Advanced

Pattern of somatic androgen receptor gene mutations in patients with hormone-refractory prostate cancer.

Hyytinen, Eija-R; Haapala, Kyllikki; Thompson, James; Lappalainen, Ilkka; Roiha, Mikko; Rantala, Immo; Helin, Heikki J; Jänne, Olli A; Vihinen, Mauno LU and Palvimo, Jorma J, et al. (2002) In Laboratory Investigation 82(11). p.1591-1598
Abstract
Progression to hormone-refractory growth of prostate cancer has been suggested to be mediated by androgen receptor (AR) gene alterations. We analyzed AR for mutations and amplifications in 21 locally recurrent prostate carcinomas treated with orchiectomy, estrogens, or a combination of orchiectomy and estramustine phosphate using fluorescence in situ hybridization, single-strand conformation polymorphism, and DNA sequence analyses. Amplification was observed in 4 of 16 (25%) and amino acid changing mutations was observed in 7 of 21 (33%) of the tumors, respectively. Two (50%) tumors with AR amplification also had missense mutation of the gene. Four of five (80%) cancers that were treated with a combination of orchiectomy and estramustine... (More)
Progression to hormone-refractory growth of prostate cancer has been suggested to be mediated by androgen receptor (AR) gene alterations. We analyzed AR for mutations and amplifications in 21 locally recurrent prostate carcinomas treated with orchiectomy, estrogens, or a combination of orchiectomy and estramustine phosphate using fluorescence in situ hybridization, single-strand conformation polymorphism, and DNA sequence analyses. Amplification was observed in 4 of 16 (25%) and amino acid changing mutations was observed in 7 of 21 (33%) of the tumors, respectively. Two (50%) tumors with AR amplification also had missense mutation of the gene. Four of five (80%) cancers that were treated with a combination of orchiectomy and estramustine phosphate had a mutation clustered at codons 514 to 533 in the N-terminal domain of AR. In functional studies, these mutations did not render AR more sensitive to testosterone, dihydrotestosterone, androstenedione, or beta-estradiol. Tumors treated by orchiectomy had mutations predominantly in the ligand-binding domain. In summary, we found molecular alterations of AR in more than half of the prostate carcinomas that recurred locally. Some tumors developed both aberrations, possibly enhancing the cancer cell to respond efficiently to low levels of androgens. Furthermore, localization of point mutations in AR seems to be influenced by the type of treatment. (Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Prostatic Neoplasms: genetics, Hormone-Dependent: therapy, Hormone-Dependent: genetics, Neoplasms, Estramustine: therapeutic use, Local: genetics, Neoplasm Recurrence, Prostatic Neoplasms: therapy, Receptors, Androgen: genetics
in
Laboratory Investigation
volume
82
issue
11
pages
1591 - 1598
publisher
Nature Publishing Group
external identifiers
  • pmid:12429819
  • scopus:0036847896
ISSN
1530-0307
language
English
LU publication?
no
id
09a0c0dd-5588-47e8-8449-8a4755fa67b6 (old id 3635587)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/12429819?dopt=Abstract
date added to LUP
2013-06-12 15:57:59
date last changed
2017-09-17 08:13:19
@article{09a0c0dd-5588-47e8-8449-8a4755fa67b6,
  abstract     = {Progression to hormone-refractory growth of prostate cancer has been suggested to be mediated by androgen receptor (AR) gene alterations. We analyzed AR for mutations and amplifications in 21 locally recurrent prostate carcinomas treated with orchiectomy, estrogens, or a combination of orchiectomy and estramustine phosphate using fluorescence in situ hybridization, single-strand conformation polymorphism, and DNA sequence analyses. Amplification was observed in 4 of 16 (25%) and amino acid changing mutations was observed in 7 of 21 (33%) of the tumors, respectively. Two (50%) tumors with AR amplification also had missense mutation of the gene. Four of five (80%) cancers that were treated with a combination of orchiectomy and estramustine phosphate had a mutation clustered at codons 514 to 533 in the N-terminal domain of AR. In functional studies, these mutations did not render AR more sensitive to testosterone, dihydrotestosterone, androstenedione, or beta-estradiol. Tumors treated by orchiectomy had mutations predominantly in the ligand-binding domain. In summary, we found molecular alterations of AR in more than half of the prostate carcinomas that recurred locally. Some tumors developed both aberrations, possibly enhancing the cancer cell to respond efficiently to low levels of androgens. Furthermore, localization of point mutations in AR seems to be influenced by the type of treatment.},
  author       = {Hyytinen, Eija-R and Haapala, Kyllikki and Thompson, James and Lappalainen, Ilkka and Roiha, Mikko and Rantala, Immo and Helin, Heikki J and Jänne, Olli A and Vihinen, Mauno and Palvimo, Jorma J and Koivisto, Pasi A},
  issn         = {1530-0307},
  keyword      = {Prostatic Neoplasms: genetics,Hormone-Dependent: therapy,Hormone-Dependent: genetics,Neoplasms,Estramustine: therapeutic use,Local: genetics,Neoplasm Recurrence,Prostatic Neoplasms: therapy,Receptors,Androgen: genetics},
  language     = {eng},
  number       = {11},
  pages        = {1591--1598},
  publisher    = {Nature Publishing Group},
  series       = {Laboratory Investigation},
  title        = {Pattern of somatic androgen receptor gene mutations in patients with hormone-refractory prostate cancer.},
  volume       = {82},
  year         = {2002},
}