PURPOSE: To understand prognostic immune cell infiltration signatures in neuroendocrine neoplasms (NENs), particularly pheochromocytoma and paraganglioma (PCPG), we analyzed tumor transcriptomic data from The Cancer Genome Atlas (TCGA) and other published tumor transcriptomic data of NENs. METHODS: We used CIBERSORT to infer immune cell infiltrations from bulk tumor transcriptomic data from PCPGs, in comparison to gastroenteropancreatic neuroendocrine tumors (GEPNETs) and small cell lung carcinomas (SCLCs). PCPG immune signature was validated with NanoString immune panel in an independent cohort. Unsupervised clustering of the immune infiltration scores from CIBERSORT was used to find immune clusters. A prognostic immune score model for PCPGs and the other NENs were calculated as a linear combination of the estimated infiltration of activated CD8+/CD4+ T cells, activated NK cells, and M0 and M2 macrophages. RESULTS: In PCPGs, we found five dominant immune clusters, associated with M2 macrophages, monocytes, activated NK cells, M0 macrophages and regulatory T cells, and CD8+/CD4+ T cells respectively. Non-metastatic tumors were associated with activated NK cells and metastatic tumors were associated with M0 macrophages and regulatory T cells. In GEPNETs and SCLCs, M0 macrophages and regulatory T cells were associated with unfavorable outcomes and features, such as metastasis and high-grade tumors. The prognostic immune score model for PCPGs and the NENs could predict non-aggressive and non-metastatic diseases. In PCPGs, the immune score was also an independent predictor of metastasis-free survival in a multivariate Cox regression analysis. CONCLUSION: The transcriptomic immune signature in PCPG correlates with clinical features like metastasis and prognosis.

• Klíčová slova
• Biomarkers, Immunologic signature, Metastasis, Paraganglioma, Pheochromocytoma,
• MeSH
• feochromocytom * genetika   MeSH
• lidé MeSH
• nádorové biomarkery MeSH
• nádory nadledvin * genetika   MeSH
• nádory slinivky břišní MeSH
• nádory žaludku MeSH
• neuroendokrinní nádory * genetika   MeSH
• paragangliom * genetika   MeSH
• prognóza MeSH
• střevní nádory MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• 4-carboxyphenylglyoxal MeSH Prohlížeč
• nádorové biomarkery MeSH

Mitochondrial complex II (CII), also called succinate dehydrogenase (SDH), is a central purveyor of the reprogramming of metabolic and respiratory adaptation in response to various intrinsic and extrinsic stimuli and abnormalities. In this review we discuss recent findings regarding SDH biogenesis, which requires four known assembly factors, and modulation of its enzymatic activity by acetylation, succinylation, phosphorylation, and proteolysis. We further focus on the emerging role of both genetic and epigenetic aberrations leading to SDH dysfunction associated with various clinical manifestations. This review also covers the recent discovery of the role of SDH in inflammation-linked pathologies. Conceivably, SDH is a potential target for several hard-to-treat conditions, including cancer, that remains to be fully exploited.

• MeSH
• lidé MeSH
• mitochondrie enzymologie   metabolismus   MeSH
• sukcinátdehydrogenasa metabolismus   MeSH
• zánět metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• sukcinátdehydrogenasa MeSH

PURPOSE OF REVIEW: To summarize the recent advances in the genetics of pheochromocytoma and paraganglioma (PHEO/PGL), focusing on the new susceptibility genes and dividing PHEOs/PGLs into two groups based on their transcription profile. RECENT FINDINGS: Recently, TMEM127, MYC-associated factor X, and hypoxia-inducible factor (HIF) 2α have been described in the pathogenesis of PHEOs/PGLs. Thus, now about 30-40% of these tumors are linked to the germline mutations, which also include mutations in the VHL, RET, NF1, SDHx, and SDHAF2 genes. Furthermore, PHEOs/PGLs have been divided into two groups, cluster 1 (SDHx/VHL) and cluster 2 (RET/NF1), based on the transcription profile revealed by genome-wide expression microarray analysis. SUMMARY: PHEOs/PGLs are the most inherited tumors among (neuro)endocrine tumors. Future approaches in genetics, including whole-genome sequencing, will allow the discovery of additional PHEO/PGL susceptibility genes. The current division of PHEOs/PGLs into cluster 1 and 2 provides us with additional knowledge related to the pathogenesis of these tumors, including the introduction of new treatment options for patients with metastatic PHEOs/PGLs. New discoveries related to the role of the HIF-1/HIF-2α genes in the pathogenesis of almost all inherited PHEOs/PGLs may call for a new regrouping of these tumors and discoveries of new treatment targets.

• MeSH
• feochromocytom genetika   metabolismus   terapie   MeSH
• genetická predispozice k nemoci MeSH
• izoenzymy genetika   metabolismus   MeSH
• lidé MeSH
• mutace * MeSH
• nádorový supresorový protein VHL genetika   metabolismus   MeSH
• nádory nadledvin genetika   metabolismus   terapie   MeSH
• neurofibromin 1 genetika   metabolismus   MeSH
• paragangliom genetika   metabolismus   terapie   MeSH
• protoonkogenní proteiny c-ret genetika   metabolismus   MeSH
• sukcinátdehydrogenasa genetika   metabolismus   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• izoenzymy MeSH
• nádorový supresorový protein VHL MeSH
• neurofibromin 1 MeSH
• protoonkogenní proteiny c-ret MeSH
• RET protein, human MeSH Prohlížeč
• sukcinátdehydrogenasa MeSH
• VHL protein, human MeSH Prohlížeč

Pheochromocytomas (PHEOs) and paragangliomas (PGLs) are rare neuroendocrine tumors. About 30% or more of them are thought to be of inherited origin due to germ-line mutations in at least 10 well-characterized genes. There are data linking specific genotypes of these tumors to specific locations, typical biochemical phenotypes or future clinical behaviors. Conversely, clinical features, catecholamine production and immunohistochemistry evaluation can help with the proper order of genetic testing for PHEO and PGL. The identification of a germ-line mutation can lead to an early diagnosis, appropriate treatment, regular surveillance and better prognosis not only for the patient but also for their family members. Moreover, the latest discoveries in molecular pathogenesis of these tumors will provide an important basis for future personalized therapy.

• MeSH
• dědičnost MeSH
• fenotyp MeSH
• feochromocytom diagnóza   genetika   metabolismus   terapie   MeSH
• genetická predispozice k nemoci MeSH
• genetické testování MeSH
• individualizovaná medicína MeSH
• katecholaminy metabolismus   MeSH
• lidé MeSH
• nádory nadledvin diagnóza   genetika   metabolismus   terapie   MeSH
• nechromafinní paragangliom diagnóza   genetika   metabolismus   terapie   MeSH
• prediktivní hodnota testů MeSH
• prognóza MeSH
• výběr pacientů MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Research Support, N.I.H., Intramural MeSH
• Názvy látek
• katecholaminy MeSH