TY - JOUR
T1 - Polymorphisms in androgen metabolism genes with serum testosterone levels and prognosis in androgen-deprivation therapy
AU - Shiota, Masaki
AU - Endo, Satoshi
AU - Fujimoto, Naohiro
AU - Tsukahara, Shigehiro
AU - Ushijima, Miho
AU - Kashiwagi, Eiji
AU - Takeuchi, Ario
AU - Inokuchi, Junichi
AU - Uchiumi, Takeshi
AU - Eto, Masatoshi
N1 - Funding Information:
This work was supported by the JSPS KAKENHI grant [17K11145], the Research Promotion Grant from the Japanese Urological Association, and the Medical Research Promotion Grant from Takeda Science Foundation.
PY - 2020/11
Y1 - 2020/11
N2 - Objective: Androgen metabolism is a key component in therapeutic resistance to androgen deprivation therapy (ADT). This study aimed to reveal the significance of genetic polymorphisms in genes involved in androgen metabolism, including CYP17A1, AKR1C3, and HSD17B, on serum testosterone levels during ADT, as well as the prognosis of men undergoing ADT for metastatic prostate cancer (CaP). Materials and methods: This study included 104 Japanese patients with metastatic CaP, for whom serum testosterone data during ADT were available for 80 patients. The association of CYP17A1 (rs743572), AKR1C3 (rs12529), HSD17B1 (rs605059), HSD17B3 (rs2066479), and HSD17B4 (rs7737181) with serum testosterone levels during ADT and prognosis (progression-free survival and overall survival) was examined. Enzymatic activity in AKR1C3 H5Q was examined using recombinant protein. Results: Homozygous wild-type (GG allele; median [interquartile range], 12.0 ng/ml [8.0–19.0 ng/ml]) AKR1C3 rs12529 was associated with higher serum testosterone levels during ADT compared with variant-type (GC/CC alleles; median [interquartile range], 9.0 ng/ml [6.4–10.8 ng/ml]). Consistently, variant-type (GC/CC alleles) AKR1C3 rs12529 showed significantly lower risk of progression (hazard ratio [95% confidence interval], 0.47 [0.24–0.96], P = 0.039) compared with homozygous wild-type (GG allele) on multivariate analysis. Meanwhile, other genetic variations were associated with neither serum testosterone during ADT nor prognosis. Enzyme activity of wild-type AKR1C3 was comparable to the H5Q mutant. Conclusions: Taken together, this study demonstrated that AKR1C3 polymorphism, which was associated with serum testosterone levels during ADT, may be a prognostic factor of the progression to castration-resistant prostate cancer in Japanese men with metastatic CaP.
AB - Objective: Androgen metabolism is a key component in therapeutic resistance to androgen deprivation therapy (ADT). This study aimed to reveal the significance of genetic polymorphisms in genes involved in androgen metabolism, including CYP17A1, AKR1C3, and HSD17B, on serum testosterone levels during ADT, as well as the prognosis of men undergoing ADT for metastatic prostate cancer (CaP). Materials and methods: This study included 104 Japanese patients with metastatic CaP, for whom serum testosterone data during ADT were available for 80 patients. The association of CYP17A1 (rs743572), AKR1C3 (rs12529), HSD17B1 (rs605059), HSD17B3 (rs2066479), and HSD17B4 (rs7737181) with serum testosterone levels during ADT and prognosis (progression-free survival and overall survival) was examined. Enzymatic activity in AKR1C3 H5Q was examined using recombinant protein. Results: Homozygous wild-type (GG allele; median [interquartile range], 12.0 ng/ml [8.0–19.0 ng/ml]) AKR1C3 rs12529 was associated with higher serum testosterone levels during ADT compared with variant-type (GC/CC alleles; median [interquartile range], 9.0 ng/ml [6.4–10.8 ng/ml]). Consistently, variant-type (GC/CC alleles) AKR1C3 rs12529 showed significantly lower risk of progression (hazard ratio [95% confidence interval], 0.47 [0.24–0.96], P = 0.039) compared with homozygous wild-type (GG allele) on multivariate analysis. Meanwhile, other genetic variations were associated with neither serum testosterone during ADT nor prognosis. Enzyme activity of wild-type AKR1C3 was comparable to the H5Q mutant. Conclusions: Taken together, this study demonstrated that AKR1C3 polymorphism, which was associated with serum testosterone levels during ADT, may be a prognostic factor of the progression to castration-resistant prostate cancer in Japanese men with metastatic CaP.
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U2 - 10.1016/j.urolonc.2020.06.033
DO - 10.1016/j.urolonc.2020.06.033
M3 - Article
C2 - 32712140
AN - SCOPUS:85088360121
VL - 38
SP - 849.e11-849.e18
JO - Urologic Oncology
JF - Urologic Oncology
SN - 1078-1439
IS - 11
ER -