Risk of metastatic pheochromocytoma and paraganglioma in <i>SDHx</i> mutation carriers: a systematic review and updated meta-analysis

Lee, Hansong; Jeong, Seongdo; Yu, Yeuni; Kang, Junmo; Sun, Hokeun; Rhee, Je-Keun; Kim, Yun Hak

doi:10.1136/jmedgenet-2019-106324

Cited by 26 publications

(23 citation statements)

References 52 publications

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“…To our knowledge, this is the first systematic study of a single tertiary centre cohort of 59 individuals with germline SDHX variants describing the associations between the genotype on the one hand and both the clinical and histopathological phenotype on the other. SDHB variants were the most frequent, which is in accordance with previous reports (9,10,12,18,21). Two patients were diagnosed with a variant in SDHA and four patients were diagnosed with SDHC variants, which corroborates previous findings that these are much less common (9,10,12,22).…”

Section: Discussionsupporting

confidence: 91%

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Genotype–phenotype associations in PPGLs in 59 patients with variants in SDHX genes

Main

Rossing

Borgwardt

et al. 2020

Endocrine Connections

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Phaeochromocytomas and paragangliomas (PPGLs) are tumours of the adrenal medulla and extra-adrenal sympathetic nervous system which often secrete catecholamines. Variants of the SDHX (SDHA, -AF2, -B, -C, -D) genes are a frequent cause of familial PPGLs. In this study from a single tertiary centre we aimed to characterize the genotype-phenotype associations in patients diagnosed with germline variants in SDHX genes. We also assessed whether systematic screening of family members resulted in earlier detection of tumours. The study cohort comprised all individuals (n=59) diagnosed with a rare variant in SDHX during a thirteen-year period. Patient- and pathology records were checked for clinical characteristics and histopathological findings. We found distinct differences in the clinical and histopathological characteristics between genetic variants in SDHB. We identified two SDHB variants with distinct phenotypical patterns. Family screening for SDHB variants resulted in earlier detection of tumours in two families. Patients with SDHA, SDHC and SDHD variants also had malignant phenotypes, underlining the necessity for a broad genetic screening of the proband. Our study corroborates previous findings of poor prognostic markers and found that the genetic variants and clinical phenotype are linked and therefore useful in the decision of clinical follow-up. Regular tumour screening of carriers of pathogenic variants may lead to an earlier diagnosis and expected better prognosis. The development of a combined algorithm with clinical, genetic, morphological, and biochemical factors may be the future for improved clinical risk stratification, and forming a basis for larger multi-centre follow up studies.

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Section: Discussionsupporting

confidence: 91%

“…Thus, existing prognostic markers cannot fully predict PPGL behaviour ( 6 , 18 ), which is a clinical challenge. To our knowledge, there is no previous systematic study of the genotype–phenotype associations in patients with solely germline variants in SDHX genes.…”

Section: Introductionmentioning

confidence: 99%

Genotype–phenotype associations in PPGLs in 59 patients with variants in SDHX genes

Main

Rossing

Borgwardt

et al. 2020

Endocrine Connections

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“…Succinate dehydrogenase is an important tricarboxylic-acid-cycle-related enzyme in the mitochondria, and mutations to this enzyme frequently occur in cancer ( 43 , 44 ). It has also been reported that the mutation rate of SDHC was higher among the succinate dehydrogenase complex subunits in cancer ( 26 ). Therefore, when we showed that SDHC was downregulated in MQ-treated ESCC cells, we hypothesized that SDHC may play an important role in ESCC tumor growth.…”

Section: Discussionmentioning

confidence: 91%

“…Succinate dehydrogenase as a key component of the mitochondrial respiratory chain (RC) of all living organisms (22), SDH mutation frequently occurred in cancer (23)(24)(25). SDHC has a higher mutation rate compared with SDHD (26). Firstly, we tested the SDHC protein level in human ESCC tissues and found the protein level of SDHC was higher in ESCC tissues than normal tissues ( Figure 5A).…”

Section: Sdhc Is Highly Expressed In Escc Tissues and Knocking Sdhc Dmentioning

confidence: 99%

Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy

Xie

Zhang

et al. 2020

Front. Oncol.

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Esophageal squamous cell carcinoma (ESCC) has a worldwide impact on human health, due to its high incidence and mortality. Therefore, identifying compounds to increase patients' survival rate is urgently needed. Mefloquine (MQ) is an FDA-approved anti-malarial drug, which has been reported to inhibit cellular proliferation in several cancers. However, the anti-tumor activities of the drug have not yet been completely defined. In this study, mass spectrometry was employed to profile proteome changes in ESCC cells after MQ treatment. Sub-cellular localization and gene ontology term enrichment analysis suggested that MQ treatment mainly affect mitochondria. The KEGG pathway enrichment map of down-regulated pathways and Venn diagram indicated that all of the top five down regulated signaling pathways contain four key mitochondrial proteins (succinate dehydrogenase complex subunit C (SDHC), succinate dehydrogenase complex subunit D, mitochondrially encoded cytochrome c oxidase III and NADH: ubiquinone oxidoreductase subunit V3). Meanwhile, mitochondrial autophagy was observed in MQ-treated KYSE150 cells. More importantly, patient-derived xenograft mouse models of ESCC with SDHC high expression were more sensitive to MQ treatment than low SDHC-expressing xenografts. Taken together, mefloquine inhibits ESCC tumor growth by inducing mitochondrial autophagy and SDHC plays a vital role in MQ-induced anti-tumor effect on ESCC.

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“…In PPGLs' patients, it is well established that the presence of inactivating germline mutations in the Metastatic Paragangliomas and Pheochromocytomas: An Epigenetic View DOI: http://dx.doi.org /10.5772/intechopen.96126 SDHB gene is the most important molecular predictor of malignancy. More than 40% of patients with metastatic PPGLs (especially extra-adrenal tumors) carry germline SDHB mutations [6,7]. Although mutations in other PPGL-predisposing genes, such as FH, SDHC, SDHD, SDHA, and TMEM127 have been found in some patients with metastatic PPGLs, these mutations account for only <5% of cases.…”

Section: Epigenetic and Sdh-deficiency: A Connection With Metastatic mentioning

confidence: 99%

Metastatic Paragangliomas and Pheochromocytomas: An Epigenetic View

Chiara¹,

Celada²,

Martínez³

et al. 2021

Pheochromocytoma, Paraganglioma and Neuroblastoma

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Paragangliomas and pheochromocytoma (PPGLs) are hereditary tumors in about 40% of cases. Mutations in the genes encoding for components of the mitochondrial succinate dehydrogenase protein complex (SDHB, SDHD, SDHC) are among the most prevalent. Most PPGLs have a benign behavior, but patients with germline SDHB mutations may develop metastatic PPGLs in up to 30% of cases. This suggest that the SDH substrate, succinate, is key for the activation of the metastatic cascade. The last decade has witnessed significant advances in our understanding of how succinate may have oncogenic properties. It is now widely accepted that succinate is an oncometabolite that modifies the epigenetic landscape of SDH-deficient tumors via modulating the activities of DNA and histone modification enzymes. In this chapter, we summarize recent discoveries linking SDH-deficiency and metastasis in SDH-deficient PPGLs via inhibition of DNA methylcytosine dioxygenases, histone demethylases and modified expression of non-coding RNAs. We also highlight promising therapeutic avenues that may be used to counteract epigenetic deregulations.

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Risk of metastatic pheochromocytoma and paraganglioma in SDHx mutation carriers: a systematic review and updated meta-analysis

Cited by 26 publications

References 52 publications

Genotype–phenotype associations in PPGLs in 59 patients with variants in SDHX genes

Genotype–phenotype associations in PPGLs in 59 patients with variants in SDHX genes

Mefloquine Inhibits Esophageal Squamous Cell Carcinoma Tumor Growth by Inducing Mitochondrial Autophagy

Metastatic Paragangliomas and Pheochromocytomas: An Epigenetic View

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