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SDH deficient GIST

Edward Kim, Michael Jp Wright, Loretta Sioson, Talia Novos, Anthony J Gill, Diana E Benn, Christopher White, Trisha Dwight, Roderick J Clifton-Bligh
OBJECTIVE: Mutations of genes encoding the four subunits of succinate dehydrogenase (SDH) have been associated with pheochromocytoma and paraganglioma (PPGLs), gastrointestinal stromal tumors (GISTs) and renal cell carcinomas (RCCs). These tumors have not been characterized in a way that reflects severity of SDH dysfunction. Mass spectrometric analysis now allows measurement of metabolites extracted from formalin fixed paraffin embedded (FFPE) specimens. We assess whether SDH deficiency in various tumor types characterized by loss of SDHB protein expression correlates with SDH dysfunction as assessed by the ratio of succinate:fumarate in FFPE specimens...
March 2017: Molecular Genetics and Metabolism Reports
Christina H Wei, Jonas Pettersson, Mihaela Campan, Shefali Chopra, Wesley Naritoku, Sue E Martin, Pamela M Ward
Patients with succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumor (GIST) have few therapeutic options. Despite lack of KIT or platelet-derived growth factor receptor A (PDGFRA) driver mutations, SDH-deficient GISTs display strong expression of KIT by immunohistochemistry and these patients are often treated with tyrosine kinase inhibitors, including imatinib as a first-line therapy. Using a targeted next-generation sequencing panel of mutation hotspots of 50-clinically relevant genes, we investigated (1) concurrence of somatic/actionable mutations and (2) tumor molecular evolution by comparing 2 resection specimens 1...
December 23, 2016: Applied Immunohistochemistry & Molecular Morphology: AIMM
Maureen O'Sullivan
Since its foundation by remarkably talented and insightful individuals, prominently including Pepper Dehner, pediatric soft tissue tumor pathology has developed at an immense rate. The morphologic classification of tumoral entities has extensively been corroborated, but has also evolved with refinement or realignment of these classifications, through accruing molecular data, with many derivative ancillary diagnostic assays now already well-established. Tumors of unclear histogenesis, classically morphologically undifferentiated, are prominent amongst pediatric sarcomas, however, the classes of undifferentiated round- or spindle-cell-tumors-not-otherwise-specified are being dismantled gradually with the identification of their molecular underpinnings...
November 2016: Seminars in Diagnostic Pathology
Maria Abbondanza Pantaleo, Gloria Ravegnini, Annalisa Astolfi, Vittorio Simeon, Margherita Nannini, Maristella Saponara, Milena Urbini, Lidia Gatto, Valentina Indio, Giulia Sammarini, Donatella Santini, Manuela Ferracin, Massimo Negrini, Patrizia Hrelia, Guido Biasco, Sabrina Angelini
AIM: Currently, little is known about differences in miRNA expression between KIT/PDGFRA mutant and KIT/PDGFRA wild-type (WT)-SDH deficient gastrointestinal stromal tumors (GIST). This prompted us to perform an integrated multiple expression profile of miRNA and mRNA, constructing an original miRNA-mRNA regulatory network in KIT/PDGFRA WT-SDH deficient GIST patients. PATIENTS & METHODS: Analyses were carried out on KIT/PDGFRA mutant versus KIT/PDGFRA WT-SDH deficient GIST...
October 2016: Epigenomics
Ryuichi Wada, Hiroki Arai, Shoko Kure, Wei-Xia Peng, Zenya Naito
Gastrointestinal stromal tumor (GIST) is a mesenchymal tumor of the gastrointestinal tract. Mutation of KIT and PDGFRA genes is implicated in the tumorigenesis. Approximately 10% of GISTs do not harbor mutation of these genes, and they are designated as "wild type" GIST. They are classified into succinate dehydrogenase (SDH)-deficient and non-SDH-deficient groups. SDH-deficient group includes Carney triad and Carney Stratakis syndrome. The patients are young women. Tumors occur in the antrum of the stomach, and tumor cells are epithelioid...
August 2016: Pathology International
E Ben-Ami, C M Barysauskas, M von Mehren, M C Heinrich, C L Corless, J E Butrynski, J A Morgan, A J Wagner, E Choy, J T Yap, A D Van den Abbeele, S M Solomon, J A Fletcher, G D Demetri, S George
BACKGROUND: This investigator-initiated trial provided the justification for the phase III GRID study resulting in worldwide regulatory approval of regorafenib as a third-line therapy for patients with metastatic gastrointestinal stromal tumors (GIST). We report the genotype analyses, long-term safety, and activity results from this initial trial of regorafenib in GIST. PATIENTS AND METHODS: The trial was conducted between February 2010 and January 2014, among adult patients with metastatic GIST, after failure of at least imatinib and sunitinib...
September 2016: Annals of Oncology: Official Journal of the European Society for Medical Oncology
Emily F Mason, Jason L Hornick
Gastrointestinal stromal tumors (GISTs) that lack kinase mutations often show loss of function of the succinate dehydrogenase (SDH) complex, due to germline mutation or promoter hypermethylation. SDH-deficient GISTs are exclusive to the stomach and have a multinodular architecture. It has been suggested that conventional risk stratification criteria may not predict outcome for this group of tumors, although data are limited. Here, we report the clinical, histologic, and genetic findings from a large cohort of 76 SDH-deficient GISTs diagnosed from 2005 to 2015, identified on the basis of histologic features or family history (45 female/31 male; mean age at diagnosis 32 y; range 11 to 71 y; 10 patients 50 y of age or above)...
June 23, 2016: American Journal of Surgical Pathology
Sosipatros A Boikos, Alberto S Pappo, J Keith Killian, Michael P LaQuaglia, Chris B Weldon, Suzanne George, Jonathan C Trent, Margaret von Mehren, Jennifer A Wright, Josh D Schiffman, Margarita Raygada, Karel Pacak, Paul S Meltzer, Markku M Miettinen, Constantine Stratakis, Katherine A Janeway, Lee J Helman
IMPORTANCE: Wild-type (WT) gastrointestinal stromal tumors (GISTs), which lack KIT and PDGFRA gene mutations, are the primary form of GIST in children and occasionally occur in adults. They respond poorly to standard targeted therapy. Better molecular and clinical characterization could improve management. OBJECTIVE: To evaluate the clinical and tumor genomic features of WT GIST. DESIGN, SETTING, AND PARTICIPANTS: Patients enrolled in an observational study at the National Institutes of Health starting in 2008 and were evaluated in a GIST clinic held once or twice yearly...
July 1, 2016: JAMA Oncology
A Agaimy
Succinate dehydrogenase (SDH) represents a type II mitochondrial complex related to the respiratory chain and Krebs cycle. The complex is composed of four major subunits, SDHA, SDHB, SDHC and SDHD. The oncogenic role of this enzyme complex has only recently been recognized and the complex is currently considered an important oncogenic signaling pathway with tumor suppressor properties. In addition to the familial paraganglioma syndromes (types 1-5) as prototypical SDH-related diseases, many other tumors have been defined as SDH-deficient, in particular a subset of gastrointestinal stromal tumors (GIST), rare hypophyseal adenomas, a subset of pancreatic neuroendocrine neoplasms (recently added) and a variety of other tumor entities, the latter mainly described as rare case reports...
March 2016: Der Pathologe
Yuanhua Cheng, Zhongfeng Zhang, Hefen Zhu, Lixin Guo, Yuandong Cheng
OBJECTIVE: To investigate clinicopathologic features of succinate dehydrogenase-deficient gastrointestinal stromal tumors (SDH-deficient GIST). METHODS: Immunohistochemical EnVision technique was used to assess the expression of succinate dehydrogenase subunit B (SDHB) in 192 cases of GIST. Cases of SDH-deficient GIST were further evaluated for the presence of CKIT exons 9, 11, 13 and 17 mutations and PDGFRA exons 12 and 18 mutations with clinical followed-up data...
March 2016: Zhonghua Bing Li Xue za Zhi Chinese Journal of Pathology
M R Ghigna, P Dorfmuller, A Crutu, E Fadel, V Thomas de Montpréville
Though most paragangliomas arise as sporadic tumors, the recent advantages in the genetic screening revealed that about 30 % of paragangliomas are linked to hereditary mutations, such as those involving SDH genes. A 22-year-old woman carrying a left main bronchus tumor underwent surgery in our institution. Her past medical history included a GIST without KIT or PDGFRA mutation. The histological examination revealed a nested proliferation of medium-sized cells expressing neuroendocrine markers (chromogranin A and synaptophysin)...
December 2016: Endocrine Pathology
Nicolasine D Niemeijer, Thomas G Papathomas, Esther Korpershoek, Ronald R de Krijger, Lindsey Oudijk, Hans Morreau, Jean-Pierre Bayley, Frederik J Hes, Jeroen C Jansen, Winand N M Dinjens, Eleonora P M Corssmit
CONTEXT: Mutations in genes encoding the subunits of succinate dehydrogenase (SDH) can lead to pheochromocytoma/paraganglioma formation. However, SDH mutations have also been linked to nonparaganglionic tumors. OBJECTIVE: The objective was to investigate which nonparaganglionic tumors belong to the SDH-associated tumor spectrum. DESIGN: This was a retrospective cohort study. SETTING: The setting was a tertiary referral center...
October 2015: Journal of Clinical Endocrinology and Metabolism
Eva Szarek, Evan R Ball, Alessio Imperiale, Maria Tsokos, Fabio R Faucz, Alessio Giubellino, François-Marie Moussallieh, Izzie-Jacques Namer, Mones S Abu-Asab, Karel Pacak, David Taïeb, J Aidan Carney, Constantine A Stratakis
Carney triad (CTr) describes the association of paragangliomas (PGL), pulmonary chondromas, and gastrointestinal (GI) stromal tumors (GISTs) with a variety of other lesions, including pheochromocytomas and adrenocortical tumors. The gene(s) that cause CTr remain(s) unknown. PGL and GISTs may be caused by loss-of-function mutations in succinate dehydrogenase (SDH) (a condition known as Carney-Stratakis syndrome (CSS)). Mitochondrial structure and function are abnormal in tissues that carry SDH defects, but they have not been studied in CTr...
June 2015: Endocrine-related Cancer
Ya-Mei Wang, Meng-Li Gu, Feng Ji
Most gastrointestinal stromal tumors (GISTs) are characterized by KIT or platelet-derived growth factor alpha (PDGFRA) activating mutations. However, there are still 10%-15% of GISTs lacking KIT and PDGFRA mutations, called wild-type GISTs (WT GISTs). Among these so-called WT GISTs, a small subset is associated with succinate dehydrogenase (SDH) deficiency, known as SDH-deficient GISTs. In addition, GISTs that occur in Carney triad and Carney-Stratakis syndrome represent specific examples of SDH-deficient GISTs...
February 28, 2015: World Journal of Gastroenterology: WJG
J Keith Killian, Markku Miettinen, Robert L Walker, Yonghong Wang, Yuelin Jack Zhu, Joshua J Waterfall, Natalia Noyes, Parvathy Retnakumar, Zhiming Yang, William I Smith, M Scott Killian, C Christopher Lau, Marbin Pineda, Jennifer Walling, Holly Stevenson, Carly Smith, Zengfeng Wang, Jerzy Lasota, Su Young Kim, Sosipatros A Boikos, Lee J Helman, Paul S Meltzer
Succinate dehydrogenase (SDH) is a conserved effector of cellular metabolism and energy production, and loss of SDH function is a driver mechanism in several cancers. SDH-deficient gastrointestinal stromal tumors (dSDH GISTs) collectively manifest similar phenotypes, including hypermethylated epigenomic signatures, tendency to occur in pediatric patients, and lack of KIT/PDGFRA mutations. dSDH GISTs often harbor deleterious mutations in SDH subunit genes (SDHA, SDHB, SDHC, and SDHD, termed SDHx), but some are SDHx wild type (WT)...
December 24, 2014: Science Translational Medicine
Jaclyn Frances Hechtman, Ahmet Zehir, Talia Mitchell, Laetitia Borsu, Samuel Singer, William Tap, Alifya Oultache, Marc Ladanyi, Khedoudja Nafa
Among gastrointestinal stromal tumors (GISTs) of 10-15% are negative for KIT and PDGFRA, and most of these cases are SDH deficient. Recent studies have provided data on additional molecular alterations such as KRAS in KIT mutant GISTs. We aimed to assess the frequency and spectrum of somatic mutations in common oncogenes as well as copy number variations in GISTs negative for KIT and PDGFRA mutations. GISTs with wild type KIT/PDGFRA were tested via next generation sequencing for somatic mutations in 341 genes...
March 2015: Genes, Chromosomes & Cancer
S H Tirumani, H Tirumani, J P Jagannathan, A B Shinagare, J L Hornick, S George, A J Wagner, N H Ramaiya
OBJECTIVE: To describe the multidetector CT (MDCT) features and metastatic pattern of succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumours (GISTs). METHODS: In this institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study, we retrospectively identified 34 patients (20 females; mean age, 34 years; range, 12-59 years) with histopathology-confirmed SDH-deficient GIST, who were seen at our institution from 1999 through 2012...
November 2014: British Journal of Radiology
Maria A Pantaleo, Cristian Lolli, Margherita Nannini, Annalisa Astolfi, Valentina Indio, Maristella Saponara, Milena Urbini, Stefano La Rovere, Antony Gill, David Goldstein, Claudio Ceccarelli, Donatella Santini, Giulio Rossi, Michelangelo Fiorentino, Valerio Di Scioscio, Pietro Fusaroli, Anna Mandrioli, Lidia Gatto, Fausto Catena, Umberto Basso, Giorgio Ercolani, Antonio Daniele Pinna, Guido Biasco
PURPOSE: A subset of patients with KIT/PDGFRA wild-type gastrointestinal stromal tumors show loss of function of succinate dehydrogenase, mostly due to germ-line mutations of succinate dehydrogenase subunits, with a predominance of succinate dehydrogenase subunit A. The clinical outcome of these patients seems favorable, as reported in small series in which patients were individually described. This work evaluates a retrospective survival analysis of a series of patients with metastatic KIT/PDGFRA wild-type succinate dehydrogenase-deficient gastrointestinal stromal tumors...
May 2015: Genetics in Medicine: Official Journal of the American College of Medical Genetics
Maria Jové, Jaume Mora, Xavier Sanjuan, Eva Rodriguez, Mercedes Robledo, Leandre Farran, Xavier Garcia del Muro
No abstract text is available yet for this article.
November 2014: Histopathology
Sean R Williamson, John N Eble, Mahul B Amin, Nilesh S Gupta, Steven C Smith, Lynette M Sholl, Rodolfo Montironi, Michelle S Hirsch, Jason L Hornick
Patients with germline mutation of succinate dehydrogenase (SDH) subunit genes are prone to develop paraganglioma, gastrointestinal stromal tumor, and rarely renal cell carcinoma (RCC). However, SDH-deficient RCC is not yet widely recognized. We identified such tumors by distinctive morphology and confirmed absence of immunohistochemical staining for SDHB. Immunohistochemical features were evaluated using a panel of antibodies to renal tumor antigens. Targeted next-generation sequencing was performed on DNA extracted from paraffin-embedded tissue...
January 2015: Modern Pathology: An Official Journal of the United States and Canadian Academy of Pathology, Inc
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