type allele, whereas none had lost
the variant allele. This observation might explain the better treatment outcome when ARPIs were used as
first-line therapy. Third, Hearn et al. concluded that the influence of HSD3B1 depends on the tumor
[21]
burden (the extent of metastatic disease), which might be worth in-depth study. At last, it remains to be
studied whether HSD3B1 can be treated as a therapeutic target for PCa, about which no work has been
reported up to now. However, the therapeutic potential of targeting HSD3B1 was reported in triple-negative