SDHA Immunohistochemistry in Pheochromocytomas And
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SUPPLEMENTARY FIGURES and TABLES Genetic Hallmarks of Recurrent/Metastatic Adenoid Cystic Carcinoma
SUPPLEMENTARY FIGURES AND TABLES Genetic Hallmarks Of Recurrent/Metastatic Adenoid Cystic Carcinoma SUPPLEMENTARY FIGURES Figure S1. Flow diagram of study design. Figure S2. Primary and recurrent/metastatic adenoid cystic carcinoma distribution by anatomic site. Figure S3. Variant allelic frequency (VAF) density histogram for NOTCH1 mutations observed in recurrent/metastatic adenoid cystic carcinoma (R/M ACC). Figure S4. Downsampling analysis of R/M MSK-IMPACT cohort (n=94) to simulate mutation detection at 100x coverage. Figure S5. Representative PyClone plots demonstrating intratumoral heterogeneity quantified as number of genomically distinct subclonal populations in adenoid cystic carcinoma. Figure S6. MRI of the neck with contrast of adenoid cystic carcinoma of right parotid gland involving masseter muscle and ascending ramus. Figure S7. Histologic confirmation of 6 representative distant metastatic sites of a single case with parotid adenoid cystic carcinoma. Figure S8. Fluorescence in situ hybridization (FISH) of distant lung metastatic lesions in a single case of parotid adenoid cystic carcinoma. Figure S9. Two-way plots of cancer cell fraction in a single case of parotid adenoid cystic carcinoma, comparing primary tumor with eight metastatic lesions. Figure S10. Multiregion clonal evolution heatmap analysis of two breast adenoid cystic carcinoma cases with transformation to high grade triple-negative breast cancer (TNBC) histology. SUPPLEMENTARY TABLES Table S1. Study distribution of primary and recurrent/metastatic (R/M) adenoid cystic carcinoma (ACC) cases. Mixed entails head and neck, lung, and breast disease sites. Table S2. Top gene alteration incidence by tumor site (includes primary and recurrent/metastatic cases). Table S3. Top gene alteration incidence of recurrent/metastatic adenoid cystic carcinoma (R/M ACC) cases comparing primary site with distant metastatic site. -
Paraganglioma (PGL) Tumors in Patients with Succinate Dehydrogenase-Related PCC–PGL Syndromes: a Clinicopathological and Molecular Analysis
T G Papathomas and others Non-PCC/PGL tumors in the SDH 170:1 1–12 Clinical Study deficiency Non-pheochromocytoma (PCC)/paraganglioma (PGL) tumors in patients with succinate dehydrogenase-related PCC–PGL syndromes: a clinicopathological and molecular analysis Thomas G Papathomas1, Jose Gaal1, Eleonora P M Corssmit2, Lindsey Oudijk1, Esther Korpershoek1, Ketil Heimdal3, Jean-Pierre Bayley4, Hans Morreau5, Marieke van Dooren6, Konstantinos Papaspyrou7, Thomas Schreiner8, Torsten Hansen9, Per Arne Andresen10, David F Restuccia1, Ingrid van Kessel6, Geert J L H van Leenders1, Johan M Kros1, Leendert H J Looijenga1, Leo J Hofland11, Wolf Mann7, Francien H van Nederveen12, Ozgur Mete13,14, Sylvia L Asa13,14, Ronald R de Krijger1,15 and Winand N M Dinjens1 1Department of Pathology, Josephine Nefkens Institute, Erasmus MC, University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands, 2Department of Endocrinology, Leiden University Medical Center, Leiden,The Netherlands, 3Section for Clinical Genetics, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway, 4Department of Human and Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands, 5Department of Pathology, Leiden University Medical Center, Leiden, The Netherlands, 6Department of Clinical Genetics, Erasmus MC, University Medical Center, Rotterdam, The Netherlands, 7Department of Otorhinolaryngology, Head and Neck Surgery, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany, 8Section for Specialized Endocrinology, -
A Computational Approach for Defining a Signature of Β-Cell Golgi Stress in Diabetes Mellitus
Page 1 of 781 Diabetes A Computational Approach for Defining a Signature of β-Cell Golgi Stress in Diabetes Mellitus Robert N. Bone1,6,7, Olufunmilola Oyebamiji2, Sayali Talware2, Sharmila Selvaraj2, Preethi Krishnan3,6, Farooq Syed1,6,7, Huanmei Wu2, Carmella Evans-Molina 1,3,4,5,6,7,8* Departments of 1Pediatrics, 3Medicine, 4Anatomy, Cell Biology & Physiology, 5Biochemistry & Molecular Biology, the 6Center for Diabetes & Metabolic Diseases, and the 7Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202; 2Department of BioHealth Informatics, Indiana University-Purdue University Indianapolis, Indianapolis, IN, 46202; 8Roudebush VA Medical Center, Indianapolis, IN 46202. *Corresponding Author(s): Carmella Evans-Molina, MD, PhD ([email protected]) Indiana University School of Medicine, 635 Barnhill Drive, MS 2031A, Indianapolis, IN 46202, Telephone: (317) 274-4145, Fax (317) 274-4107 Running Title: Golgi Stress Response in Diabetes Word Count: 4358 Number of Figures: 6 Keywords: Golgi apparatus stress, Islets, β cell, Type 1 diabetes, Type 2 diabetes 1 Diabetes Publish Ahead of Print, published online August 20, 2020 Diabetes Page 2 of 781 ABSTRACT The Golgi apparatus (GA) is an important site of insulin processing and granule maturation, but whether GA organelle dysfunction and GA stress are present in the diabetic β-cell has not been tested. We utilized an informatics-based approach to develop a transcriptional signature of β-cell GA stress using existing RNA sequencing and microarray datasets generated using human islets from donors with diabetes and islets where type 1(T1D) and type 2 diabetes (T2D) had been modeled ex vivo. To narrow our results to GA-specific genes, we applied a filter set of 1,030 genes accepted as GA associated. -
Crystal Structure of Bacterial Succinate:Quinone Oxidoreductase Flavoprotein Sdha in Complex with Its Assembly Factor Sdhe
Crystal structure of bacterial succinate:quinone oxidoreductase flavoprotein SdhA in complex with its assembly factor SdhE Megan J. Mahera,1, Anuradha S. Heratha, Saumya R. Udagedaraa, David A. Dougana, and Kaye N. Truscotta,1 aDepartment of Biochemistry and Genetics, La Trobe Institute for Molecular Science, La Trobe University, Melbourne, VIC 3086, Australia Edited by Amy C. Rosenzweig, Northwestern University, Evanston, IL, and approved February 14, 2018 (received for review January 4, 2018) Succinate:quinone oxidoreductase (SQR) functions in energy me- quinol:FRD), respectively (13, 15). The importance of this protein tabolism, coupling the tricarboxylic acid cycle and electron transport family, in normal cellular metabolism, is manifested by the iden- chain in bacteria and mitochondria. The biogenesis of flavinylated tification of a mutation in human SDHAF2 (Gly78Arg), which is SdhA, the catalytic subunit of SQR, is assisted by a highly conserved linked to an inherited neuroendocrine disorder, PGL2 (10). Cur- assembly factor termed SdhE in bacteria via an unknown mecha- rently, however, the role of SdhE in flavinylation remains poorly nism. By using X-ray crystallography, we have solved the structure understood. To date, three different modes of action for SdhE/ of Escherichia coli SdhE in complex with SdhA to 2.15-Å resolution. Sdh5 have been proposed, suggesting that SdhE facilitates the Our structure shows that SdhE makes a direct interaction with the binding and delivery of FAD (13), acts as a chaperone for SdhA flavin adenine dinucleotide-linked residue His45 in SdhA and main- (10), or catalyzes the attachment of FAD (10). Moreover, the re- tains the capping domain of SdhA in an “open” conformation. -
Inhibition of Mitochondrial Complex II in Neuronal Cells Triggers Unique
www.nature.com/scientificreports OPEN Inhibition of mitochondrial complex II in neuronal cells triggers unique pathways culminating in autophagy with implications for neurodegeneration Sathyanarayanan Ranganayaki1, Neema Jamshidi2, Mohamad Aiyaz3, Santhosh‑Kumar Rashmi4, Narayanappa Gayathri4, Pulleri Kandi Harsha5, Balasundaram Padmanabhan6 & Muchukunte Mukunda Srinivas Bharath7* Mitochondrial dysfunction and neurodegeneration underlie movement disorders such as Parkinson’s disease, Huntington’s disease and Manganism among others. As a corollary, inhibition of mitochondrial complex I (CI) and complex II (CII) by toxins 1‑methyl‑4‑phenylpyridinium (MPP+) and 3‑nitropropionic acid (3‑NPA) respectively, induced degenerative changes noted in such neurodegenerative diseases. We aimed to unravel the down‑stream pathways associated with CII inhibition and compared with CI inhibition and the Manganese (Mn) neurotoxicity. Genome‑wide transcriptomics of N27 neuronal cells exposed to 3‑NPA, compared with MPP+ and Mn revealed varied transcriptomic profle. Along with mitochondrial and synaptic pathways, Autophagy was the predominant pathway diferentially regulated in the 3‑NPA model with implications for neuronal survival. This pathway was unique to 3‑NPA, as substantiated by in silico modelling of the three toxins. Morphological and biochemical validation of autophagy markers in the cell model of 3‑NPA revealed incomplete autophagy mediated by mechanistic Target of Rapamycin Complex 2 (mTORC2) pathway. Interestingly, Brain Derived Neurotrophic Factor -
One in Three Highly Selected Greek Patients with Breast Cancer Carries A
Cancer genetics J Med Genet: first published as 10.1136/jmedgenet-2019-106189 on 12 July 2019. Downloaded from ORIGINAL ARTICLE One in three highly selected Greek patients with breast cancer carries a loss-of-function variant in a cancer susceptibility gene Florentia Fostira, 1 Irene Kostantopoulou,1 Paraskevi Apostolou,1 Myrto S Papamentzelopoulou,1 Christos Papadimitriou,2 Eleni Faliakou,3 Christos Christodoulou,4 Ioannis Boukovinas,5 Evangelia Razis,6 Dimitrios Tryfonopoulos,7 Vasileios Barbounis,8 Andromache Vagena,1 Ioannis S Vlachos,9 Despoina Kalfakakou, 1 George Fountzilas,10 Drakoulis Yannoukakos1 ► Additional material is ABSTRact individuals carrying such pathogenic variants (PVs) published online only. To view Background Gene panel testing has become the norm face an increased lifetime risk for cancer diagnoses.1 please visit the journal online (http:// dx. doi. org/ 10. 1136/ for assessing breast cancer (BC) susceptibility, but actual The implementation of BRCA1 and BRCA2 genetic jmedgenet- 2019- 106189). cancer risks conferred by genes included in panels are testing into clinical practice has enabled the identifi- not established. Contrarily, deciphering the missing cation of individuals at high risk and the application For numbered affiliations see hereditability on BC, through identification of novel of tailored management guidelines, significantly end of article. candidates, remains a challenge. We aimed to investigate improving both cancer prevention and survival.2 the mutation prevalence and spectra in a highly Mutations -
Multiple Endocrine Neoplasia Type 2: an Overview Jessica Moline, MS1, and Charis Eng, MD, Phd1,2,3,4
GENETEST REVIEW Genetics in Medicine Multiple endocrine neoplasia type 2: An overview Jessica Moline, MS1, and Charis Eng, MD, PhD1,2,3,4 TABLE OF CONTENTS Clinical Description of MEN 2 .......................................................................755 Surveillance...................................................................................................760 Multiple endocrine neoplasia type 2A (OMIM# 171400) ....................756 Medullary thyroid carcinoma ................................................................760 Familial medullary thyroid carcinoma (OMIM# 155240).....................756 Pheochromocytoma ................................................................................760 Multiple endocrine neoplasia type 2B (OMIM# 162300) ....................756 Parathyroid adenoma or hyperplasia ...................................................761 Diagnosis and testing......................................................................................756 Hypoparathyroidism................................................................................761 Clinical diagnosis: MEN 2A........................................................................756 Agents/circumstances to avoid .................................................................761 Clinical diagnosis: FMTC ............................................................................756 Testing of relatives at risk...........................................................................761 Clinical diagnosis: MEN 2B ........................................................................756 -
Mitochondrial Genetics
Mitochondrial genetics Patrick Francis Chinnery and Gavin Hudson* Institute of Genetic Medicine, International Centre for Life, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK Introduction: In the last 10 years the field of mitochondrial genetics has widened, shifting the focus from rare sporadic, metabolic disease to the effects of mitochondrial DNA (mtDNA) variation in a growing spectrum of human disease. The aim of this review is to guide the reader through some key concepts regarding mitochondria before introducing both classic and emerging mitochondrial disorders. Sources of data: In this article, a review of the current mitochondrial genetics literature was conducted using PubMed (http://www.ncbi.nlm.nih.gov/pubmed/). In addition, this review makes use of a growing number of publically available databases including MITOMAP, a human mitochondrial genome database (www.mitomap.org), the Human DNA polymerase Gamma Mutation Database (http://tools.niehs.nih.gov/polg/) and PhyloTree.org (www.phylotree.org), a repository of global mtDNA variation. Areas of agreement: The disruption in cellular energy, resulting from defects in mtDNA or defects in the nuclear-encoded genes responsible for mitochondrial maintenance, manifests in a growing number of human diseases. Areas of controversy: The exact mechanisms which govern the inheritance of mtDNA are hotly debated. Growing points: Although still in the early stages, the development of in vitro genetic manipulation could see an end to the inheritance of the most severe mtDNA disease. Keywords: mitochondria/genetics/mitochondrial DNA/mitochondrial disease/ mtDNA Accepted: April 16, 2013 Mitochondria *Correspondence address. The mitochondrion is a highly specialized organelle, present in almost all Institute of Genetic Medicine, International eukaryotic cells and principally charged with the production of cellular Centre for Life, Newcastle energy through oxidative phosphorylation (OXPHOS). -
First-Positive Surveillance Screening in an Asymptomatic SDHA Germline Mutation Carrier
ID: 19-0005 -19-0005 G White and others SDHA surveillance screen ID: 19-0005; May 2019 detected PGL DOI: 10.1530/EDM-19-0005 First-positive surveillance screening in an asymptomatic SDHA germline mutation carrier Correspondence should be addressed Gemma White, Nicola Tufton and Scott A Akker to S A Akker Email Department of Endocrinology, St. Bartholomew’s Hospital, Barts Health NHS Trust, London, UK [email protected] Summary At least 40% of phaeochromocytomas and paraganglioma’s (PPGLs) are associated with an underlying genetic mutation. The understanding of the genetic landscape of these tumours has rapidly evolved, with 18 associated genes now identified.Amongthese,mutationsinthesubunitsofsuccinatedehydrogenasecomplex(SDH) are the most common, causing around half of familial PPGL cases. Occurrence of PPGLs in carriers of SDHB, SDHC and SDHD subunit mutations has been long reported, but it is only recently that variants in the SDHA subunit have been linked to PPGL formation. Previously documented cases have, to our knowledge, only been found in isolated cases where pathogenic SDHA variants wereidentifiedretrospectively.Wereportthecaseofanasymptomaticsuspectedcarotidbodytumourfoundduring surveillance screening in a 72-year-old female who is a known carrier of a germline SDHA pathogenic variant. To our knowledge,thisisthefirstscreenthatdetectedPPGLfoundinapreviouslyidentifiedSDHA pathogenic variant carrier, duringsurveillanceimaging.Thisfindingsupportstheuseofcascadegenetictestingandsurveillancescreeninginall carriers of a pathogenic SDHA variant. Learning points: •• SDH mutations are important causes of PPGL disease. •• SDHA is much rarer compared to SDHB and SDHD mutations. •• Pathogenicity and penetrance are yet to be fully determined in cases of SDHA-related PPGL. •• Surveillance screening should be used for SDHA PPGL cases to identify recurrence, metastasis or metachronous disease. •• Surveillance screening for SDH-relateddiseaseshouldbeperformedinidentifiedcarriersofapathogenicSDHA variant. -
Recent Advances in the Genetics of SDH-Related Paraganglioma and Pheochromocytoma
View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by DSpace at VU Familial Cancer (2011) 10:355–363 DOI 10.1007/s10689-010-9402-1 Recent advances in the genetics of SDH-related paraganglioma and pheochromocytoma Erik F. Hensen • Jean-Pierre Bayley Published online: 17 November 2010 Ó The Author(s) 2010. This article is published with open access at Springerlink.com Abstract The last 10 years have seen enormous progress lack of expression of SDHD and SDHAF2 mutations when in the field of paraganglioma and pheochromocytoma inherited via the maternal line. Little is still known of the genetics. The identification of the first gene related to par- origins and causes of truly sporadic tumors, and the role of aganglioma, SDHD, encoding a subunit of mitochondrial oxygen in the relationships between high-altitude, familial succinate dehydrogenase (SDH), was quickly followed by and truly sporadic paragangliomas remains to be elucidated. the identification of mutations in SDHC and SDHB. Very recently several new SDH-related genes have been dis- Keywords Paraganglioma Á Pheochromocytoma Á covered. The SDHAF2 gene encodes an SDH co-factor SDHA Á SDHAF1 Á SDHAF2 Á SDHB Á SDHC Á SDHD Á related to the function of the SDHA subunit, and is currently TMEM127 exclusively associated with head and neck paragangliomas. SDHA itself has now also been identified as a paragangli- oma gene, with the recent identification of the first mutation Introduction in a patient with extra-adrenal paraganglioma. Another SDH-related co-factor, SDHAF1, is not currently known to Prior to the year 2000, knowledge of the genetics of para- be a tumor suppressor, but may shed some light on the ganglioma and pheochromocytoma was confined to mutations mechanisms of tumorigenesis. -
Succinate Dehydrogenase Deficiency in a PDGFRA Mutated GIST Martin G
Belinsky et al. BMC Cancer (2017) 17:512 DOI 10.1186/s12885-017-3499-7 RESEARCH ARTICLE Open Access Succinate dehydrogenase deficiency in a PDGFRA mutated GIST Martin G. Belinsky1* , Kathy Q. Cai 2, Yan Zhou3, Biao Luo4, Jianming Pei5, Lori Rink1 and Margaret von Mehren1 Abstract Background: Most gastrointestinal stromal tumors (GISTs) harbor mutually exclusive gain of function mutations in the receptor tyrosine kinase (RTK) KIT (70–80%) or in the related receptor PDGFRA (~10%). These GISTs generally respond well to therapy with the RTK inhibitor imatinib mesylate (IM), although initial response is genotype-dependent. An alternate mechanism leading to GIST oncogenesis is deficiency in the succinate dehydrogenase (SDH) enzyme complex resulting from genetic or epigenetic inactivation of one of the four SDH subunit genes (SDHA, SDHB, SDHC, SDHD, collectively referred to as SDHX). SDH loss of function is generally seen only in GIST lacking RTK mutations, and SDH-deficient GIST respond poorly to imatinib therapy. Methods: Tumor and normal DNA from a GIST case carrying the IM-resistant PDGFRA D842V mutation was analyzed by whole exome sequencing (WES) to identify additional potential targets for therapy. The tumors analyzed were separate recurrences following progression on imatinib, sunitinib, and the experimental PDGFRA inhibitor crenolanib. Tumor sections from the GIST case and a panel of ~75 additional GISTs were subjected to immunohistochemistry (IHC) for the SDHB subunit. Results: Surprisingly, a somatic, loss of function mutation in exon 4 of the SDHB subunit gene (c.291_292delCT, p.I97Mfs*21) was identified in both tumors. Sanger sequencing confirmed the presence of this inactivating mutation, and IHC for the SDHB subunit demonstrated that these tumors were SDH-deficient. -
Metastatic Pheochromocytomas and Paragangliomas: Proceedings of the MEN2019 Workshop
27 8 Endocrine-Related P L M Dahia et al. Metastatic pheochromocytomas/ 27:8 T41–T52 Cancer paragangliomas THEMATIC REVIEW HEREDITARY ENDOCRINE TUMOURS: CURRENT STATE-OF-THE-ART AND RESEARCH OPPORTUNITIES Metastatic pheochromocytomas and paragangliomas: proceedings of the MEN2019 workshop Patricia L M Dahia1, Roderick Clifton-Bligh2, Anne-Paule Gimenez-Roqueplo3,4, Mercedes Robledo5,6 and Camilo Jimenez7 1Division of Hematology and Medical Oncology, Department of Medicine, Mays Cancer Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA 2Department of Endocrinology, Royal North Shore Hospital, Northern Clinical School, Kolling Institute of Medical Research, University of Sydney, Sydney, New South Wales, Australia 3Université de Paris, INSERM, PARCC, Paris, France 4AP-HP, Hôpital Européen Georges Pompidou, Genetics Department, Paris, France 5Human Cancer Genetics Program, Spanish National Cancer Research Center, Madrid, Spain 6Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain 7Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence should be addressed to P L M Dahia: [email protected] This paper is part of a thematic section on current knowledge and future research opportunities in hereditary endocrine tumours, as discussed at MEN2019: 16th International Workshop on Multiple Endocrine Neoplasia, 27–29 March 2019, Houston, TX, USA. This meeting was sponsored by Endocrine-Related Cancer Abstract Key Words Pheochromocytomas and paragangliomas (PPGLs) are adrenal or extra-adrenal f pheochromocytomas autonomous nervous system-derived tumors. Most PPGLs are benign, but approximately f paragangliomas 15% progress with metastases (mPPGLs). mPPGLs are more likely to occur in patients f metastatic with large pheochromocytomas, sympathetic paragangliomas, and norepinephrine- f mutation secreting tumors.