Variant allele of HSD3B1 increases progression to castration-resistant prostate cancer.
BACKGROUND
3β-hydroxysteroid dehydrogenase type 1 (3βHSD1), which is a rate-limiting enzyme that catalyzes the conversion of adrenal-derived steroid dehydroepiandrosterone to dihydrotestosterone (DHT), may be a promising target for treating castration-resistant prostate cancer (CRPC).


METHODS
From 2004 to 2011, a total of 103 consecutive patients presenting with advanced prostate cancer were included in this study. All patients were treated with surgical castration as androgen-deprivation therapy (ADT). Germline DNA was extracted from archived tissue from each patient and sequenced. PSA half-time (representing rate to PSA nadir after ADT), the incidence of, and time to CRPC occurrence, and cause-specific mortality rates were determined during the 3-10 years follow-up. The perioperative data and postoperative outcomes are compared. The patients were retrospectively analyzed for survival time.


RESULTS
Of the 103 patient samples analyzed, 18 harbored a heterozygous variant (1245C) HSD3B1 gene, while 85 patients were homozygous wild-type (1245A) for HSD3B1. The two groups were homogenous for age, PSA, Gleason and metastases rate preoperatively. The incidence of CRPC observed in the variant group was significantly higher than that of wild-type group (100% vs. 64.7%, respectively; P = 0.003). Despite this higher incidence of CRPC, there were no significant differences in time to develop CRPC, or in cause-specific mortality. Further, neither PSA half-time, nor time to biochemical recurrence were different between the variant and wild-type groups.


CONCLUSIONS
Prostate cancer patients who harbored the heterozygous variant HSD3B1 (1245C) are more likely to develop to CRPC, but do not have shorter time to biochemical recurrence, shorter survival time or higher mortality risk.
Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai, PR China.
Gang
G
Wu
Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai, PR China.
Shengsong
S
Huang
Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, New York, USA.
Kent L
KL
Nastiuk
Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai, PR China.
Jinliang
J
Li
Department of Pathology, Tongji Hospital, Tongji University School of Medicine, Shanghai, PR China.
Jun
J
Gu
Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai, PR China.
Ming
M
Wu
Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai, PR China.
Qimin
Q
Zhang
State Key Laboratory of Molecular Biology, Shanghai Key Laboratory of Andrology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, PR China.
Hanqing
H
Lin
Department of Urology, Tongji Hospital, Tongji University School of Medicine, Shanghai, PR China.
Denglong
D
Wu
D000368:Aged; D001483:Base Sequence; D004273:DNA, Neoplasm / Q000737:chemistry / Q000235:genetics; D018450:Disease Progression; D014644:Genetic Variation; D006801:Humans; D007610:Kallikreins / Q000097:blood; D053208:Kaplan-Meier Estimate; D008297:Male; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000235:genetics / Q000378:metabolism*; D011375:Progesterone Reductase / Q000235:genetics / Q000378:metabolism*; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000097:blood / Q000201:enzymology / Q000235:genetics / Q000378:metabolism*; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D013251:Steroid Isomerases / Q000235:genetics / Q000378:metabolism*
C021425:3 beta-hydroxysteroid oxidoreductase-delta(5) 3-ketosteroid isomerase; D004273:DNA, Neoplasm; D009097:Multienzyme Complexes; D011375:Progesterone Reductase; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen; D013251:Steroid Isomerases
HSD3B; androgen deprivation therapy; castration-resistant prostate cancer; germline mutation; prostate cancer