Germline <i>SDHA</i> mutations in children and adults with cancer

Gault, Marianne Dubard; Mandelker, Diana; DeLair, Deborah F.; Stewart, Carolyn; Kemel, Yelena; Sheehan, Margaret; Siegel, Beth; Kennedy, Jennifer A.; Marcell, Vanessa; Arnold, Angela G.; Al‐Ahmadie, Hikmat; Modak, Shakeel; Shukla, Neerav; Roberts, Stephen S.; Vijai, Joseph; Topka, Sabine; Kentsis, Alex; Cadoo, Karen A.; Carlo, Maria I.; Schwark, Alicia Latham; Reznik, Ed; DiNatale, Renzo G.; Hechtman, Jaclyn F.; Flores, Ester B.; Jairam, Sowmaya; Yang, Ciyu; Li, Yirong; Bayraktar, Erol C.; Ceyhan‐Birsoy, Ozge; Zhang, Liying; Kohlman, Wendy; Schiffman, Joshua D.; Stadler, Zsofia K.; Birsoy, Kıvanç; Kung, Andrew L.; Offit, Kenneth; Walsh, Michael F.

doi:10.1101/mcs.a002584

Cited by 37 publications

(29 citation statements)

References 30 publications

(40 reference statements)

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“…Likewise, in one of our patients, GIST and RCC were not related to SDHA mutations based on IHC. By contrast, in one study, 1 patient with germline SDHA mutation was found to be associated with GIST complicated by RCC (24), whereas in another study, germline SDHA mutation was found to be associated with GIST in 2 patients and neuroblastoma in 1 patient (20). Whether other tumors and autoimmune disorders described in this cohort and their family members are a part of syndromic presentation awaits confirmation.…”

Section: Discussionmentioning

confidence: 91%

Clinical, Diagnostic, and Treatment Characteristics of SDHA-Related Metastatic Pheochromocytoma and Paraganglioma

et al. 2019

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Background: Pheochromocytoma and paraganglioma (PHEO/PGL) are rare neuroendocrine tumors which may cause potentially life-threatening complications, with about a third of cases found to harbor specific gene mutations. Thus, early diagnosis, treatment, and meticulous monitoring are of utmost importance. Because of low incidence of succinate dehydrogenase complex subunit A ( SDHA )-related metastatic PHEO/PGL, currently there exists insufficient clinical information, especially with regards to its diagnostic and treatment characteristics. Methods: Ten patients with SDHA -related metastatic PHEO/PGL were followed-up prospectively and/or retrospectively between January 2010–July 2018. They underwent biochemical tests ( n = 10), 123 I-MIBG ( n = 9) scintigraphy, and multiple whole-body positron emission tomography/computed tomography (PET/CT) scans with 68 Ga-DOTATATE ( n = 10), 18 F-FDG ( n = 10), and 18 F-FDOPA ( n = 6). Results: Our findings suggest that these tumors can occur early and at extra-adrenal locations, behave aggressively, and have a tendency to develop metastatic disease within a short period of time. None of our patients had a family history of PHEO/PGL, making them appear sporadic. Nine out of 10 patients showed abnormal PHEO/PGL-specific biochemical markers with predominantly noradrenergic and/or dopaminergic phenotype, suggesting their utility in diagnosing and monitoring the disease. Per patient detection rates of 68 Ga-DOTATATE ( n = 10/10), 18 F-FDG ( n = 10/10), 18 F-FDOPA ( n = 5/6) PET/CT, and 123 I-MIBG ( n = 7/9) scintigraphy were 100, 100, 83.33, and 77.77%, respectively. Five out of 7 123 I-MIBG positive patients had minimal 123 I-MIBG avidity or detected very few lesions compared to widespread metastatic disease on 18 F-FDG PET/CT, implying that diagnosis and treatment with 123/131 I-MIBG is not a good option. 68 Ga-DOTATATE PET/CT was found to be superior or equal to 18 F-FDG PET/CT in 7 out of 10 patients and hence, is recommended for evaluation and follow-up of these patients. All 7 out of 7 patients who received conventional therapies (chemotherapy, somatostatin analog therapy, radiation therapy, 131 I-MIBG, peptide receptor radionuclide therapy) in addition to surgery showed disease progression. Conclusion: In our cohort of patients, SDHA -related metastatic PHEO/PGL followed a diseas...

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Section: Discussionmentioning

confidence: 91%

Clinical, Diagnostic, and Treatment Characteristics of SDHA-Related Metastatic Pheochromocytoma and Paraganglioma

et al. 2019

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“…Isolated and partial SDH defects are rare human conditions that are generally associated with neurological or cardiac phenotypes [3]. However, in addition to the profound SDH defects evidenced in phaeochromocytomas and paragangliomas or gastrointestinal stromal tumor tissues of patients with germline mutations in the SDH tumor suppressor genes [47–50], a partial SDH deficiency has been observed in a number of human diseases that affect one or several organs, i . e ., FRDA [51], Barth syndrome [52], various leukoencephalopathies [53] [54] [55], asthenozoospermia male infertility [56], myopathy [57], rare hemolytic uremic syndromes and rhabdomyolysis [58].…”

Section: Discussionmentioning

confidence: 99%

Evolutionarily conserved susceptibility of the mitochondrial respiratory chain to SDHI pesticides and its consequence on the impact of SDHIs on human cultured cells

et al. 2019

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Succinate dehydrogenase (SDH) inhibitors (SDHIs) are used worldwide to limit the proliferation of molds on plants and plant products. However, as SDH, also known as respiratory chain (RC) complex II, is a universal component of mitochondria from living organisms, highly conserved through evolution, the specificity of these inhibitors toward fungi warrants investigation. We first establish that the human, honeybee, earthworm and fungal SDHs are all sensitive to the eight SDHIs tested, albeit with varying IC50 values, generally in the micromolar range. In addition to SDH, we observed that five of the SDHIs, mostly from the latest generation, inhibit the activity of RC complex III. Finally, we show that the provision of glucose ad libitum in the cell culture medium, while simultaneously providing sufficient ATP and reducing power for antioxidant enzymes through glycolysis, allows the growth of RC-deficient cells, fully masking the deleterious effect of SDHIs. As a result, when glutamine is the major carbon source, the presence of SDHIs leads to time-dependent cell death. This process is significantly accelerated in fibroblasts derived from patients with neurological or neurodegenerative diseases due to RC impairment (encephalopathy originating from a partial SDH defect) and/or hypersensitivity to oxidative insults (Friedreich ataxia, familial Alzheimer’s disease).

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“…Metastatic disease was reported in 0% to 33% of PGL patients with SDHA mutations, although these reports included few patients (n = 4‐34) . GISTs and pituitary adenomas were reported in a small subset of patients . In a large pediatric GIST study of Boikos et al, a SDHA mutation, germline or somatic, was the most common molecular subtype Neuroblastoma was reported in one SDHA mutation carrier where it was possible to confirm loss of heterozygosity (LoH) in tumor tissue …”

Section: Phenotype Of Sdhx Mutation Carriersmentioning

confidence: 99%

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

et al. 2019

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Succinate dehydrogenase (SDH) mutations lead to the accumulation of succinate, which acts as an oncometabolite. Germline SDHx mutations predispose to paraganglioma (PGL) and pheochromocytoma (PCC), as well as to renal cell carcinoma and gastro-intestinal stromal tumors. The SDHx genes were the first tumor suppressor genes discovered which encode for a mitochondrial enzyme, thereby supporting Otto Warburg's hypothesis in 1926 that a direct link existed between mitochondrial dysfunction and cancer. Accumulation of succinate is the hallmark of tumorigenesis in PGL and PCC. Succinate accumulation inhibits several α-ketoglutarate dioxygenases, thereby inducing the pseudohypoxia pathway and causing epigenetic changes. Moreover, SDH loss as a consequence of SDHx mutations can lead to reprogramming of cell metabolism. Metabolomics can be used as a diagnostic tool, as succinate and other metabolites can be measured in tumor tissue, plasma and urine with different techniques. Furthermore, these pathophysiological characteristics provide insight into therapeutic targets for metastatic disease. This review provides an overview of the pathophysiology and clinical implications of oncometabolite succinate in SDHx mutations. K E Y W O R D S oncometabolites, paraganglioma, pheochromocytoma, SDH mutation, succinate 1 | INTRODUCTION Mutations of genes encoding for the succinate dehydrogenase (SDH) complex, associated with familial paraganglioma (PGL) and pheochromocytoma (PCC), lead to accumulation of succinate, which disturbs the metabolic regulation of the cell. Nowadays metabolic dysregulation is recognized as one of the eight hallmarks of cancer. 1 Although germline mutations in SDHx genes are predominantly linked to PGL and PCC, these mutations also predispose to renal cell carcinoma (RCC), gastrointestinal stromal tumors (GISTs) and, possibly, pituitary adenomas. PCC, PGL and head and neck PGL (HNPGL) are rare neuroendocrine tumors arising from chromaffin cells that can synthesize and release catecholamines. Sympathetic PGLs are derived from sympathetic paraganglia in the chest, abdomen or pelvis. PCC are PGLs located in the adrenal medulla. 2 HNPGLs are derived from parasympathetic paraganglia. Common locations for HNPGLs include the carotid body and the middle ear, as well as the vagus nerve and internal jugular vein. While parasympathetic PGLs are most often non-functional tumors, PCC and sympathetic PGL release catecholamines into the circulation and can

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Germline SDHA mutations in children and adults with cancer

Cited by 37 publications

References 30 publications

Clinical, Diagnostic, and Treatment Characteristics of SDHA-Related Metastatic Pheochromocytoma and Paraganglioma

Clinical, Diagnostic, and Treatment Characteristics of SDHA-Related Metastatic Pheochromocytoma and Paraganglioma

Evolutionarily conserved susceptibility of the mitochondrial respiratory chain to SDHI pesticides and its consequence on the impact of SDHIs on human cultured cells

Clinical implications of the oncometabolite succinate in SDHx‐mutation carriers

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