Succinate Dehydrogenase Mutations Research Articles

Concurrent multiple cerebral cavernous malformations and cauda equina paraganglioma: illustrative case.

Cauda equina neuroendocrine tumors (CENETs), previously known as cauda equina paragangliomas, and multiple cerebral cavernous malformations (CCMs) are uncommon conditions affecting the central nervous system. To the authors' knowledge, they have not been reported in the same patient. The authors present the case of a 45-year-old male with CENET and concurrent incidental MRI findings of multiple CCMs. Familial CCMs are associated with mutations in the KRIT1 (CCM1), MGC4607 (CCM2), and PDCD10 (CCM3) genes. Peripheral paragangliomas have been associated with mutations in succinate dehydrogenase (SDHx), RET (multiple endocrine neoplasia 2), VHL (von Hippel-Lindau syndrome), and NF1 (neurofibromatosis type 1) genes. Except for a single case, cauda equina paragangliomas have not been associated with any underlying genetic mutations. It is unclear whether the co-occurrence of these two rare conditions in the same patient is coincidental or suggests a possible shared pathogenesis. https://thejns.org/doi/10.3171/CASE24102.

Various amino acid substitutions in succinate dehydrogenase complex regulating differential resistance to pydiflumetofen in Magnaporthe oryzae

Rice blast, caused by Magnaporthe oryzae, is a devastating fungal disease worldwide. Pydiflumetofen (Pyd) is a new succinate dehydrogenase inhibitor (SDHI) that exhibited anti-fungal activity against M. oryzae. However, control of rice blast by Pyd and risk of resistance to Pyd are not well studied in this pathogen. The baseline sensitivity of 109 M. oryzae strains to Pyd was determined using mycelial growth rate assay, with EC50 values ranging from 0.291 to 2.1313 μg/mL, and an average EC50 value of 1.1005 ± 0.3727 μg/mL. Totally 28 Pyd-resistant (PydR) mutants with 15 genotypes of point mutations in succinate dehydrogenase (SDH) complex were obtained, and the resistance level could be divided into three categories of very high resistance (VHR), high resistance (HR) and moderate resistance (MR) with the resistance factors (RFs) of >1000, 105.74–986.13 and 81.92–99.48, respectively. Molecular docking revealed that all 15 mutations decreased the binding-force score for the affinity between Pyd and target subunits, which further confirmed that these 15 genotypes of point mutations were responsible for the resistance to Pyd in M. oryzae. There was positive cross resistance between Pyd and other SDHIs, such as fluxapyroxad, penflufen or carboxin, while there was no cross-resistance between Pyd and carbendazim, prochloraz or azoxystrobin in M. oryzae, however, PydR mutants with SdhBP198Q, SdhCL66F or SdhCL66R genotype were still sensitive to the other 3 SDHIs, indicating lack of cross resistance. The results of fitness study revealed that the point mutations in MoSdhB/C/D genes might reduce the hyphae growth and sporulation, but could improve the pathogenicity in M. oryzae. Taken together, the risk of resistance to Pyd might be moderate to high, and it should be used as tank-mixtures with other classes of fungicides to delay resistance development when it is used for the control of rice blast in the field.

SEVERE COURSE OF PARAGANGLIOMAS IN CHILDREN WITH SUCCINATE DEHYDROGENASE MUTATIONS – A REPORT OF TWO CASES

Objective: Paragangliomas and pheochromocytoma (PPGL) are rare causes of arterial hypertension (AH) in children. This study aimed to present the clinical course in two adolescents with PPGL tumors due to succinate dehydrogenase mutations. Design and method: We analyzed age, gender, clinical manifestations, laboratory findings, including plasma methoxycatecholamines, genetic and imaging findings, pharmacological and surgical treatment, and outcome. Results: Case 1: A 14-year-old boy presented with tinnitus, dizziness, and balance disorders. A computed tomography (CT) revealed a paraganglioma in the area of the left internal jugular vein bulb, causing ear and bone destruction. The boy was diagnosed with AH; his plasma normetanephrine was 343pg/mL (normal range: 18-138), metanephrine and 3-methoxytramine were normal. The patient was started on doxazosin, and the tumor was removed. A genetic study showed a pathogenic variant in the SDHD gene (c.33C>A). PET/CT showed another tumor between the inferior vena cava and diaphragm. A successful tumor resection was performed. Currently, the boy is 17 years old, methoxycatecholamine levels are normal. The patient has AH (primary hypertension) and is treated with rampiril and amlodipine. Case 2: A 17.5-year-old girl was admitted to the hospital due to headaches and AH lasting about six months. Laboratory tests revealed a markedly elevated plasma normetanephrine - 8734.59pg/mL (normal range: 16-142) and a slightly elevated 3-methoxytramine - 25.52pg/mL (normal range < 14). CT showed a large tumor (11x7x7cm) at the level of the diaphragm, modeling the heart, liver, and inferior vena cava. Whole-body PET/CT and MIBG scintigraphy did not detect other tumors. A genetic test showed a pathogenic variant in the SDHB gene (c.181dupT). The girl was treated with doxazosin. Surgical treatment included two transarterial embolizations, followed by surgical removal of the tumor. Currently, the patient is 18 years and 2 months old, has normal methoxycatecholamines, and does not require antihypertensive drugs. The same variant of the SDHB gene was found in the patient's father and older brother. Conclusions: 1.PPGL can have an unusual clinical course in children, and patients may present with a variety of symptoms 2.Pediatric patients with PPGL require genetic tests and individualized, multidisciplinary medical care.

Fungicide Sensitivity Profile of Pyrenophora teres f. teres in Field Population.

Pyrenophora teres f. teres (Ptt) is a severe pathogen to spring barley in Northern Europe. Ptt with relevant mutations in fungicide target proteins, sterol 14α-demethylase (CYP51A), cytochrome b (Cyt b), and succinate dehydrogenase (SDH) would put efficient disease control at risk. In the growing seasons of 2021 and 2022, 193 Ptt isolates from Estonia were analysed. In this study, mutation detection and in vitro fungicide sensitivity assays of single-spore isolates were carried out. Reduced sensitivity phenotype to mefentrifluconazole was evident in Ptt isolates with a F489L mutation in CYP51A or with 129 bp insert in the Cyp51A gene-promoter region. However, sensitivity to a prothioconazole-desthio remained high regardless of these molecular changes. The Ptt population was mostly sensitive to bixafen, fluxapyroxad, pyraclostrobin, and azoxystrobin. The sensitivity of fluxapyroxad and bixafen has been affected by two mutations, C-S135R and D-H134R, found in SDH subunits. The F129L mutation in Cyt b influenced azoxystrobin but not pyraclostrobin sensitivity. In total, 30 isolates from five fields had relevant mutations in three target protein genes simultaneously. Most of these isolates had a reduced sensitivity phenotype to mefentrifluconazole, fluxapyroxad, and azoxystrobin, while sensitivity to other tested fungicides remained high. Furthermore, possible sexual reproduction may enhance the pathogen's fitness and help it adapt to fungicides.

Knowledge-Based Therapeutics for Tricarboxylic Acid (TCA) Cycle-Deficient Cancers.

With the foundation pre-laid, research in the new millennium has readily excavated and expanded upon the architectural framework laid out by Otto Warburg's seminal work in a new wave of "westward expansion," ever widening our understanding of cancer metabolism beyond the telescopic vision seen over a century ago. On this path, the unique circuitry of the cancer metabolic program has been elucidated, illuminating mutations of conserved cellular pathways implicated in tumorigenesis. Paramount among these are mutations in tricarboxylic acid cycle enzymes, succinate dehydrogenase, and fumarate hydratase, leading to deleterious accumulations in metabolic intermediates, "oncometabolites," the pilots of the disease process. In this work, we seek to reflect on the advancements in the field in recent years, updating knowledge on the exact biochemical mechanisms at the helm of the tumor, providing rationale for clinical trials currently underway, and anticipating directions for the future on this expansive frontier.

Succinate dehydrogenase mutations in head and neck paragangliomas: A systematic review and meta-analysis of individual patients' data.

Head and neck paragangliomas (HNPs) have been associated with gene mutations in the succinate dehydrogenase (SDH) complex, but the clinical significance remains unclear. We sought to explore the demographics, clinical characteristics, treatment methods, and outcomes of SDH-mutated HNPs. Databases were systematically searched. Pooled event ratio and relative 95% confidence intervals were calculated for dichotomous outcomes. Meta-regression was performed. Cochran's Q test and I2 test assessed heterogeneity. Funnel plot and Egger's regression test assessed publication bias. Forty-two studies with 8849 patients were included. Meta-regression revealed a significant correlation between multifocality and SDHD mutations (0.03 ± 0.006, p < 0.0001) and between distant metastases and SDHB mutations (0.06 ± 0.023, p = 0.008). There was no correlation between sex, age, tumor size, or familial occurrences and SDH-related mutations. Multifocality of HNPs correlates with the SDHD mutational subtype, and metastases correlate with the SDHB subtype. Knowledge of HNP phenotypes associated with SDH-related mutations has the potential to influence the management approach to such HNPs.

Malignant carotid body tumors: What we know, what we do, and what we need to achieve. A systematic review of the literature.

Malignant carotid body tumors (MCBT) are rare and diagnosed after detection of nodal or distant metastases. This systematic review (SR) focuses on MCBT initially approached by surgery. Preferred Reporting Items for SR and Meta-Analysis (MA) guided the articles search from 2000 to 2023 on PubMed, Scopus, and Web of Science. Among 3548 papers, 132 (337 patients) were considered for SR; of these, 20 (158 patients) for MA. Malignancy rate was 7.3%, succinate dehydrogenase (SDH) mutation 17%, age at diagnosis between 4th and 6th decades, with a higher prevalence of females. MCBTs were mostly Shamblin III, with nodal and distant metastasis in 79.7% and 44.7%, respectively. Malignancy should be suspected if CBT >4 cm, Shamblin III, painful or otherwise symptomatic, at the extremes of age, bilateral, with multifocal disease, and SDHx mutations. Levels II-III clearance should be performed to exclude nodal metastases and adjuvant treatments considered on a case-by-case basis.

The Utility of Phosphohistone-H3 Immunohistochemistry (PHH3) in Pheochromocytomas

Abstract Introduction/Objective Most pheochromocytomas (PCC) are sporadic; ~40% present as part of familial syndromes and some cases are associated with germline mutations of succinate dehydrogenase (SDH) genes. Few cases are malignant. The Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) is a scoring system to predict behavior that includes evaluation of mitotic count, among other parameters. PHH3 has been used to assess mitosis in breast and glial tumors. The aim of this study was to assess the potential utility of PHH3 in pheochromocytomas. Methods/Case Report 50 cases of PCC diagnosed between 2016 and 2020 at our institution were included in the study. Clinicopathologic data was recorded. One hematoxylin and eosin (H&amp;E) slide was selected per case and mitotic count was evaluated at 40x high power-fields (HPF). PHH3 was performed on the same block to assess mitoses. Cells with dark and coarsely clumped staining were considered positive for PHH3. PHH3-positive cells were counted also at 40x HPF. In one case with bilateral pheochromocytomas, the largest tumor was evaluated. Follow-up was available in 39 cases and recorded as no evidence of disease (NED), alive with disease (AWD), or dead of disease (DOD). Results (if a Case Study enter NA) 21 patients were female, 29 were males. Age ranged from 24 to 95 (mean: 56). Tumor size ranged from 1.1 to 16.0 cm (mean: 5.6 cm). Mean follow-up was 13.6 months (1-32 months range). Mitotic count ranged from 0 to 7 and 0 to 21 per 10 HPFs, on H&amp;E and PHH3, respectively. PHH3 showed higher mitotic count in 33 cases compared to H&amp;E. In 11 cases, mitotic count was equal on H&amp;E and PHH3, and in the remaining cases, mitotic count was higher on H&amp;E than PHH3. In cases with PASS score ≥ 4, 50% and 27% of cases had mitotic count &amp;gt;3/10HPF on PHH3 and H&amp;E, respectively. Follow-up showed two patients AWD and one DOD, all of whom had PASS score ≥ 4, with mitotic count on H&amp;E 7, 1 and 6 and mitotic count on PHH3 8, 4, and 21 respectively. Conclusion This is the first study evaluating the use of PHH3 in pheochromocytomas. Overall, mitotic count was higher on PHH3 than on H&amp;E. This indicates PHH3 is a helpful tool in counting mitosis. Since the PASS score is an imperfect system to predict outcome, additional studies are needed to evaluate the use of PHH3 in prognostic scoring systems for PCC.

FRI224 A Rare Case Of Recurrent Paraganglioma Presented With Liver Metastasis

Abstract Disclosure: E. Gupta: None. M. Al Mushref: None. Malignant Paragangliomas (PGLs) and Pheochromocytomas (PCC) are extremely rare. Approximately 10% of PCCs and 25% of PGLs are metastatic. Metastatic PGLs typically occur in patients with predisposing genetic mutations. We present a case of recurrent metastatic PGL in a young female with no known genetic predisposition to metastatic disease occurring after surgical resection. Our patient is a 28-year-old female with a history of PGL status post left adrenalectomy and nephrectomy two and a half years prior who presented to the ED for abdominal pain. She was first diagnosed after being admitted for hypertensive emergency. During time of diagnosis, plasma and urinary metanephrines were significantly elevated at 1.13 nmol/L and 907 ug/gCr respectively and plasma and urinary normetanephrines were elevated at 80.2 nmol/L and 52043 ug/gCr respectively. MRI showed a 16 cm left retroperitoneal mass and MIBG scan showed increased uptake in the mass however no evidence of metastatic disease was noted then. The patient had immigrated from Haiti. Her mother had passed away at age 20 of unknown cause and her father has no known history. Genetic testing was negative for hereditary gene mutations including multiple SDHDs, VHL, NF1, MEN1 and MAX. Surgical exploration showed a giant left retroperitoneal neoplasm involving the left kidney and left adrenal and both organs were resected. Pathology revealed PGL, focally extending to peripheral specimen margin and benign retroperitoneal lymph nodes and soft tissues. Post-resection meta- and normetanephrines levels were normal. Unfortunately, the patient was lost to follow up after surgery. On this admission, she endorsed right lower quadrant abdominal pain. Plasma normetanephrine was 1.72 nmol/L, metanephrine was normal, and chromogranin A level was elevated at 545 ng/mL. CT scan revealed multiple hepatic lesions and MIBG scan further showed new increased uptake suggesting metastasis. The patient was asymptomatic and blood pressure remained normal during her hospitalization. Due to concerns of recurrent PGL with metastasis, she established care with Oncology for initiation of treatment. PGL is an extremely rare neuroendocrine tumor and is closely related to PCC. Sympathetic PGLs cause catecholamine surge symptoms but low volume disease may remain asymptomatic. Genetic predisposition is common in malignant PGL particularly succinate dehydrogenase mutation subunit B. Patients should be closely followed up to screen for recurrence and genetic testing should also be done. In our patient’s case, despite surgical resection and negative genetic testing, she developed recurrence of the PGL with new metastasis emphasizing the importance of close surveillance in the case of PGL to monitor for recurrence. Presentation: Friday, June 16, 2023

Gastrointestinal Stromal Tumor of Esophageal Location: A Rare Case with Surgical Discussion. Case Report and Literature Review

Gastrointestinal stromal tumors (GISTs) are rare mesenchymal neoplasms. They arise from the intestinal wall and usually present as subepithelial neoplasms in the stomach and small intestine; however, they can appear anywhere in the gastrointestinal (GI) tract. Most of these tumors have mutations in KIT or platelet-derived growth receptor alpha (PDGFRA), while mutations in succinate dehydrogenase (SDH) or other genes are less frequent. New molecules have shown promising results in the therapy of these tumors.

Unraveling the functional consequences of a novel germline missense mutation (R38C) in the yeast model of succinate dehydrogenase subunit B: insights into neurodegenerative disorders.

This study explores the implications of a novel germline missense mutation (R38C) in the succinate dehydrogenase (SDH) subunit B, which has been linked to neurodegenerative diseases. The mutation was identified from the SDH mutation database and corresponds to the SDH2R32C allele, mirroring the human SDHBR38C mutation. By subjecting the mutant yeast model to hydrogen peroxide (H2O2) stress, simulating oxidative stress, we observed heightened sensitivity to oxidative conditions. Quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR) analysis revealed significant regulation (p < 0.05) of genes associated with antioxidant systems and energy metabolism. Through gas chromatography-mass spectrometry (GC-MS) analysis, we examined yeast cell metabolites under oxidative stress, uncovering insights into the potential protective role of o-vanillin. This study elucidates the biological mechanisms underlying cellular oxidative stress responses, offering valuable insights into its repercussions. These findings shed light on innovative avenues for addressing neurodegenerative diseases, potentially revolutionizing therapeutic strategies.

Multidisciplinary Management of Lateral Skull Base Paragangliomas: A 20-Year Experience.

Objectives Paragangliomas of the lateral skull base are rare, largely benign, neuroendocrine tumors. Little evidence exists to support clinicians in the management of these tumors. The present study evaluates considerations in the multidisciplinary workup and management of paragangliomas affecting the lateral skull base. Methods A STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) checklist compliant retrospective review of adult patients with lateral skull base paragangliomas over 20 years (2002-2021) was performed. Patient and tumor data were collected from patient health care records. Results Seventy patients were identified including 21 (30.0%) males and 49 (70.0%) females. The mean length of follow-up was 87.3 months (range: 12-239 months). Twenty-nine (41.4%) patients had Fisch A or B tumors. Overall, 57 patients (81.4%) were offered treatment upfront, with 13 patients (18.6%) initially undergoing active surveillance. Younger age and reduced American Society of Anesthesiologists (ASA) grade was significantly associated with a decision to offer treatment at presentation (both p = 0.03), while all patients with succinate dehydrogenase (SDH) mutations ( n = 10) and tumor secretion ( n = 4) were offered treatment. Patients with Fisch A/B tumors ( p = 0.01), cranial neuropathies ( p = 0.01), and smaller tumors ( p = 0.01) were more likely to undergo surgical resection. At the time of the last follow-up, the proportion of patients with a cranial neuropathy was notably lower in the observation (3/12, 25.0%) and radiotherapy (1/6, 16.7%) groups. Conclusion In our series, younger, fitter patients with SDH mutations, cranial neuropathies, or tumor secretion were more likely to be offered upfront treatment. There was a low incidence of new cranial neuropathy in the patients selected for observation during long-term follow-up.

The aggressiveness of succinate dehydrogenase subunit B-deficient chromaffin cells is reduced when their bioelectrical properties are restored by glibenclamide.

Pheochromocytomas/paragangliomas (PPGLs) are neuroendocrine tumours, mostly resulting from mutations in predisposing genes. Mutations of succinate dehydrogenase (SDH) subunit B (SDHB) are associated with high probability of metastatic disease. Since bioelectrical properties and signalling in cancer are an emerging field, we investigated the metabolic, functional and electrophysiological characteristics in human succinate dehydrogenase subunit B (SDHB)-deficient pheochromocytoma cells. These cells exhibited reduced SDH function with elevated succinate-to-fumarate ratio and reduced intracellular ATP levels. The analysis of membrane passive properties revealed a more hyperpolarized membrane potential and a lower cell capacitance of SDHB-deficient cells compared to the parental ones. These bioelectrical changes were associated with reduced proliferation and adhesion capacity of SDHB-deficient cells. Only in SDHB-deficient cells, we also observed an increased amplitude of potassium currents suggesting an activation of ATP-sensitive potassium channels (KATP). Indeed, exposure of the SDHB-deficient cells to glibenclamide, a specific KATP inhibitor, or to ATP caused normalization of potassium current features and altered proliferation and adhesion. In this work, we show for the first time that reduced intracellular ATP levels in SDHB-deficient chromaffin cells impaired cell bioelectrical properties, which, in turn, are associated with an increased cell aggressiveness. Moreover, we first ever demonstrated that glibenclamide not only reduced the outward potassium currents in SDHB-deficient cells but increased their growth capacity, reduced their ability to migrate and shifted their phenotype towards one more similar to that of parental one.

Absolute Configuration, Enantioselective Bioactivity, and Mechanism Study of the Novel Chiral Fungicide Benzovindiflupyr.

Benzovindiflupyr has gained increasing attention as a new chiral succinate dehydrogenase inhibitor fungicide; however, its determination, bioactivity, and mechanism at the enantiomeric level are very limited. In the present study, optical rotation determination and X-ray single-crystal diffraction results identified that the absolute configurations were (+)-(1R,4S)-benzovindiflupyr and (-)-(1S,4R)-benzovindiflupyr. A quantitative determination method for enantiomers was established using high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) for pesticide detection. The stereoselective bioactivity assay indicated that (-)-(1S,4R)-benzovindiflupyr exhibited greater potency than (+)-(1R,4S)-benzovindiflupyr against seven phytopathogenic fungi. Molecular docking analysis showed that (-)-(1S,4R)-benzovindiflupyr possessed a stronger binding affinity to succinate dehydrogenase than (+)-(1R,4S)-benzovindiflupyr. The binding modes between enantiomers and the mutant with H272(B) predicted that the phytopathogenic fungi with H272(B) of succinate dehydrogenase mutation would not be resistant to benzovindiflupyr enantiomers. This study provides a basis for residue evaluation, risk assessment, and the safe application of benzovindiflupyr at the enantiomer level.

Mitochondrial SENP2 regulates the assembly of SDH complex under metabolic stress.

Succinate dehydrogenase (SDH) is a heterotetrameric enzyme complex belonging to the mitochondrial respiratory chain and uniquely links the tricarboxylic acid (TCA) cycle with oxidative phosphorylation. Cancer-related SDH mutations promote succinate accumulation, which is regarded as an oncometabolite. Post-translational modifications of SDH complex components are known to regulate SDH activity, although the contribution of SUMOylation remains unclear. Here, we show that SDHA is SUMOylated by PIAS3 and deSUMOylated by SENP2, events dictating the assembly and activity of the SDH complex. Moreover, CBP acetylation of SENP2 negatively regulates its deSUMOylation activity. Under glutamine deprivation, CBP levels decrease, and the ensuing SENP2 activation and SDHA deSUMOylation serve to concurrently dampen the TCA cycle and electron transport chain (ETC) activity. Along with succinate accumulation, this mechanism avoids excessive reactive oxygen species (ROS) production to promote cancer cell survival. This study elucidates a major function of mitochondrial-localized SENP2 and expands our understanding of the role of SUMOylation in resolving metabolic stress.

A New Mutation Site of Succinate Dehydrogenase-Related Carney-Stratakis Syndrome: A Case Report

Carney-Stratakis Syndrome (CSS), first described in 2002 [1], encompasses Gastrointestinal Stromal Tumors (GISTs) and Paragangliomas (PGLs) and has autosomal dominant inheritance with incomplete penetrance [2]. Germline mutations of Succinate Dehydrogenase (SDH) complex subunits and consequent SDH functional deficiency have been identified as responsible for CSS [3]. Here, we present a case with a new mutation site in SDHB that has not yet been reported.

Pseudohypoxia in paraganglioma and pheochromocytoma is associated with an immunosuppressive phenotype.

Metastatic pheochromocytoma and paraganglioma (PPGL) have poor prognosis and limited therapeutic options. The recent advent of immunotherapies showing remarkable clinical efficacies against various cancer types offers the possibility of novel opportunities also for metastatic PPGL. Most PPGLs are pathogenically linked to inactivating mutations in genes encoding different succinate dehydrogenase (SDH) subunits. This causes activation of the hypoxia-inducible factor 2 (HIF2)-mediated transcriptional program in the absence of decreased intratumoral oxygen levels, a phenomenon known as pseudohypoxia. Genuine hypoxia in a tumor creates an immunosuppressive tumor microenvironment. However, the impact of pseudohypoxia in the immune landscape of tumors remains largely unexplored. In this study, tumoral expression of programmed death-ligand 1 (PD-L1) and HIF2α and tumor infiltration of CD8 T lymphocytes (CTLs) were examined in PPGL specimens from 102 patients. We assessed associations between PD-L1, CTL infiltration, HIF2α expression, and the mutational status of SDH genes. Our results show that high PD-L1 expression levels in tumor cells and CTL tumor infiltration were more frequent in metastatic than nonmetastatic PPGL. However, this phenotype was negatively associated with SDH mutations and high HIF2α protein expression. These data were validated by analysis of mRNA levels of genes expressing PD-L1, CD8, and HIF2α in PPGL included in The Cancer Genome Atlas database. Further, PD-L1 and CD8 expression was lower in norepinephrine than epinephrine-secreting PPGL. This in silico analysis also revealed the low PD-L1 or CD8 expression levels in tumors with inactivating mutations in VHL or activating mutations in the HIF2α-coding gene, EPAS1, which, together with SDH-mutated tumors, comprise the pseudohypoxic molecular subtype of PPGL. These findings suggest that pseudohypoxic tumor cells induce extrinsic signaling toward the immune cells promoting the development of an immunosuppressive environment. It also provides compelling support to explore the differential response of metastatic PPGL to immune checkpoint inhibitors. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Succinate as an Oncometabolite in Endocrine, Mesenchymal, and Epithelial Tumors

Succinate dehydrogenase (SDH) is a multifaceted enzyme for the mitochondria of eukaryotes, which is responsible for converting succinate to fumarate as a component in the Krebs cycle. Its dysfunction occurs in several malignancies associated with endocrine and epithelial tumors. SDH is an enzymatic complex made of some subunits. Succinate is recognized as an oncometabolite; therefore, the discovery of SDH mutations can give a straight connection between the changes of succinate and tumorigenesis. Progresses in laboratory technologies made it possible to make profiles of and identify succinate accumulation in several types of cancer. In this study, we reviewed the potential roles of SDH mutation and alteration of succinate in tumorigenesis and as tumor markers for the early detection of malignancies.

Succinate dehydrogenase inversely regulates red cell distribution width and healthy life span in chronically hypoxic mice.

Increased red cell distribution width (RDW), which measures erythrocyte mean corpuscular volume (MCV) variability (anisocytosis), has been linked to early mortality in many diseases and in older adults through unknown mechanisms. Hypoxic stress has been proposed as a potential mechanism. However, experimental models to investigate the link between increased RDW and reduced survival are lacking. Here, we show that lifelong hypobaric hypoxia (~10% O2) increased erythrocyte numbers, hemoglobin, and RDW, while reducing longevity in male mice. Compound heterozygous knockout (hKO) mutations in succinate dehydrogenase (Sdh; mitochondrial complex II) genes Sdhb, Sdhc, and Sdhd reduced Sdh subunit protein levels, reduced RDW, and increased healthy life span compared with WT mice in chronic hypoxia. RDW-SD, a direct measure of MCV variability, and the SD of MCV showed the most statistically significant reductions in Sdh hKO mice. Tissue metabolomic profiling of 147 common metabolites showed the largest increase in succinate with elevated succinate/fumarate and succinate/oxoglutarate (2-ketoglutarate) ratios in Sdh hKO mice. These results demonstrate that mitochondrial complex II level is an underlying determinant of both RDW and healthy life span in hypoxia and suggest that therapeutic targeting of Sdh might reduce high RDW–associated clinical mortality in hypoxic diseases.

SDHx mutations and temozolomide in malignant pheochromocytoma and paraganglioma

Malignant pheochromocytomas (PHEOs)/paragangliomas (PGLs) are rare tumors for which clinical outcomes remain poorly defined and therapeutic options are limited. Approximately 27% carry pathogenic germline succinate dehydrogenase (SDHx) mutations; the presence of such mutations has been correlated with response to temozolomide (TMZ). We aimed to investigate the association between germline mutations in SDHx and response to TMZ. We retrospectively identified patients with metastatic malignant PHEO/PGLs treated with TMZ- based chemotherapy at Dana-Farber Cancer Institute between 2003 and 2020. The correlation between response by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and PET Response Criteria in Solid Tumors (PERCIST) and the presence of SDHx mutations in the germline and tumor was evaluated. Nineteen patients received TMZ. Seventeen underwent germline assessment: 9 (53%) carried a pathogenic SDHx germline mutation. Fifteen patients were evaluable for response by RECIST 1.1: 6 (40%) partial response, 4 (27%) stable disease, and 5 (33%) progressive disease. Overall median progression-free survival was 2.2 years. Three-year overall survival (OS) was 58%. Median PFS was 1.3 years and 5.5 years for carriers and non-carriers, respectively and OS was 1.5 years and not estimable for carriers and non-carriers, respectively. The response by PERCIST criteria in nine patients correlated with the RECIST 1.1 assessment. Our series represents one of the largest analyses of patients with malignant PHEOs/PGLs treated with TMZ who have available germline data. The incidence of pathogenic germline SDHx mutations was similar to what has been previously published, though our analysis suggests that there may be a limited association between response to TMZ and pathogenic germline SDHx mutations.