Abstract
Recently, genetic polymorphism in HSD3B1 encoding 3β-hydroxysteroid dehydrogenase-1 has been shown to be associated with oncological outcome when treated with androgen-deprivation therapy (ADT) for prostate cancer. Upfront abiraterone combined with ADT has proved survival benefit. However, its effect on oncological outcome among different ethnicities and in abiraterone treatment remain unclear. To investigate the significance of missense polymorphism in HSD3B1 gene among men treated with primary ADT or abiraterone. This prognostic study included Japanese patients with metastatic hormone-sensitive prostate cancer between June 1993 and July 2005 and with castration-resistant prostate cancer between September 2014 and February 2018. Genome DNA was obtained from patient whole blood samples, and genotyping on HSD3B1 (rs1047303, 1245C) was performed by Sanger sequencing. Primary ADT for metastatic hormone-sensitive prostate cancer and abiraterone for castration-resistant prostate cancer. The association of genotype in HSD3B1 with clinicopathological parameters and oncological outcome, including prostate-specific antigen response, progression-free survival, treatment failure-free survival, and overall survival was examined. Of 203 men, 104 were in the primary ADT cohort (median [interquartile range] age, 72 [67-76] years) and 99 men were in the abiraterone group (median [interquartile range] age, 74 [67-80] years). Most patients carried metastatic lesions in each cohort. Among the cohort of primary ADT, men carrying heterozygous and homozygous variant types in HSD3B1 gene showed higher progression risk (hazard ratio [HR], 2.34; 95% CI, 1.08-4.49; P = .03) but not any-caused death risk (HR, 1.36; 95% CI, 0.52-2.92; P = .50), compared with men carrying homozygous wild type. In contrast, among the abiraterone cohort, men carrying variant type in HSD3B1 gene showed lower progression risk (HR, 0.32; 95% CI, 0.12-0.69; P = .006) and lower all-cause mortality risk (HR, 0.40; 95% CI, 0.13-0.94; P = .04) compared with men carrying homozygous wild type. This study showed that HSD3B1 genetic variant is distinctly associated with oncological outcome between primary ADT and abiraterone in Japanese men, suggesting universal significance among different ethnicities in primary ADT, as well as promise as a predictive biomarker of ADT and abiraterone.
Highlights
Androgens play critical roles in prostate carcinogenesis as well as prostate cancer progression
Among the cohort of primary androgen-deprivation therapy (ADT), men carrying heterozygous and homozygous variant types in HSD3B1 gene showed higher progression risk but not any-caused death risk (HR, 1.36; 95% CI, 0.52-2.92; P = .50), compared with men carrying homozygous wild type
This study showed that HSD3B1 genetic variant is distinctly associated with oncological outcome between primary ADT and abiraterone in Japanese men
Summary
Androgens play critical roles in prostate carcinogenesis as well as prostate cancer progression. Since 1941, androgen-deprivation therapy (ADT), which reduces testosterone production and inhibits androgen action in prostate cancer cells, has been the criterion standard therapy for metastatic prostate cancer.[1] initially most prostate cancers respond well to ADT, most patients eventually progress to castration-resistant prostate cancer (CRPC), which is mainly thought to be because androgen receptor reactivation is induced by several mechanisms.[2] One of those mechanisms has been identified to be intratumoral androgen synthesis mostly from adrenal precursor steroids and at least in part due to de novo synthesis from cholesterol,[3,4] which is supported by increased expression of several genes encoding steroidogenic enzymes including HSD3B, HSD17B, and SRD5A in CRPC.[5] Among them, HSD3B1 encodes 3β-hydroxysteroid dehydrogenase-1, which is mainly expressed in peripheral tissues including the prostate, breast, skin, and placenta (another isoform, 3β-hydroxysteroid dehydrogenase-2 was mainly expressed in adrenal gland and gonad in human) and is a rate-limiting enzyme required for all pathways of dihydrotestosterone synthesis.[6] Recently, a mutation (1245A→C) in HSD3B1 was shown to provide a novel mechanism of resistance to ADT,[7] where amino acid 367 Asn→Thr is changed and 3β-hydroxysteroid dehydrogenase-1 is rendered to be resistant to proteasomal degradation, causing substantial accumulation of this enzyme and gain of function. The HSD3B1 (1245C) allele can be acquired by mutation, germ-line single-nucleotide polymorphism (rs1047303) is known to exist
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