Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas
Background: Somatic mutations, copy-number variations, and genome instability of mitochondrial DNA (mtDNA) have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is scarce information about pheochromocytomas and...
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MDPI AG
2022-01-01
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| Series: | Cancers |
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| author | Mouna Tabebi Małgorzata Łysiak Ravi Kumar Dutta Sandra Lomazzi Maria V. Turkina Laurent Brunaud Oliver Gimm Peter Söderkvist |
| author_facet | Mouna Tabebi Małgorzata Łysiak Ravi Kumar Dutta Sandra Lomazzi Maria V. Turkina Laurent Brunaud Oliver Gimm Peter Söderkvist |
| author_sort | Mouna Tabebi |
| collection | DOAJ |
| description | Background: Somatic mutations, copy-number variations, and genome instability of mitochondrial DNA (mtDNA) have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is scarce information about pheochromocytomas and paragangliomas (PCCs/PGLs) formation. Material: To determine the potential roles of mtDNA alterations in sporadic PCCs/PGLs, we analyzed a panel of 26 nuclear susceptibility genes and the entire mtDNA sequence of seventy-seven human tumors, using next-generation sequencing, and compared the results with normal adrenal medulla tissues. We also performed an analysis of copy-number alterations, large mtDNA deletion, and gene and protein expression. Results: Our results revealed that 53.2% of the tumors harbor a mutation in at least one of the targeted susceptibility genes, and 16.9% harbor complementary mitochondrial mutations. More than 50% of the mitochondrial mutations were novel and predicted pathogenic, affecting mitochondrial oxidative phosphorylation. Large deletions were found in 26% of tumors, and depletion of mtDNA occurred in more than 87% of PCCs/PGLs. The reduction of the mitochondrial number was accompanied by a reduced expression of the regulators that promote mitochondrial biogenesis (PCG1α, NRF1, and TFAM). Further, P62 and LC3a gene expression suggested increased mitophagy, which is linked to mitochondrial dysfunction. Conclusion: The pathogenic role of these finding remains to be shown, but we suggest a complementarity and a potential contributing role in PCCs/PGLs tumorigenesis. |
| first_indexed | 2024-03-10T01:46:55Z |
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| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-10T01:46:55Z |
| publishDate | 2022-01-01 |
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| series | Cancers |
| spelling | doaj.art-310724d3301743949bfbbfbdd59fb59f2023-11-23T13:12:11ZengMDPI AGCancers2072-66942022-01-0114226910.3390/cancers14020269Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in PheochromocytomasMouna Tabebi0Małgorzata Łysiak1Ravi Kumar Dutta2Sandra Lomazzi3Maria V. Turkina4Laurent Brunaud5Oliver Gimm6Peter Söderkvist7Department of Biomedical and Clinical Sciences (BKV), Linköping University, 581 83 Linköping, SwedenDepartment of Biomedical and Clinical Sciences (BKV), Linköping University, 581 83 Linköping, SwedenDepartment of Biomedical and Clinical Sciences (BKV), Linköping University, 581 83 Linköping, SwedenCentre de Ressources Biologiques (CRB) Lorraine, CHRU de Nancy, 54511 Nancy, FranceDepartment of Biomedical and Clinical Sciences (BKV), Linköping University, 581 83 Linköping, SwedenDepartment of Gastrointestinal, Metabolic, and Oncology Surgery (CVMC), Section of Metabolic, Endocrine, and Thyroid Surgery (UMET) at the CHRU Nancy, Hôpital de Brabois, Inserm U1256, Faculté de Médecine, Université de Lorraine, 54511 Vandoeuvre-les-Nancy, FranceDepartment of Biomedical and Clinical Sciences (BKV), Linköping University, 581 83 Linköping, SwedenDepartment of Biomedical and Clinical Sciences (BKV), Linköping University, 581 83 Linköping, SwedenBackground: Somatic mutations, copy-number variations, and genome instability of mitochondrial DNA (mtDNA) have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is scarce information about pheochromocytomas and paragangliomas (PCCs/PGLs) formation. Material: To determine the potential roles of mtDNA alterations in sporadic PCCs/PGLs, we analyzed a panel of 26 nuclear susceptibility genes and the entire mtDNA sequence of seventy-seven human tumors, using next-generation sequencing, and compared the results with normal adrenal medulla tissues. We also performed an analysis of copy-number alterations, large mtDNA deletion, and gene and protein expression. Results: Our results revealed that 53.2% of the tumors harbor a mutation in at least one of the targeted susceptibility genes, and 16.9% harbor complementary mitochondrial mutations. More than 50% of the mitochondrial mutations were novel and predicted pathogenic, affecting mitochondrial oxidative phosphorylation. Large deletions were found in 26% of tumors, and depletion of mtDNA occurred in more than 87% of PCCs/PGLs. The reduction of the mitochondrial number was accompanied by a reduced expression of the regulators that promote mitochondrial biogenesis (PCG1α, NRF1, and TFAM). Further, P62 and LC3a gene expression suggested increased mitophagy, which is linked to mitochondrial dysfunction. Conclusion: The pathogenic role of these finding remains to be shown, but we suggest a complementarity and a potential contributing role in PCCs/PGLs tumorigenesis.https://www.mdpi.com/2072-6694/14/2/269mitochondrial DNAgenetic alterationspheochromocytomas and paragangliomas |
| spellingShingle | Mouna Tabebi Małgorzata Łysiak Ravi Kumar Dutta Sandra Lomazzi Maria V. Turkina Laurent Brunaud Oliver Gimm Peter Söderkvist Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas Cancers mitochondrial DNA genetic alterations pheochromocytomas and paragangliomas |
| title | Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas |
| title_full | Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas |
| title_fullStr | Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas |
| title_full_unstemmed | Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas |
| title_short | Genetic Alterations in Mitochondrial DNA Are Complementary to Nuclear DNA Mutations in Pheochromocytomas |
| title_sort | genetic alterations in mitochondrial dna are complementary to nuclear dna mutations in pheochromocytomas |
| topic | mitochondrial DNA genetic alterations pheochromocytomas and paragangliomas |
| url | https://www.mdpi.com/2072-6694/14/2/269 |
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