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Somatic mutations at the SRD5A2 locus encoding prostatic steroid 5alpha-reductase during prostate cancer progression
A Akalu1, D A Dlmajian, R A Highshaw
1Institute for Genetic Medicine and Department of Biochemistry, University of Southern California, School of Medicine, Los Angeles 90033, USA.
Abstract:
Prostate cancer is a serious public health problem in many industrialized countries. Androgens appear to play a critical role in its etiology. Specifically, the active androgen in the prostate, dihydrotestosterone (DHT) which is synthesized by the enzyme steroid 5alpha-reductase from testosterone (T), acts as a mitogen. Hence androgen-deprivation is commonly used during prostate cancer therapy. Two isozymes for steroid 5alpha-reductase have been reported. The type II enzyme is prostate-specific and encoded by the SRD5A2 gene. We have investigated a polymorphic (TA)n dinucleotide repeat in the 3' UTR (untranslated region) of the SRD5A2 gene in 30 matched samples of constitutional ("germline") DNA from peripheral blood lymphocytes and microdissected, pure tumor DNA. We report here 8 LOH (loss of heterozygosity) events and 9 cases of microsatellite instability at this marker. Therefore, almost 57% of the samples examined showed evidence of somatic mutations at the 3' UTR of the SRD5A2 locus. Our data suggest that the SRD5A2 gene may be involved in prostate cancer progression and that this may have relevance for treatment of the disease.
Insights
Genetic mutations in the SRD5A2 gene are common in prostate cancer. These alterations in the 3' untranslated region may drive cancer progression and influence treatment strategies.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Prostate cancer is a significant public health concern.
- Androgens, particularly dihydrotestosterone (DHT), are crucial in prostate cancer development.
- Steroid 5alpha-reductase synthesizes DHT from testosterone (T), making it a therapeutic target.
Purpose of the Study:
- To investigate mutations in the polymorphic (TA)n dinucleotide repeat within the 3' untranslated region (UTR) of the SRD5A2 gene.
- To determine the potential role of the SRD5A2 gene in prostate cancer progression.
Main Methods:
- Analysis of matched constitutional DNA (peripheral blood lymphocytes) and tumor DNA from 30 prostate cancer patients.
- Genotyping of a (TA)n dinucleotide repeat polymorphism in the 3' UTR of the SRD5A2 gene.
- Assessment for loss of heterozygosity (LOH) and microsatellite instability (MSI).
Main Results:
- 8 cases of loss of heterozygosity (LOH) were observed.
- 9 cases of microsatellite instability (MSI) were detected at the SRD5A2 marker.
- Approximately 57% of the samples exhibited somatic mutations in the 3' UTR of the SRD5A2 locus.
Conclusions:
- The SRD5A2 gene, specifically its 3' UTR, frequently undergoes somatic mutations in prostate cancer.
- These genetic alterations suggest the SRD5A2 gene's involvement in prostate cancer progression.
- Findings may have implications for androgen-deprivation therapy strategies in prostate cancer treatment.