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Analysis of genetic changes underlying local recurrence of prostate carcinoma during androgen deprivation therapy
P Koivisto1, E Hyytinen, C Palmberg
1Laboratory of Cancer Genetics, Tampere University, Institute of Medical Technology, Finland.
Abstract:
The molecular mechanisms and genetic changes that lead to the progression of prostate cancer during endocrine therapy are poorly characterized. Here, paired specimens from both untreated primary tumors and from local recurrences were collected from 10 prostate cancer patients treated by conventional androgen deprivation therapy. The genetic progression of the tumors was studied by using interphase fluorescence in situ hybridization and chromosome-specific probes. Six primary tumors (60%) and all ten recurrent tumors were aneuploid by fluorescence in situ hybridization. The recurrent tumors also showed a high degree of chromosome copy number variability from one cell to another. Increased copy number of chromosome X was particularly common in the recurrent tumors. In addition, specific high level amplification of the androgen receptor (AR) gene (Xq12) was detected in three highly aneuploid recurrent tumors. Our findings suggest that hormone-refractory prostate cancers are genetically very complex and show intratumor genetic heterogeneity. Increased copy number of chromosome X and the amplification of the androgen receptor (AR) gene may confer proliferative advantage during androgen deprivation and thus contribute to the development of recurrence.
Insights
Prostate cancer recurrence during hormone therapy is linked to genetic changes. Aneuploidy and androgen receptor (AR) gene amplification in recurrent tumors may drive resistance to treatment.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Prostate cancer progression under endocrine therapy lacks clear molecular understanding.
- Genetic alterations driving resistance to androgen deprivation therapy are poorly defined.
Purpose of the Study:
- To investigate the genetic changes in prostate tumors progressing during androgen deprivation therapy.
- To characterize the genomic complexity and heterogeneity of recurrent prostate cancers.
Main Methods:
- Paired analysis of untreated primary and recurrent tumors from 10 prostate cancer patients.
- Interphase fluorescence in situ hybridization (FISH) and chromosome-specific probes used for genetic analysis.
- Assessment of chromosome copy number and gene amplification, specifically for the androgen receptor (AR) gene.
Main Results:
- All ten recurrent tumors and six primary tumors (60%) exhibited aneuploidy via FISH.
- Recurrent tumors displayed significant chromosome copy number variability and increased copy number of chromosome X.
- High-level amplification of the androgen receptor (AR) gene was identified in three aneuploid recurrent tumors.
Conclusions:
- Hormone-refractory prostate cancers are genetically complex with substantial intratumor heterogeneity.
- Increased chromosome X copy number and AR gene amplification may promote tumor growth during androgen deprivation.
- These genetic alterations likely contribute to the development of recurrent, treatment-resistant prostate cancer.