Nuclear and mitochondrial DNA alterations in pheochromocytomas and paragangliomas, and their potential treatment.

Mitochondrial DNA (mtDNA) alterations have been reported in different types of cancers and are suggested to play important roles in cancer development and metastasis. However, there is little information about its involvement in pheochromocytomas and paragangliomas (PCCs/PGLs) formation. PCCs and PGLs are rare endocrine tumors of the chromaffin cells in the adrenal medulla and extra-adrenal paraganglia that can synthesize and secrete catecholamines. Over the last 3 decades, the genetic background of about 60% of PCCs/PGLs involving nuclear DNA alterations has been determined. Recently, a study showed that mitochondrial alterations can be found in around 17% of the remaining PCCs/PGLs. In this review, we summarize recent knowledge regarding both nuclear and mitochondrial alterations and their involvement in PCCs/PGLs. We also provide brief insights into the genetics and the molecular pathways associated with PCCs/PGLs and potential therapeutical targets.

Effect of Disease-Associated Germline Mutations on Structure Function Relationship of DNA Methyltransferases.

Despite a large body of evidence supporting the role of aberrant DNA methylation in etiology of several human diseases, the fundamental mechanisms that regulate the activity of mammalian DNA methyltransferases (DNMTs) are not fully understood. Recent advances in whole genome association studies have helped identify mutations and genetic alterations of DNMTs in various diseases that have a potential to affect the biological function and activity of these enzymes. Several of these mutations are germline-transmitted and associated with a number of hereditary disorders, which are potentially caused by aberrant DNA methylation patterns in the regulatory compartments of the genome. These hereditary disorders usually cause neurological dysfunction, growth defects, and inherited cancers. Biochemical and biological characterization of DNMT variants can reveal the molecular mechanism of these enzymes and give insights on their specific functions. In this review, we introduce roles and regulation of DNA methylation and DNMTs. We discuss DNMT mutations that are associated with rare diseases, the characterized effects of these mutations on enzyme activity and provide insights on their potential effects based on the known crystal structure of these proteins.

Germline SDHB and SDHD mutations in pheochromocytoma and paraganglioma patients.

Pheochromocytoma and paragangliomas (PCC/PGL) are neuroendocrine tumors that arise from chromaffin cells of the adrenal medulla and sympathetic/parasympathetic ganglia, respectively. Of clinical relevance regarding diagnosis is the highly variable presentation of symptoms in PCC/PGL patients. To date, the clear-cut correlations between the genotypes and phenotypes of PCC/PGL have not been entirely established. In this study, we reviewed the medical records of PCC/PGL patients with pertinent clinical, laboratory and genetic information. Next-generation sequencing (NGS) performed on patient samples revealed specific germline mutations in the SDHB (succinate dehydrogenase complex iron-sulfur subunit B) and SDHD (succinate dehydrogenase complex subunit D) genes and these mutations were validated by Sanger sequencing. Of the 119 patients, two were identified with SDHB mutation and one with SDHD mutation. Immunohistochemical (IHC) staining was used to analyze the expression of these mutated genes. The germline mutations identified in the SDH genes were c343C>T and c.541-542A>G in the SDHB gene and c.334-337delACTG in the SDHD gene. IHC staining of tumors from the c.343C>T and c.541-2A>G carriers showed positive expression of SDHB. Tumors from the c.334-337delACTG carrier showed no expression of SDHD and a weak diffused staining pattern for SDHB. We strongly recommend genetic testing for suspected PCC/PGL patients with a positive family history, early onset of age, erratic hypertension, recurrence or multiple tumor sites and loss of SDHB and/or SDHD expression. Tailored personal management should be conducted once a patient is confirmed as an SDHB and/or SDHD mutation carrier or diagnosed with PCC/PGL.