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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 242

[15]
As shown in Table 1, since Ross et al. first reported in 2008 that SNPs rs1870050 in CYP19A1 [hazard
ratio (HR) = 0.60; P = 0.0007], rs1856888 in HSD3B1 (HR = 0.58; P = 0.0047), and rs7737181 in HSD17B4
(HR = 0.70; P = 0.0096) were related to shorter time to progression, the role of HSD3B1 in PCa has been
paid close attention by researchers because 3βHSD1 encoded by HSD3B1 is necessary for the synthesis of
non-testicular testosterone or DHT. Wu et al. in 2015 first summarized that HSD3B1(1245C) PCa is more
[16]
likely to progress to CRPC, according to a retrospective study involving 85 patients with AA genotype and
18 with AC genotype who were diagnosed as advanced PCa and underwent surgical castration. However, no
significant disparity of overall survival time was shown related to HSD3B1.

Hearn et al. reported that HSD3B1(1245C) is significantly associated with PCa resistance to ADT. As a
[17]
multi-cohort study, they enrolled 443 patients treated with ADT after prostatectomy from three cohorts: the
post-prostatectomy cohort from the Cleveland Clinic registry, the post-prostatectomy validation cohort
from the Mayo Clinic SPORE registry, and the metastatic validation cohort from the Mayo Clinic metastatic
prostate cancer registry. The frequency of variant was 26%-36%. In the primary cohort, compared with the
AA genotype group, the CC genotype groups (HR = 2.4; P = 0.029) and the AC group (HR = 1.7; P = 0.041)
were associated with worse progression-free survival (PFS). However, in the other two cohorts, CC showed
the same significant effect on development to CRPC, while the association between the AC genotype and
the progression of CRPC was not significant (HR = 1.1; P = 0.38). In addition, the variant allele was
predictive to a worse overall survival.

[18]
Subsequently, a few studies came to similar conclusions. Agarwal et al. retrospectively analyzed 102
patients with metastatic CSPC accepting ADT. The frequency of variant was 31%. Compared with the PFS
in the AA genotype group, in the CC genotype group, PFS was shorter (11 months vs. 21 months; HR =
2.16; P = 0.046), while that in the AC genotype groups was similar (19 months vs. 21 months; HR = 1.04; P =
0.86). Shiota et al. also performed an analysis on a primary ADT cohort with 104 Japanese patients of
[19]
metastatic CSPC where the frequency of variant was 5%. The results shown that patients with the CC
genotype and the AC genotype were more likely to be resistant to ADT (HR = 2.34; P = 0.03) but had no
significant difference for mortality.

[20]
Hearn et al. furthered their studies on the basis of their original report. Instead of post-prostatectomy,
focusing on patients undergoing ADT post-radiotherapy, the study proved that HSD3B1(1245C) was also
associated with rapid development of metastases. Furthermore, analyses were performed on the E3805
Chemohormonal Therapy Versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate
Cancer cohort which included patients with metastatic PCa undergoing ADT with or without docetaxel.
They concluded that HSD3B1(1245C) was related to earlier development of CRPC (HR = 1.89; P = 0.02) and
shorter overall survival (HR = 1.74; P = 0.045) in patients with low-volume disease but not in patients with
high-volume disease .
[21]

The current clinical studies on the role of HSD3B1 in CSPC patients treated with ADT are discussed above.
With regard to the effect of HSD3B1 (CC) for accelerating the resistance to ADT and progression to CRPC,
the results of current studies are in agreement. A meta-analysis by Han et al. confirmed this conclusion
[22]
and also concluded that HSD3B1 had no association with mortality. Except the outcome in the primary
cohort of the Hearn’s study in 2016 , HSD3B1(1245C) was noted to have no impact on the mortality of
[17]
[23]
CSPC. At a more fundamental level, Chen et al. reported that HSD3B1 was marginally significantly
associated with impaired survival outcome. Based on the study by Hearn et al. , the effect of HSD3B1 was
[21]
only found in patients with low-volume PCa. It was difficult to derive a precise conclusion from the analysis
for the overall cohort. In addition, it is worth noting that the association between the AC genotype and