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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 244

survival outcome remains unclear. The effect of the AC genotype on promoting resistance to ADT was
[17]
statistically significant in only one study . In contrast, in the other two cohorts of Hearn’s study in 2016
and the cohort in Agarwal’s study, no difference in overall survival was observed between the AC and AA
genotype groups.

Impact of HSD3B1(1245C) on the other medical management is waiting to define
Since the function of germline variants in HSD3B1 was confirmed to promote the development of resistance
to ADT, several works focused on how it influences the outcome when coming to the state of CRPC. It has
been reported that HSD3B1(1245C) might have a negative effect on the overall survival of CRPC. However,
there are contradictions in the existing results about its association with the response to medical
management, such as abiraterone and enzalutamide, in the state of CRPC.

Stangl-Kremser et al. and Chen et al. both summarized the association between HSD3B1(1245C) and
[23]
[24]
survival outcome of patients with CRPC via genetic sequencing of prostate tissue. The former concluded
that there was no relation between HSD3B1(1245C) and survival outcome of CRPC . Similarly, the latter
[24]
reported that HSD3B1(1245C) was related to a trend of worse prognosis for CRPC because of increased
[23]
tumor expression of cell proliferation and cell cycle genes , but without significant difference.

It is not clear whether HSD3B1(1245C) induces an impaired survival outcome in the state of CRPC. It
would also be valuable to explore if germline HSD3B1 is predictive for the reaction to the related medical
management for CRPC. Hearn et al. reported no relation between HSD3B1 and response to docetaxel. In
[21]
addition, as mentioned above, the key mechanism of CRPC development is intertumoral androgen
synthesis and reactivation of AR. Some medical therapies aiming at blocking this process, known as AR
pathway inhibitors (ARPIs), are widely accepted to be applied in the treatment of CRPC, such as AR
antagonists including enzalutamide and CYP17A1 inhibitors including 17α-hydroxylase/17,20-lyase. In
addition, CYP17A1 inhibitors include nonsteroidal and steroidal types. Steroidal CYP17A1 inhibitors, such
as abiraterone, are converted by 3βHSD1, the downstream metabolites of which act as AR agonists, inducing
an opposite effect [25,26] .

Biologically, HSD3B1(1245C) is supposed to invalidate both abiraterone and enzalutamide.
Alyamani et al. [Table 2] conducted a study on the pharmacokinetics and metabolites of the steroidal
[27]
CYP17A1 inhibitor abiraterone. They concluded that HSD3B1 might negate the efficiency of abiraterone
based on the results that the downstream metabolite of abiraterone, 3-keto-5α-abiraterone, which is an AR
agonist, significantly increased with more copies of HSD3B1(1245C), while the level of another metabolite,
D4A, which is an AR antagonist, did not increase. Theoretically, in addition to abiraterone, enzalutamide
may also be negated by HSD3B1(1245C). The permissive adrenal effect of HSD3B1(1245C) causes an
increase of testosterone. It has been reported that increased the AR natural ligand might decrease the
activity of enzalutamide .
[28]
Several clinical studies were performed to identify the role of HSD3B1. Almassi et al. focused on the
[29]
relation between HSD3B1 and the curative effect of the nonsteroidal CYP17A1 inhibitor ketoconazole
among patients with metastatic CRPC. They concluded that HSD3B1(1245C) marginally significantly
prolonged time of progression. Compared with the AA genotype group, the HR of the AC genotype group
for disease progression was 0.6 (P = 0.06) and the HR of the CC genotype group was 0.5 (P = 0.08).
Hahn et al. focused on the predictive effect of HSD3B1(1245C) for patients with CRPC treated with
[30]
abiraterone as first-line therapy, showing that there were no significant associations.