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Gastrointestinal Stromal Tumors: From Molecular Pathogenesis to Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Joaquina Baranda, Stafinur Atay, Andrew K. Godwin
Carney Triad is an extremely rare syndrome with fewer than 30 complete cases (all three tumors diagnosed in the same individual) and 100 incomplete cases (diagnoses of two of three tumors) reported. Approximately 85% of Carney triad patients are female with onset in the majority of patients before the age of 30. The GIST component of the triad predominately arises in the stomach and these tumors typically lack detectable KIT and PDGFRA mutations. In contrast to the Carney-Stratakis syndrome (discussed below), no germline mutations in the succinate dehydrogenase (SDH) subunits A, B, C, D (SDHA, SDHB, SDHC, SDHD) have been found in patients with the Carney Triad [81]. Increasing evidence suggest a potential role for the SDH complex in all pediatric cases since, as discussed earlier in this chapter, they lack SDHB protein expression [22]. In addition, this disorder displays a chronic yet indolent course [83]. Therefore, the similarities between sporadic pediatric GISTs and those occurring as part of the Carney triad are clear and making a distinction between the two can be quite difficult given that other components of the triad may not present until several years later. IHC analysis, performed in our laboratory, shows strong KIT expression in a primary GIST and a subsequent paraganglioma from a pediatric patient diagnosed with Carney’s triad. This is in agreement with a previous report showing expression of KIT in both the GIST and paraganglioma samples from a Carney triad patient [86], although others contradict this observation [85].
Hereditary Pheochromocytoma and Paraganglioma Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The SDHB (succinate dehydrogenase complex iron sulfur subunit B) gene encodes a protein specifically involved in the oxidation of succinate, transporting electrons from FADH to ubiquinone. Sporadic and germline mutations in SDHB cause paraganglioma and pheochromocytoma [13,14].
Genetics in Otology and Neurotology
Published in John C Watkinson, Raymond W Clarke, Louise Jayne Clark, Adam J Donne, R James A England, Hisham M Mehanna, Gerald William McGarry, Sean Carrie, Basic Sciences Endocrine Surgery Rhinology, 2018
Identification of an SDHB gene mutation is also a factor of poor prognosis.92 Multivariate analysis of a series of 54 subjects followed in France for PG or malignant pheochromocytoma demonstrated that identification of an SDHB mutation was the only risk factor for mortality. The 5-year survival probability was 36% for subjects with an SDHB mutation versus 67% for subjects without an SDHB mutation with a calculated median survival of 42 months for SDHB-mutant patients versus 244 months for wild-type SDHB patients.93
Genotype-phenotype associations in paragangliomas of the temporal bone in a multi-ethnic cohort
Published in Acta Oto-Laryngologica, 2023
Simon I. Angeli, Juan A. Chiossone K, Stefania Goncalves, Fred F. Telischi
Our patient with a SDHB-associated stage D2 GJ presented with advanced skull base and intracranial disease as well as with local and distant metastasis, and eventually died of her disease. This young woman from Cuba had the pathogenic missense c.689G > A, p.R230H mutation. As many as 20% of familial hereditary HNPGL are attributable to SDHB mutations. SDHB-associated disease has a high penetrance, as about 90% mutation carriers develop abdominal paragangliomas or HNPGL by the age of 60 years. [3,13] Carriers of SDHB mutations also have a higher risk of malignancy and metastatic disease (38% in some series), particularly paediatric cases [14], including non-paraganglioma cancers such as renal cell cancer, than other SDH-mutation carriers. [13] Given the relative high risk of malignancy and penetrance of SDHB-associated tumours, individuals who are mutation carriers should undergo life-long surveillance. Whole-body functional imaging is recommended, with 18F-DOPA-PET as a first-line scan in all SDH-associated paragangliomas and, in cases of confirmed or suspected malignancy, 18FDG-PET should be offered due to its greater sensitivity. [15] Furthermore, although most malignant HNPGLs are not functional, tests of catecholamine metabolism are also recommended, as elevated plasma methoxytyramine is a risk factor for metastatic disease. [16]
Yiqi Huoxue Tongluo recipe regulates NR4A1 to improve renal mitochondrial function in unilateral ureteral obstruction (UUO) rats
Published in Pharmaceutical Biology, 2022
Zhen He, Mengjuan Zhang, Hepeng Xu, Wenping Zhou, Chang Xu, Zheng Wang, Ming He, Xiangting Wang
Thus, we examined the function of mitochondria in the kidney of UUO rats, whose main function is to support the TCA cycle and aerobic respiration through OXPHOS and to produce ATP through mitochondrial ETC to meet the energy required for cell survival (Wallace 1999; Newmeyer and Ferguson-Miller 2003). CS is a key enzyme and the first rate-limiting enzyme in the mitochondrial TCA cycle, and decreased CS expression directly affects the process of the TCA cycle, leading to decreased ATP production, excessive superoxide production, and apoptosis (Cai et al. 2017). SDH is the only enzyme complex involved in both the TCA cycle and ETC, and a decreasing the activity of SDH leads to an increased formation of ROS (Rasheed and Tarjan 2018). SDHB gene encodes one of the four subunits of succinate dehydrogenase and succinate dehydrogenase activity is usually assessed qualitatively by immunohistochemical staining of SDHB protein (Rasheed and Tarjan 2018). We found that abnormal expression of these key metabolic enzymes in UUO affects the TCA cycle, ultimately leading to decreased ATP production and more ROS synthesis, which are involved in the development of CKD (Figure 4). YHTR and eplerenone could significantly increase these key metabolic enzymes in 14-day UUO rats (Figure 4). In HK2 cells, YHTR pre-incubation could upregulate CS and SDHB expression inhibited by TGF-β1 via promoting NR4A1 expression (Figure 6).
Prevalence of succinate dehydrogenase deficiency in paragangliomas and phaeochromocytomas at a tertiary hospital in Cape Town: a retrospective review
Published in Journal of Endocrinology, Metabolism and Diabetes of South Africa, 2021
Cassandra Bruce-Brand, Abraham C van Wyk
Mutations of one of the SDH subunits are almost always due to germline mutations and are very rarely somatic.31–34 Loss of SDHB immunohistochemical staining in these cases therefore signifies likely syndromic disease due to germline SDH mutations or, rarely, hypermethylation of SDHC.35 Apart from the identification of tumours with underlying germline mutations with implications for patients and family members, loss of SDHB staining can also identify abdominal PGLs with a high risk for malignant behaviour. This is helpful because metastatic potential in PC and PGLs is difficult to predict and there is conflicting data on the use of histologic features to do so.1