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Analysis of nuclear and mitochondrial DNA alterations in thyroid and renal oncocytic tumors
G Tallini1, M Ladanyi, J Rosai
1Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021.
Abstract:
The search for mitochondrial DNA (mtDNA) defects in oncocytic neoplasms has been the subject of several recent studies. We have performed qualitative and quantitative analysis of nuclear and mitochondrial DNAs in a series of 19 renal and 12 thyroid oncocytic tumors to identify specific alterations that might predict the clinical and biological behavior of these tumors. Allelic losses were seen in 2 of 19 renal tumors and 5 of 12 thyroid tumors. Among all loci (3p, 3q, 9q, 10q, 11p, 17p, and 17q) that showed losses, losses at 10q (one renal tumor and three thyroid tumors) were significantly higher (P < 0.05) than expected. Analysis of the COX I region previously reported to be altered in oncocytomas and the delta-loop region of mtDNA showed no detectable abnormalities in the restriction pattern in 10 renal and five thyroid tumors. PCR analysis of the commonly deleted 4,977-bp region failed to detect an increased frequency of mtDNA deletions in tumors compared to the controls. In addition, segmental amplification of the complete mtDNA from a renal oncocytoma using nine sets of primers revealed no gross alteration in mtDNA. Oncocytic tumors showed a mean 5-fold increase in mitochondrial DNA, which was significant (P < 0.001) when compared to corresponding controls. The relative increase in the cellular content of mtDNA may be associated with alterations in the normal coordinated interaction between the nuclear and mitochondrial genomes. Allelic deletions at 10q may be significant in the biology of oncocytic tumors, and their impact on the clinical behavior of these tumors warrants further investigation.
Insights
Oncocytic tumors show a significant five-fold increase in mitochondrial DNA (mtDNA). Researchers found no specific mtDNA defects but identified significant allelic losses at 10q in these neoplasms.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Oncocytic neoplasms are characterized by abundant mitochondria.
- Previous studies have investigated mitochondrial DNA (mtDNA) defects in these tumors.
- The role of nuclear and mitochondrial genome alterations in oncocytic tumor behavior is not fully understood.
Purpose of the Study:
- To investigate nuclear and mitochondrial DNA alterations in renal and thyroid oncocytic tumors.
- To identify genetic changes that may predict tumor behavior.
- To analyze the frequency of mtDNA defects and allelic losses in oncocytic neoplasms.
Main Methods:
- Qualitative and quantitative analysis of nuclear and mitochondrial DNA.
- Analysis of specific loci (3p, 3q, 9q, 10q, 11p, 17p, 17q) for allelic losses.
- Restriction pattern analysis of mtDNA (COX I region, delta-loop region).
- Polymerase Chain Reaction (PCR) for common mtDNA deletions (4,977-bp region).
- Segmental amplification of complete mtDNA.
Main Results:
- Allelic losses were observed in 2/19 renal and 5/12 thyroid tumors.
- Significantly higher than expected losses were found at 10q (P < 0.05).
- No detectable abnormalities were found in the analyzed mtDNA regions (COX I, delta-loop, 4,977-bp deletion).
- Complete mtDNA sequencing revealed no gross alterations.
- Oncocytic tumors exhibited a significant mean 5-fold increase in mtDNA content (P < 0.001).
Conclusions:
- A significant increase in cellular mitochondrial DNA content is a hallmark of oncocytic tumors.
- Specific mtDNA defects were not identified as a primary driver.
- Allelic deletions at 10q may play a significant role in the biology of oncocytic tumors.
- Further research is needed to understand the clinical implications of 10q allelic losses.