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Mutational analysis of the TrkA gene in prostate cancer
D J George1, H Suzuki, G S Bova
1Department of Medical Oncology, Johns Hopkins Medical Institution, Baltimore, Maryland, USA.
Background:
TrkA, the high affinity, tyrosine kinase receptor for nerve growth factor (NGF) has been implicated as an oncogene in several neoplasms. In prostate cancer, inhibitors of the NGF/TrkA signal pathway results in tumor growth inhibition. In contrast, inhibition of this trk pathway in the normal prostate produces no effect. One explanation for this difference between normal and malignant prostate is that TrkA is mutated in prostate cancer, changing its function. To test this possibility human primary prostate cancers were screened for evidence of mutations in the TrkA gene to identify how this gene might be activated in prostate cancer.
Methods:
Single-strand conformation polymorphism was used to screen genomic DNA, isolated from 42 human primary prostate cancers. In samples in which an aberrant banding pattern was identified, the screen was repeated using both the tumor DNA and DNA isolated from normal tissue of the same patients. Genetic changes were confirmed by direct sequencing of the aberrantly migrating bands.
Results:
Although somatic mutations were not identified in any of the exons screened, four polymorphisms were detected in three different exons. Some of these polymorphisms occurred in the majority of the patients screened, but their frequencies were similar when compared with DNA isolated from a control group.
Conclusions:
Genetic mutations of TrkA do not seem to play a significant role in activation of this pathway in prostate cancer. However, the absence of mutations in otherwise genetically unstable prostate tumor DNA suggests that intact NGF/TrkA pathways may be important in prostate cancer development.
Insights
Genetic mutations in the TrkA gene do not appear to drive prostate cancer. The NGF/TrkA pathway may still be crucial for prostate tumor development, even without TrkA mutations.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- The TrkA receptor tyrosine kinase, activated by nerve growth factor (NGF), is implicated in various cancers.
- Inhibition of the NGF/TrkA pathway slows prostate cancer growth but not normal prostate tissue.
- This suggests TrkA may be altered in prostate cancer, prompting investigation into its mutations.
Purpose of the Study:
- To screen human prostate cancers for mutations in the TrkA gene.
- To understand how the TrkA gene might be activated in prostate cancer development.
Main Methods:
- Screening of genomic DNA from 42 primary prostate cancers using single-strand conformation polymorphism.
- Confirmation of genetic changes through direct sequencing of aberrantly migrating bands.
Main Results:
- No somatic mutations were found in the screened TrkA exons.
- Four polymorphisms were detected in three exons, with similar frequencies in patients and controls.
Conclusions:
- TrkA gene mutations do not seem to significantly activate the NGF/TrkA pathway in prostate cancer.
- The lack of TrkA mutations in prostate tumors suggests the intact NGF/TrkA pathway is important for prostate cancer development.