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Low incidence of androgen receptor gene mutations in human prostatic tumors using single strand conformation
B A Evans1, M E Harper, C E Daniells
1Department of Child Health, Tenovus Cancer Research Centre, University of Wales College of Medicine, Health Park, Cardiff, United Kingdom.
Abstract:
It is possible that structural changes of the androgen receptor (AR) contribute to the insensitivity of prostatic carcinomas to endocrine therapy. We have isolated DNA from 58 human prostate tumor specimens (31 carcinomas pretreatment, 13 carcinomas after relapse to hormonal therapy, and 14 benign prostatic hyperplasia), three established human prostate carcinoma cell lines and two transplantable human prostatic carcinoma xenografts. Twelve pairs of oligonucleotide primers were used to amplify the majority of the coding region of the AR gene and the products screened for mutations using single-strand conformation polymorphism (SSCP) techniques. In one tumor sample a cytosine to guanine transition in exon F which leads to substitution of glutamic acid for the wild type glutamine at position 798 of the ligand binding domain was detected. The same mutation was also found in the patient's genomic DNA and as been described in a patient with partial androgen insensitivity syndrome. Intronic mutations were detected in two of the benign prostatic hyperplasia samples, and a silent mutation at nucleotide 995 was found to be present in eight poorly differentiated carcinomas, one BPH specimen, as well as in the cell line DU145 (18% of the samples studied). In agreement with most of the literature, these studies indicate that AR mutations are rare both prior to therapy and even in androgen relapsed tumors.
Insights
Androgen receptor (AR) gene mutations are uncommon in prostate cancer, even after hormonal therapy. This study found AR mutations rarely contribute to endocrine therapy insensitivity in prostatic carcinomas.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Prostate carcinomas can develop resistance to endocrine therapy.
- Structural changes in the androgen receptor (AR) may underlie this insensitivity.
Purpose of the Study:
- To investigate the frequency and types of androgen receptor (AR) gene mutations in human prostate tumor specimens and cell lines.
- To determine if AR mutations are associated with endocrine therapy resistance in prostatic carcinomas.
Main Methods:
- DNA was isolated from 58 human prostate tumor specimens (pretreatment, post-relapse, and benign hyperplasia), 3 cell lines, and 2 xenografts.
- The coding region of the AR gene was amplified using 12 primer pairs.
- Single-strand conformation polymorphism (SSCP) techniques were used to screen for mutations.
Main Results:
- A mutation in exon F (cytosine to guanine transition) leading to a glutamine to glutamic acid substitution at position 798 in the ligand binding domain was detected in one tumor sample and the patient's genomic DNA.
- This specific mutation has been previously described in partial androgen insensitivity syndrome.
- Intronic mutations were found in two benign prostatic hyperplasia samples.
- A silent mutation at nucleotide 995 was present in 18% of samples studied, including poorly differentiated carcinomas, BPH, and the DU145 cell line.
Conclusions:
- Androgen receptor (AR) mutations appear to be rare in prostatic carcinomas, both before and after hormonal therapy.
- The findings suggest that AR mutations are infrequently responsible for endocrine therapy insensitivity in prostate cancer.