SDHD Research Articles

Prevalence and prognosis of hypoxia-inducible factor-2α (HIF-2α) pathway gene mutations across advanced solid tumors.

Hypoxia-inducible factor-2α (HIF-2α) modulates the hypoxic response pathway in tumors; however, mutations in pathways (including SDHA, SDHB, SDHC, SDHD, FH, and VHL genes) that are suspected to activate HIF-2α are poorly understood, with limited understanding of the prevalence and clinical prognosis. This retrospective observational study used a de-identified nationwide (US-based) clinico-genomic database (CGDB) across 15 available tumor types. Among the 9467 adult patients with advanced/metastatic solid tumors included in the analysis, any mutation at the above-mentioned six genes was observed in 1.8% (95% CI: 1.5-2.1) of patients. The mutation prevalence ranged from 0.05% of SDHD to 0.93% of VHL. When further stratified by tumor type, the prevalence of gene mutation in each tumor type was well below 1%, except for VHL with 44% in renal cell carcinomas (RCC). Excluding RCC, the prevalence of any HIF-2α gene mutations in the study population was 0.9% (95% CI: 0.8-1.2). The median overall survival (OS) from 1 and 2 L therapy among patients with any HIF-2α gene mutation was 14.5 (95% CI: 11.5-24.2) and 9.3 (95% CI: 6.0-18.1) months, respectively, compared with 13.4 (95% CI: 12.9-13.9) and 9.8 (95% CI: 9.3-10.4) months among patients without HIF-2α gene mutations. The prevalence of HIF-2α related gene mutations was generally low (<1%) across the 15 solid tumor types, except for VHL in RCC. No significant association between HIF-2α gene mutation status and OS was identified among patients evaluated in this study.

Standard-definition White-light, High-definition White-light versus Narrow-band Imaging Endoscopy for Detecting Colorectal Adenomas: A Multicenter Randomized Controlled Trial.

This study aimed to compare the performance of standard-definition white-light endoscopy (SD-WL), high-definition white-light endoscopy (HD-WL), and high-definition narrow-band imaging (HD-NBI) in detecting colorectal lesions in the Chinese population. This was a multicenter, single-blind, randomized, controlled trial with a non-inferiority design. Patients undergoing endoscopy for physical examination, screening, and surveillance were enrolled from July 2017 to December 2020. The primary outcome measure was the adenoma detection rate (ADR), defined as the proportion of patients with at least one adenoma detected. The associated factors for detecting adenomas were assessed using univariate and multivariate logistic regression. Out of 653 eligible patients enrolled, data from 596 patients were analyzed. The ADRs were 34.5% in the SD-WL group, 33.5% in the HD-WL group, and 37.5% in the HD-NBI group (P=0.72). The advanced neoplasm detection rates (ANDRs) in the three arms were 17.1%, 15.5%, and 10.4% (P=0.17). No significant differences were found between the SD group and HD group regarding ADR or ANDR (ADR: 34.5% vs. 35.6%, P=0.79; ANDR: 17.1% vs. 13.0%, P=0.16, respectively). Similar results were observed between the HD-WL group and HD-NBI group (ADR: 33.5% vs. 37.7%, P=0.45; ANDR: 15.5% vs. 10.4%, P=0.18, respectively). In the univariate and multivariate logistic regression analyses, neither HD-WL nor HD-NBI led to a significant difference in overall adenoma detection compared to SD-WL (HD-WL: OR 0.91, P=0.69; HD-NBI: OR 1.15, P=0.80). HD-NBI and HD-WL are comparable to SD-WL for overall adenoma detection among Chinese outpatients. It can be concluded that HD-NBI or HD-WL is not superior to SD-WL, but more effective instruction may be needed to guide the selection of different endoscopic methods in the future. Our study's conclusions may aid in the efficient allocation and utilization of limited colonoscopy resources, especially advanced imaging technologies.

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&gt;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 &lt; 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.

Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors.

Objective: The vast majority of gastrointestinal stromal tumors (GISTs) are driven by activating mutations in KIT, PDGFRA, or components of the succinate dehydrogenase (SDH) complex (SDHA, SDHB, SDHC, and SDHD genes). A small fraction of GISTs lack alterations in KIT, PDGFRA, and SDH. We aimed to further characterize the clinical and genomic characteristics of these so-called "triple-negative" GISTs. Methods: We extracted clinical and genomic data from patients seen at MD Anderson Cancer Center with a diagnosis of GIST and available clinical next generation sequencing data to identify "triple-negative" patients. Results: Of the 20 patients identified, 11 (55.0%) had gastric, 8 (40.0%) had small intestinal, and 1 (5.0%) had rectal primary sites. In total, 18 patients (90.0%) eventually developed recurrent or metastatic disease, and 8 of these presented with de novo metastatic disease. For the 13 patients with evaluable response to imatinib (e.g., neoadjuvant treatment or for recurrent/metastatic disease), the median PFS with imatinib was 4.4 months (range 0.5-191.8 months). Outcomes varied widely, as some patients rapidly developed progressive disease while others had more indolent disease. Regarding potential genomic drivers, four patients were found to have alterations in the RAS/RAF/MAPK pathway: two with a BRAF V600E mutation and two with NF1 loss-of-function (LOF) mutations (one deletion and one splice site mutation). In addition, we identified two with TP53 LOF mutations, one with NTRK3 fusion (ETV6-NTRK3), one with PTEN deletion, one with FGFR1 gain-of-function (GOF) mutation (K654E), one with CHEK2 LOF mutation (T367fs*), one with Aurora kinase A fusion (AURKA-CSTF1), and one with FANCA deletion. Patients had better responses with molecularly targeted therapies than with imatinib. Conclusions: Triple-negative GISTs comprise a diverse cohort with different driver mutations. Compared to KIT/PDGFRA-mutant GIST, limited benefit was observed with imatinib in triple-negative GIST. In depth molecular profiling can be helpful in identifying driver mutations and guiding therapy.

P-06 Catecholamine-induced cardiomyopathy: A rare presentiation of pheochromocytoma

Abstract Introduction Pheochromocytoma and paraganglioma (PPGL) are rare neuroendocrine tumors. Clinical manifestations consist of various cardiovascular signs and symptoms related to excessive secretion of catecholamines. Catecholamine-induced cardiomyopathy is a rare but life-threatening complication of PPGL. Excessive discharge of catecholamines results in vasoconstriction, coronary vasospasm and myocardial ischemia. Three types of cardiomyopathies can be observed in patients with PPGL; dilated cardiomyopathy, Takotsuba cardiomyopathy and hypertrophic cardiomyopathy. Clinical Case Herein, we present a case with PPGL complicated with heart failure probably due to excessive secretion of catecholamines. A 19 years-old man was admitted to emergency department with dyspnea and hypotension. He exhibited severe signs of heart failure with very high liver function tests; ALT: 3647 U/L (8-65) and AST: 4542U/L (7-40), probably due to hepatic congestion. Echocardiogram performed in ICU reported %10 left venticular ejection fraction with diffuse akinesia. Remarkable improvement of liver function was recorded following the introduction of heart failure medicines. A computed tomography scan that was performed for abdominal pain and distension revealed a six cm tumour at the left adrenal gland compatible with pheochromocytoma. Laboratory analyses were; 24-hour urine metanephrines: 1938mcg (44-261), normetanephrines: 17934mcg (103-390). Following necessary preoperative preparations, laparoscopic left adrenalectomy was performed and a 70 mm adrenal tumor, histopathologically compatible with pheochromocytoma, was excised. His postoperative laboratory findings were; 24-hour urine metanephrines: 248 mcg (44-261), normetanephrines: 4368 mcg (103-390), chromogranin A: 554.9 ng/ml (0-100), 3-methoxytyramine: 0.34 nmol/l (0-0.17). A 68-Ga-DOTA-Peptide PET/CT following 12 weeks of surgery demonstrated hypermetabolic lesions at left suprarenal area. A second open surgery was performed and lymph node metastases were detected (Figure 1). His cardiac functions ameliorated significantly following the removal of tumors. Genetic analysis for PPGL syndromes were negative for KIF1B, SDHB, NTRK1, TMEME127, VHL, RET, SDHD genes. Work-up is still pending for the mutations of SDHA, SDHC and SDHAF2 genes. Conclusion Cathecolamine-induced cardiomyopathy is a rare entity associated with PPGL. Urgent recognition of related clinical signs and symptoms and detection of PPGL is lifesaving. It should be kept in mind in patients presenting with symptoms of heart failure, hypotension and multisystem crisis in the absence of coronary or valvular heart disease.Figure 1.Pheochromocytoma with lymph node metastasis. (H&amp;E x100)

Multi-omics integration analysis unveils heterogeneity in breast cancer at the individual level

ABSTRACT Identifying robust breast cancer subtypes will help to reveal the cancer heterogeneity. However, previous breast cancer subtypes were based on population-level quantitative gene expression, which is affected by batch effects and cannot be applied to individuals. We detected differential gene expression, genomic, and epigenomic alterations to identify driver differential expression at the individual level. The individual driver differential expression reflected the breast cancer patients’ heterogeneity and revealed four subtypes. Mesenchymal subtype as the most aggressive subtype harbored deletion and downregulated expression of genes in chromosome 11q23 region. Specifically, silencing of the SDHD gene in 11q23 promoted the invasion and migration of breast cancer cells in vitro by the epithelial–mesenchymal transition. The immunologically hot subtype displayed an immune-hot microenvironment, including high T-cell infiltration and upregulated PD-1 and CTLA4. Luminal and genomic-unstable subtypes showed opposite macrophage polarization, which may be regulated by the ligand–receptor pairs of CD99. The integration of multi-omics data at the individual level provides a powerful framework for elucidating the heterogeneity of breast cancer.

Genome sequencing-based prognosis, mutational analysis, and survival rate of clear cell renal cell carcinoma.

e16543 Background: The clear cell renal cell carcinoma (ccRCC) is the most prevalent genitourinary cancer, and carries a poor prognosis. Information regarding whole genome sequencing, a prognostic prediction system, and overall survival in ccRCC is limited. While loss of VHL is commonly implicated in ccRCC, two genes indicated in other cancers, SDHD and ARID1A, have limited literature on their correlation to ccRCC. Hence, we aimed to analyze the genomic profile, epidemiological characteristics and overall survival of ccRCC. Methods: We utilized cBioPortal cancer genomics [The Cancer Genome Atlas (TCGA) PanCancer Atlas, TCGA Firehose Legacy, and TCGA Nature 2013] to study the genetic mutations associated with ccRCC. Epidemiological characteristics and genetic profiles were evaluated, and a query was generated to calculate 5 year and 10 year survival rate with the most common mutations. Log-rank test and Kaplan–Meier estimator were used in analyzing the survival function. Patients with two or more overlapping mutations (72) were excluded. Results: We identified 761 patients with ccRCC, out of which 442 had primary ccRCC with all demographic details available. 65.8% were males, 58.1% were Caucasian, and 7.2% were African American. Majority of patients (199) were between the ages of 50-65 years. 286 (64.7%) were alive and 156 (35.3%) were deceased. The common mutations associated with reduced survival were VHL, BAP1, SDHA, SDHD, and ARID1A. Median survival of patients with VHL, BAP1, SDHA, SDHD, ARID1A mutations was 118.85, 93.04, 40.70, 2.04, and 6.02 months respectively in comparison with unaltered mutation group (78.44 months) (p &lt; 0.0001). (Table 1) Survival was lowest amongst SDHD [2.04 months] and ARID1A [6.02 months]. (p = 3.26e-10). In survival analysis, SDHD and ARID1A were associated with lowest survival after initial diagnosis at 60 months (Figure 1) and 120 months (Figure 2). (p = 2.592e-3). Conclusions: Our study found that SDHD, ARID1A, and SDHA genes were associated with the worst prognosis in ccRCC with median survival of 2.04, 6.02, and 40.70 months. This study may provide insight for targeted therapies for ccRCC and improve the prognosis of these patients. [Table: see text]

SDHI resistance in Pyrenophora teres f teres and molecular detection of novel double mutations in sdh genes conferring high resistance.

Net blotch (NB), caused by Pyrenophora teres f. teres (Ptt), is an important disease of barley worldwide. NB control is commonly achieved through the use of fungicide mixtures including strobilurins, triazoles and carboxamides. Succinate dehydrogenase inhibitors (SDHI) are important components of fungicide management programs of barley diseases. However, during the last growing seasons in Argentina, barley fields sprayed with mixtures containing SDHI fungicides have shown failures in NB control. Here, we report the isolation and characterization of Argentine Ptt strains resistant to SDHI fungicides. Compared against a sensitive (wild-type) reference strain collected in 2008, all 21 Ptt isolates collected in 2021 exhibited resistance to pydiflumetofen and fluxapyroxad both in vitro and in vivo. Concordantly, all of them presented target-site mutations in any of the sdhB, sdhC and sdhD genes. Although the mutations detected have been previously reported in other parts of the world, this study documents for the first time the occurrence of double mutations in the same Ptt isolate. Specifically, the double mutation sdhC-N75S + sdhD-D145G confers high resistance to SDHI fungicides, while the double mutations sdhB-H277Y + sdhC-N75S and sdhB-H277Y + sdhC-H134R confer moderate levels of resistance in Ptt. SDHI-resistance in Argentine Ptt populations is expected to increase. These findings emphasize the urgent need to perform a wider survey and a more frequent monitoring of SDHI sensitivity of Ptt populations and to develop and implement effective antiresistance tactics. © 2023 Society of Chemical Industry.

Don't let your guard down - aggressive, hereditary paraganglioma associated with SDHD gene nonsense variant: c.33C&gt;A (p.(Cys11Ter))

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Resistance of Black Aspergilli Species from Grape Vineyards to SDHI, QoI, DMI, and Phenylpyrrole Fungicides.

Fungicide applications constitute a management practice that reduces the size of fungal populations and by acting as a genetic drift factor, may affect pathogen evolution. In a previous study, we showed that the farming system influenced the population structure of the Aspergillus section Nigri species in Greek vineyards. The current study aimed to test the hypothesis that the differences in the population structure may be associated with the selection of fungicide-resistant strains within the black aspergilli populations. To achieve this, we determined the sensitivity of 102, 151, 19, and 22 for the A. uvarum, A. tubingensis, A. niger, and A. carbonarious isolates, respectively, originating either from conventionally-treated or organic vineyards to the fungicides fluxapyroxad-SDHIs, pyraclostrobin-QoIs, tebuconazole-DMIs, and fludioxonil-phenylpyrroles. The results showed widespread resistance to all four fungicides tested in the A. uvarum isolates originating mostly from conventional vineyards. In contrast, all the A. tubingensis isolates tested were sensitive to pyraclostrobin, while moderate frequencies of only lowly resistant isolates were identified for tebuconazole, fludioxonil, and fluxapyroxad. Sequencing analysis of the corresponding fungicide target encoding genes revealed the presence of H270Y, H65Q/S66P, and G143A mutations in the sdhB, sdhD, and cytb genes of A. uvarum resistant isolates, respectively. No mutations in the Cyp51A and Cyp51B genes were detected in either the A. uvarum or A. tubingensis isolates exhibiting high or low resistance levels to DMIs, suggesting that other resistance mechanisms are responsible for the observed phenotype. Our results support the initial hypothesis for the contribution of fungicide resistance in the black aspergilli population structure in conventional and organic vineyards, while this is the first report of A. uvarum resistance to SDHIs and the first documentation of H270Y or H65Q/S66P mutations in sdhB, sdhD, and of the G143A mutation in the cytb gene of this fungal species.

The SDHD:p.H102R Variant Is Frequent in Russian Patients with Head and Neck Paragangliomas and Associated with Loss of 11p15.5 Region and Hypermethylation of H19-DMR

Head and neck paragangliomas (HNPGLs) are rare neuroendocrine neoplasms derived from the parasympathetic paraganglia of the head and neck. At least 30% of HNPGLs are linked to germline mutations, predominantly in SDHx genes. In this study, we analyzed an extended cohort of Russian patients with HNPGLs using whole-exome sequencing and found a highly frequent missense variant p.H102R in the SDHD gene. We determined this variant in 34% of the SDHD mutation carriers. This variant was associated with somatic loss of the gene wild-type allele. Data from the B allele frequency method and microsatellite and microdeletion analysis indicated evident LOH at the 11p15.5 region and potential loss of the whole of chromosome 11. We found hypermethylation of H19-DMR in all tumors, whereas differential methylation of KvDMR was mostly retained. These findings do not support the paternal transmission of SDHD:p.H102R but are in agreement with the Hensen model. Using targeted sequencing, we also studied the variant frequency in a control cohort; we found SDHD:p.H102R in 1.9% of cases, allowing us to classify this variant as pathogenic. The immunohistochemistry of SDHB showed that the SDHD:p.H102R mutation, even in combination with wild-type allele loss, does not always lead to SDH deficiency. The obtained results demonstrate the frequent variant associated with HNPGLs in a Russian population and support its pathogenicity. Our findings help with understanding the mechanism of tumorigenesis and are also important for the development of cost-effective genetic screening programs.

A need to tailor surveillance based on family history: describing a highly penetrant familial paraganglioma kindred with an SDHD pathogenic variant.

Pathogenic variants (PVs) in the SDHD gene increase risk for paragangliomas (PGL)/pheochromocytomas, renal cell carcinomas, and gastrointestinal stromal tumors. Penetrance in individuals with SDHD PVs varies in reported research from 40-70%, and there is limited evidence of specific genotype risks. This study aims to characterize a multi-generational family with SDHD p.Trp43* PVs and potential genotype-phenotype considerations for surveillance. Individuals with a paternally inherited SDHD p.Trp43*(c.129G > A) PV were identified. Genetic, medical and family histories were abstracted, including clinical characteristics, tumor histories, and treatment approaches. Eleven individuals with the SDHD PV in the same kindred were diagnosed with 41 SDHx-related tumors across all family members. Eight individuals developed 27 head and neck PGL of varying origins, and seven individuals developed tumors outside of the head and neck region. Many individuals had multiple tumors, and age of first tumor diagnosis ranged from age 10 to age 45years old. Individuals with SDHD p.Trp43* variants may have higher risks for SDHx related tumors than other SDHD variants. Prioritizing identification of at-risk individuals and initiating surveillance tailored to family history is recommended given the rate of multiple tumors found in one familial branch of individuals under 18years old. Individuals with strong family histories of PGL at young ages with this PV will benefit from tailored surveillance recommendations.

Identification of Putative SDHI Target Site Mutations in the SDHB, SDHC, and SDHD Subunits of the Grape Powdery Mildew Pathogen Erysiphe necator.

Succinate dehydrogenase inhibitors (SDHIs) are fungicides used in control of numerous fungal plant pathogens, including Erysiphe necator, the causal agent of grapevine powdery mildew (GPM). Here, the sdhb, sdhc, and sdhd genes of E. necator were screened for mutations that may be associated with SDHI resistance. GPM samples were collected from 2017 to 2020 from the U.S. states of California, Oregon, Washington, and Michigan, and the Canadian province of British Columbia. Forty-five polymorphisms were identified in the three sdh genes, 17 of which caused missense mutations. Of these, the SDHC-p.I244V substitution was shown in this study to reduce sensitivity of E. necator to boscalid and fluopyram, whereas the SDHC-p.G25R substitution did not affect SDHI sensitivity. Of the other 15 missense mutations, the SDHC-p.H242R substitution was shown in previous studies to reduce sensitivity of E. necator toward boscalid, whereas the equivalents of the SDHB-p.H242L, SDHC-p.A83V, and SDHD-p.I71F substitutions were shown to reduce sensitivity to SDHIs in other fungi. Generally, only a single amino acid substitution was present in the SDHB, SDHC, or SDHD subunit of E. necator isolates, but missense mutations putatively associated with SDHI resistance were widely distributed in the sampled areas and increased in frequency over time. Finally, isolates that had decreased sensitivity to boscalid or fluopyram were identified but with no or only the SDHC-p.G25R amino acid substitution present in SDHB, SDHC, and SDHD subunits. This suggests that target site mutations probably are not the only mechanism conferring resistance to SDHIs in E. necator.

Somatic Mutation Profiling in Head and Neck Paragangliomas.

ContextHead and neck paragangliomas (HNPGLs) are rare neoplasms with a high degree of heritability. Paragangliomas present as polygenic diseases caused by combined alterations in multiple genes; however, many driver changes remain unknown.ObjectiveThe objective of the study was to analyze somatic mutation profiles in HNPGLs.MethodsWhole-exome sequencing of 42 tumors and matched normal tissues obtained from Russian patients with HNPGLs was carried out. Somatic mutation profiling included variant calling and utilizing MutSig and SigProfiler packages.Results57% of patients harbored germline and somatic variants in paraganglioma (PGL) susceptibility genes or potentially related genes. Somatic variants in novel genes were found in 17% of patients without mutations in any known PGL-related genes. The studied cohort was characterized by 6 significantly mutated genes: SDHD, BCAS4, SLC25A14, RBM3, TP53, and ASCC1, as well as 4 COSMIC single base substitutions (SBS)-96 mutational signatures (SBS5, SBS29, SBS1, and SBS7b). Tumors with germline variants specifically displayed SBS11 and SBS19, when an SBS33-specific mutational signature was identified for cases without those. Beta allele frequency analysis of copy number variations revealed loss of heterozygosity of the wild-type allele in 1 patient with germline mutation c.287-2A>G in the SDHB gene. In patients with germline mutation c.A305G in the SDHD gene, frequent potential loss of chromosome 11 was observed.ConclusionThese results give an understanding of somatic changes and the mutational landscape associated with HNPGLs and are important for the identification of molecular mechanisms involved in tumor development.

SDHB knockout and succinate accumulation are insufficient for tumorigenesis but dual SDHB/NF1 loss yields SDHx-like pheochromocytomas.

SUMMARYInherited pathogenic succinate dehydrogenase (SDHx) gene mutations cause the hereditary pheochromocytoma and paraganglioma tumor syndrome. Syndromic tumors exhibit elevated succinate, an oncometabolite that is proposed to drive tumorigenesis via DNA and histone hypermethylation, mitochondrial expansion, and pseudohypoxia-related gene expression. To interrogate this prevailing model, we disrupt mouse adrenal medulla SDHB expression, which recapitulates several key molecular features of human SDHx tumors, including succinate accumulation but not 5hmC loss, HIF accumulation, or tumorigenesis. By contrast, concomitant SDHB and the neurofibromin 1 tumor suppressor disruption yields SDHx-like pheochromocytomas. Unexpectedly, in vivo depletion of the 2-oxoglutarate (2-OG) dioxygenase cofactor ascorbate reduces SDHB-deficient cell survival, indicating that SDHx loss may be better tolerated by tissues with high antioxidant capacity. Contrary to the prevailing oncometabolite model, succinate accumulation and 2-OG-dependent dioxygenase inhibition are insufficient for mouse pheochromocytoma tumorigenesis, which requires additional growth-regulatory pathway activation.

Genetics of Head and Neck Paragangliomas

Paragangliomas of the head and neck (HNPGL) are rare neurogenic tumors, in which genetic factors play a certain role. So far, 10 genes related to HNPGL (SDHA、SDHB、SDHC、SDHD、SDHAF2、VHL、HIF2A、RET、NF1 and TMEM127) have been found. The clinical phenotypes of different gene mutations are different. SDHD、SDHC and SDHAF2 gene mutations are almost 100% related to HNPGL. SDHD and SDHAF2 gene mutations tend to form multiple paragangliomas, and its genetic pattern has obviously maternal imprinting. SDHB mutations have sympathetic paraganglioma and malignant tendency. Understanding the molecular mechanism and genotype-phenotypic relationship of paraganglioma can provide significant help for genetic counseling, diagnosis and treatment and follow-up strategies in patients with HNPGL.

Dynamic Electrocardiogram under P Wave Detection Algorithm Combined with Low-Dose Betaloc in Diagnosis and Treatment of Patients with Arrhythmia after Hepatocarcinoma Resection.

This work aimed to study the diagnostic value of dynamic electrocardiogram (ECG) based on P wave detection algorithm for arrhythmia after hepatectomy in patients with primary liver cancer, and to compare the therapeutic effect of different doses of Betaloc. P wave detection algorithm was introduced for ECG automatic detection and analysis, which can be used for early diagnosis of arrhythmia. Sixty patients with arrhythmia after hepatectomy for primary liver cancer were selected as the research objects. They were randomly divided into control group, SD group, MD group, and HD group, with 15 cases in each group. No Betaloc, low-dose (≤47.5 mg), medium-dose (47.5–95 mg), and high-dose (142.5–190 mg) Betaloc were used for treatment. As a result, P wave detection algorithms can mark P waves that may be submerged in strong interference. P waves from arrhythmia database were used to verify the performance of the proposed algorithm. The prediction precision (Pp) of ventricular arrhythmia and atrial arrhythmia was 98.53% and 98.76%, respectively. Systolic blood pressure (117.35 ± 7.33, 126.44 ± 9.38, and 116.02 ± 8.2) mmHg in SD group, MD group, and HD group was significantly lower than that in control group (140.3 ± 7.21) mmHg after two weeks of treatment. Moreover, those of SD group and HD group were significantly lower than MD group (P < 0.05). The effective rate of cardiac function improvement in SD group (72.35 ± 1.21%) was significantly higher than that in control group, MD group, and HD group (38.2 ± 0.98%, 65.12 ± 1.33%, and 60.43 ± 1.25%; P < 0.05). In short, dynamic ECG based on P wave detection algorithm had high diagnostic value for arrhythmia after hepatectomy in patients with primary liver cancer. It was safe and effective for patients to choose small dose of Betaloc.

Monitoring of Brazilian wheat blast field populations reveals resistance to QoI, DMI, and SDHI fungicides

AbstractWheat blast is one of the most important and devastating fungal diseases of wheat in South America, South‐east Asia, and now in southern Africa. The disease can reduce grain yield by up to 70% and is best controlled using integrated disease management strategies. The difficulty in disease management is compounded by the lack of durable host resistance and the ineffectiveness of fungicide sprays. New succinate dehydrogenase inhibitor (SDHI) fungicides were recently introduced for the management of wheat diseases. Brazilian field populations of the wheat blast pathogen Pyricularia oryzae Triticum lineage (PoTl) sampled from different geographical regions in 2012 and 2018 were shown to be resistant to both QoI (strobilurin) and DMI (azole) fungicides. The main objective of the current study was to determine the SDHI baseline sensitivity in these populations. Moderate levels of SDHI resistance were detected in five out of the six field populations sampled in 2012 and in most of the strains isolated in 2018. No association was found between target site mutations in the sdhB, sdhC, and sdhD genes and the levels of SDHI resistance, indicating that a pre‐existing resistance mechanism not associated with target site mutations is probably present in Brazilian wheat blast populations.

A FAMILY WITH HEREDITARY PARAGANGLIOMA SECONDARY TO SDHD MUTATION

INTRODUCTIONA third of pheochromocytoma and paraganglioma (PPGL) tumours are part of a hereditary syndrome. Hereditary PPGL shows autosomal dominant inheritance with variable penetrance. Genetic testing is recommended in all patients diagnosed with PPGL regardless of age at presentation and family history. SDHD is the most frequently mutated gene in head and neck PGLs and associated tumours have low malignancy rate. This gene is maternally imprinted with silencing of the maternal allele, thus, the risk of developing paragangliomas is limited to offsprings who inherit the pathogenic variant from their father. Paternally inherited pathogenic variants are highly penetrant by age 50. We describe a family with hereditary paraganglioma due to mutation in the SDHD gene. RESULTSThe index patient is a 23 year-old female who was diagnosed to have bilateral adrenal pheochromocytoma with carotid and cardiac paragangliomas. Genetic screening revealed that she has SDHD mutation. Further family history revealed that 2 out of 3 paternal aunts have carotid paragangliomas. Her father, youngest of 5 siblings, paternal uncle and grandfather passed away at age 42, 40, 39 years old, respectively, due to severe headache and possible haemorrhagic stroke. Six other family members underwent genetic screening as well. Five family members were positive for SDHD mutation. These include the index patient’s elder sister, 3 paternal aunts (2 with carotid paragangliomas) and one male cousin. CONCLUSIONGenetic testing for family members of patients with hereditary paragangliomas is recommended after thorough genetic counselling. Genetic testing for firstand second-degree relatives is recommended for SDHDrelated paraganglioma. Healthy asymptomatic carriers for the gene mutation should undergo clinical assessment, plasma and/or urine metanephrines and normetanephrines and a combination of whole-body MRI (head and neck, abdominal and pelvic) and PET-CT imaging at initial screening. Thereafter, recommendations for long-term surveillance include annual clinical and biochemical evaluation along with whole body MRI repeated every 2-3 years.

Efficacy of Immunohistochemistry for SDHB in the Screening of Hereditary Pheochromocytoma-Paraganglioma.

Simple SummaryThe majority of hereditary pheochromocytoma and paraganglioma (PPGL) is caused by germline mutations in the SDHB, SDHC, or SDHD genes, which encode three (SDHB, SDHC, SDHD) of five subunits of succinate dehydrogenase (SDH) enzyme (SDHA, SDHDB, SDHC, SDHD, SDHAF2). The inactivation of any of the SDHx genes leads to the proteolysis of SDH. This can be detected with negative immunohistochemistry (IHC) for SDHB. However, there is no consensus of the interpretation of “weakly positive” staining. Hence, we carried out a retrospective single centre study comprising 58 patients to evaluate the efficacy of using SDHB IHC for detecting SDHx mutation in PPGL cases. Our analyses revealed that SDHB-negative IHC is a cost-effective and reliable method to predict SDHx mutations in the Korean population. Nonetheless, in the case of weakly positive staining, an additional gene study should be considered.The most common genetic backgrounds of hereditary paraganglioma and pheochromocytoma (PPGL) are SDHx germline mutations. Given the fact that the immunohistochemistry (IHC) result for SDHB is always negative regardless of the type of SDHx mutation, we aimed to evaluate the efficacy of using SDHB IHC for screening SDHx mutations in PPGL cases. In total, 52 patients who underwent surgery for PPGL treatment between 2006 and 2020 and underwent genetic analysis at diagnosis were included. Tissue microarrays (TMAs) were constructed with PPGL tissues and IHC for SDHB was performed on TMA sections. All 10 patients with SDHB-negative IHC contained SDHB or SDHD mutations. The genetic test results of patients with SDHB-weakly positive IHC varied (one SDHB, two RET, one VHL, and three unknown gene mutations). There were no SDHx mutations in the SDHB-positive IHC group. Six patients with weakly positive SDHB IHC with primarily unknown genetic status were re-called and underwent next-generation sequencing. None of them had SDHx mutations. In conclusion, SDHB-negative IHC is a cost-effective and reliable method to predict SDHx mutations. However, in the case of weakly positive SDHB staining, an additional gene study should be considered.