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Author: Suzuki, H.; Akakura, K.; Komiya, A.; Aida, S.; Akimoto, S.;
Shimazaki, J.
Year: 1996
Title: Codon 877 mutation in the androgen receptor gene in advanced
prostate cancer: relation to antiandrogen withdrawal syndrome
Journal: Prostate
Volume: 29
Issue: 3
Pages: 153-8
Label: 96424622
Keywords: Aged
Amino Acid Sequence
Androgen Antagonists/*adverse effects
Chlormadinone Acetate/therapeutic use
*Codon
*Genes
Human
Male
*Mutation
Orchiectomy
Polymerase Chain Reaction
Polymorphism, Single-Stranded Conformational
Prostate-Specific Antigen/analysis
Prostatic Neoplasms/*genetics/mortality/physiopathology
Receptors, Androgen/*genetics
Substance Withdrawal Syndrome/*genetics
Support, Non-U.S. Gov't
Variation (Genetics)
Abstract: The growth of prostate cancer is androgen responsive, and androgen
receptor (AR) is thought to play an important role in the development
of this cancer. Recently, some reports demonstrated that AR gene
mutations were detected in human prostate cancer tissues. We have
previously reported that one of eight endocrine therapy-resistant
prostate cancer cases showed AR gene mutation [Suzuki et al: J
Steroid Biochem Mol Biol 46:759-765, 1993]. To further investigate
structural abnormality of the AR in a large number of human prostate
cancers, exons B-H encoding DNA-and hormone-binding domains were
examined by single-strand conformation polymorphism analysis of
polymerase chain reaction products and direct sequencing. Tissues
surgically removed from 30 cases of stage B or C prostate cancer
and from 22 cases of endocrine therapy-resistant cancers obtained
at autopsy were used in the study. Three out of 22 cancer death
cases (14%) revealed AR gene mutations, one of which contained
two different mutations-exon D in cancerous prostate and exon
H in metastatic tissues. In the other two cases, AR gene mutations
in exon H were found in metastatic tissues. All three cases in
metastatic tissues showed the same mutation at codon 877 (877Thr-->Ala).
In stage B or C cancer tissues and the other cancer death samples,
no AR mutation was detected. The mutation in exon H was identical
to that reported in a human prostate cancer cell line, LNCaP.
These results indicate that AR gene mutation scarcely occurs in
the early stage of prostate cancer and that the mutation is found
in relation to endocrine therapy resistance. Two patients with
an AR gene mutation at codon 877 revealed a remarkable fall in
prostate-specific antigen after withdrawal of antiandrogen. Data
on the other case were not available. These results indicate that
a codon 877 mutation in the AR gene in advanced prostate cancer
evokes the antiandrogen withdrawal syndrome. To our knowledge,
this report is the first description of relationship between an
AR mutation at codon 877 and the antiandrogen withdrawal syndrome.