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PTEN/MMAC1 expression in melanoma resection specimens
M Deichmann1, M Thome, A Benner
1Department of Dermatology, University Clinics of Heidelberg, Vossstrasse 2, 69115 Heidelberg, Germany. martin_deichmann@med.uni-heidelberg.de
Abstract:
PTEN/MMAC1, a tumour suppressor gene located on chromosome 10q23.3, has been found to be deleted in several types of human malignancies. As the chromosomal region 10q22-qter commonly is affected by losses in melanomas, we addressed this gene as tumour suppressor candidate in melanomas. Investigating PTEN/MMAC1 expression at mRNA level by semi-quantitative reverse transcription-polymerase chain reaction, we did not find a statistically significant down-regulation in melanoma resection specimens in comparison to acquired melanocytic nevi from which melanomas quite often are known to arise. Upon immunohistochemistry, PTEN/MMAC1 protein expression in melanomas was not lost. Sequencing the PTEN/MMAC1 cDNAs in 26 melanoma resection specimens (21 primary melanomas, five metastases), we detected three point mutations and two nucleotide deletions which did not represent genetic polymorphisms. With respect to the predicted protein sequences, all three point mutations were silent whereas the two frame shifts at the extreme C-terminus resulted in a loss of the putative PDZ-targeting consensus sequence. As loss of this motif possibly impairs localization and function of PTEN/MMAC1 in the two corresponding primary tumours, alterations of this tumour suppressor protein may participate in some melanomas.
Insights
PTEN/MMAC1 gene alterations may play a role in melanoma development. While mRNA and protein levels were not significantly reduced, mutations were found, potentially affecting tumor suppressor function.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- PTEN/MMAC1 is a tumor suppressor gene located on chromosome 10q23.3.
- This region is frequently affected by deletions in melanomas.
- PTEN/MMAC1 is a candidate tumor suppressor for melanoma.
Purpose of the Study:
- To investigate the role of PTEN/MMAC1 in melanoma development.
- To analyze PTEN/MMAC1 expression and mutations in melanoma samples.
Main Methods:
- Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) for mRNA expression.
- Immunohistochemistry for protein expression.
- Sequencing of PTEN/MMAC1 cDNAs.
Main Results:
- No statistically significant down-regulation of PTEN/MMAC1 mRNA was observed in melanomas compared to nevi.
- PTEN/MMAC1 protein expression was not lost in melanomas.
- Three point mutations (all silent) and two nucleotide deletions (frameshifts) were detected in melanoma samples.
- The frameshift mutations resulted in the loss of a putative PDZ-targeting consensus sequence.
Conclusions:
- Alterations in PTEN/MMAC1, specifically frameshift mutations affecting the C-terminus, may contribute to melanoma development.
- Loss of the PDZ-targeting motif could impair PTEN/MMAC1 localization and function.
- PTEN/MMAC1 mutations are implicated in a subset of melanomas.