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Freitas-Castro F, Santana LS, Fagundes GFC, Lobato EC, Afonso ACF, Nakamura IT, Ledesma FL, Soares IC, Mendonca BB, Latronico AC, Stratakis CA, Almeida MQ. SLC25A11, a Novel Gene Associated With Carney-Stratakis Syndrome. J Endocr Soc 2025; 9:bvaf052. [PMID: 40242210 PMCID: PMC12000648 DOI: 10.1210/jendso/bvaf052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Indexed: 04/18/2025] Open
Abstract
Background Carney-Stratakis syndrome (CSS), a rare condition characterized by paragangliomas and/or pheochromocytomas and gastrointestinal stromal tumors (GIST), is caused by germline heterozygous pathogenic variants in the succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD). Methods Histological, genetic, and functional analyses were conducted in a 59-year-old female with CSS (9 cm left pheochromocytoma, 4.8 cm paraganglioma, and 9.3 cm GIST). Whole-exome sequencing (WES) of germline DNA paired with tumor DNA was performed. Results WES identified a rare heterozygous germline variant (c.293G>A/p.Arg98His) in the mitochondrial 2-oxoglutarate/malate carrier gene (SLC25A11). This variant, located in a highly conserved residue of the SLC25A11 mitochondrial carrier domain, is predicted to be deleterious in silico (REVEL score = 0.81). WES of pheochromocytoma, paraganglioma, and GIST did not reveal somatic pathogenic variants in genes previously associated with these tumors. A significant reduction in SLC25A11 expression was observed in the tumors of this patient with the SLC25A11 c.293G>A variant (0.69 ± 0.003) compared to tumors from cluster 1 (1.39 ± 0.45; P = 0.0229) and cluster 2 (1.79 ± 0.71; P = .0154). Consistent with the mRNA findings, SLC25A11 protein levels were markedly reduced in the pheochromocytoma and paraganglioma compared to other tumors. Negative staining for 5-hydroxymethylcytosine in all 3 tumors suggests a DNA hypermethylation profile characteristic of cluster 1A, despite normal SDHB expression levels. However, genome-wide copy number variation analysis did not reveal any loss of heterozygosity at the SLC25A11 locus. Conclusion The loss of SLC25A11 expression in tumors, the absence of somatic drivers, and the hypermethylation status strongly support the role of SLC25A11 in CSS pathogenesis.
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Affiliation(s)
- Felipe Freitas-Castro
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Lucas S Santana
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Gustavo F C Fagundes
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Eduardo C Lobato
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Ana Caroline F Afonso
- Laboratório de Hormônios e Genética Molecular LIM42 e Laboratório de Sequenciamento em Larga Escala (SELA), Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Izabel T Nakamura
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Felipe L Ledesma
- Divisão de Anatomia Patológica, Hospital das Clínicas HCFMUSP & Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Ibere C Soares
- Divisão de Anatomia Patológica, Hospital das Clínicas HCFMUSP & Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Berenice B Mendonca
- Laboratório de Hormônios e Genética Molecular LIM42 e Laboratório de Sequenciamento em Larga Escala (SELA), Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Ana Claudia Latronico
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Constantine A Stratakis
- Human Genetics & Precision Medicine, IMBB, FORTH, Heraklion, Crete & ASTREA Health, Athens 11528, Greece
| | - Madson Q Almeida
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas HCFMUSP, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
- Unidade de Oncologia Endócrina, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brasil
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Liu Y, Li XF. Characteristics and therapeutic strategies for familial gastrointestinal stromal tumors. World J Gastrointest Oncol 2025; 17:100463. [PMID: 40092960 PMCID: PMC11866256 DOI: 10.4251/wjgo.v17.i3.100463] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2024] [Revised: 11/04/2024] [Accepted: 12/16/2024] [Indexed: 02/14/2025] Open
Abstract
This editorial discusses Wang et al's article on familial gastrointestinal stromal tumors (GISTs). We read with great interest this article concerning the diagnosis, treatment, and post-treatment management of patients with familial GISTs. The actual incidence of GISTs may be underestimated due to diagnostic limitations and the long-term low-risk behavior of some GISTs. The molecular landscape of GISTs is primarily driven by mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. A subset of GISTs without these mutations known as wild-type GISTs, may harbor other rare mutations, impacting their response to targeted therapies. Clinically, patients with GISTs present with non-specific symptoms, often leading to delayed diagnosis. Genetic predispositions in familial GISTs provide insights into the genetic architecture and extragastrointestinal manifestations of GISTs. Management has evolved from surgical interventions to molecular-based therapies using tyrosine kinase inhibitors. The management of GISTs, especially in familial cases, requires a multidisciplinary approach. Cases of different gene mutations were reported in the same family, suggesting that incorporating genetic testing into routine clinical practice is crucial for the early identification of high-risk individuals and the implementation of tailored surveillance programs.
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Affiliation(s)
- Yuan Liu
- Department of Gastroenterology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China
| | - Xiao-Feng Li
- Department of Gastroenterology, The Fifth Affiliated Hospital of Sun Yat-sen University, Zhuhai 519000, Guangdong Province, China
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Min V, Corradini N, Macagno N, Orbach D, Reguerre Y, Petit P, Blay JY, Verschuur A. Gastrointestinal stromal tumours (GIST) in children: An update of this orphan disease. Bull Cancer 2025; 112:348-357. [PMID: 39455327 DOI: 10.1016/j.bulcan.2024.07.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 05/31/2024] [Accepted: 07/04/2024] [Indexed: 10/28/2024]
Abstract
BACKGROUND Gastrointestinal stromal tumours (GIST) are tumours of the digestive tract that mainly develop in adults. Recommendations for the management of GIST in pediatrics are limited. MATERIAL AND METHODS We performed an updated review of the literature serving as a basis for the development of diagnostic and therapeutic recommendations for GIST in children and young adults (YA). RESULTS GIST in pediatric population can have a sporadic presentation but occur more often in a syndromic and/or familial context. Currently more than 170 cases of sporadic GIST or in association with Carney-Stratakis syndrome or Carney's triad family cases of familial GIST have been described in children and YA. These syndromes are frequently associated with germline or somatic alterations in a sub-unit of Succinate Dehydrogenase (SDH). In contrast, the frequency of somatic KIT and PDGFRα oncogene mutations (±15%) is significantly lower as compared to adults with GIST. The recommendations for the management of children with GIST are generally comparable to those used for adult patients, although certain biological differences influence the therapeutic attitude. CONCLUSIONS International collaborations have been deployed in order to increase the clinical and biological knowledge of this orphan pathology in pediatrics.
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Affiliation(s)
- Victoria Min
- Pediatric Hematology Oncology Department, La Timone Children's Hospital, AP-HM, 264, rue St Pierre, 13385 Marseille cedex, France
| | - Nadège Corradini
- Pediatric Hematology Oncology Department, Institute of Pediatric Hematology and Oncology (IHOPe), Léon Bérard Cancer Centre, Lyon, France
| | | | - Daniel Orbach
- SIREDO Oncology Centre (Care, Innovation and Research for Children, Adolescents and Young Adults with Cancer), PSL University, Institut Curie, Paris, France
| | - Yves Reguerre
- Pediatric Oncology Department, University Hospital Center La Reunion, Saint-Denis, Reunion
| | - Philippe Petit
- Department of pediatric and prenatal radiology, La Timone Children's Hospital, Aix Marseille University, AP-HM, 264, rue St-Pierre, 13385 Marseille cedex, France
| | - Jean-Yves Blay
- Department of Medicine, Centre Leon Berard, UNICANCER & University Lyon I, Lyon, France
| | - Arnauld Verschuur
- Pediatric Hematology Oncology Department, La Timone Children's Hospital, AP-HM, 264, rue St Pierre, 13385 Marseille cedex, France.
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Florou V, Jacobs MF, Casey R, Evans D, Owens B, Raygada M, Rothschild S, Greenberg SE. A Review of Genomic Testing and SDH- Deficiency in Gastrointestinal Stromal Tumors: Getting to the GIST. Cancer Med 2025; 14:e70669. [PMID: 39927693 PMCID: PMC11808740 DOI: 10.1002/cam4.70669] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 12/02/2024] [Accepted: 01/28/2025] [Indexed: 02/11/2025] Open
Abstract
Gastrointestinal Stromal Tumors (GISTs) have seen significant advancements in their diagnosis and management, driven by targeted therapeutic development and molecular testing. The identification of mutations in genes such as KIT and PDGFRA has transformed treatment approaches, particularly through targeted therapies like imatinib, which have improved patient outcomes. This review explores the critical role of genomic testing in GIST, highlighting its importance in accurate diagnosis, treatment planning, and long-term surveillance for KIT/PDGFRA negative, SDH-deficient GISTs. SDH-deficient GISTs arise from mutations or epigenetic changes affecting the succinate dehydrogenase complex. The complexity of SDH-deficient GISTs, including their association with hereditary syndromes such as Hereditary Paraganglioma-Pheochromocytoma and/or hypermethylation of the SDHC promoter, underscores the need for comprehensive germline testing. Despite the availability of guidelines, variability exists in genomic testing recommendations across different regions, necessitating a unified approach. This review proposes a simplified algorithm for the genomic workup of GIST, and suggests all individuals with SDH-deficient GIST, regardless of germline testing result, require monitoring for additional SDHx-related tumors, given the lack of widely available methylation and full gene SDHA analysis.
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Affiliation(s)
- Vaia Florou
- Division of Oncology, Department of Internal Medicine, Huntsman Cancer InstituteUniversity of UtahSalt Lake CityUtahUSA
| | - Michelle F. Jacobs
- Division of Genetic Medicine, Department of Internal MedicineUniversity of MichiganAnn ArborMichiganUSA
| | - Ruth Casey
- Department of Medical GeneticsCambridge UniversityCambridgeUK
| | | | | | - Margarita Raygada
- Pediatric Oncology and Neuro‐Oncology BranchNational Cancer Institute/National Institutes of HealthBethesdaMarylandUSA
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Jeyaraman K, Concolino P, Falhammar H. Adrenocortical tumors and hereditary syndromes. Expert Rev Endocrinol Metab 2025; 20:1-19. [PMID: 39570085 DOI: 10.1080/17446651.2024.2431748] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Accepted: 11/15/2024] [Indexed: 11/22/2024]
Abstract
INTRODUCTION Adrenocortical tumors (ACTs) are frequently encountered in clinical practice. They vary in clinical and biological characteristics from nonfunctional to life threatening hormone excess, from benign to highly aggressive malignant tumors. Most ACTs appear to be benign and nonfunctioning. It has been controversial how these apparently benign and nonfunctioning tumors should be monitored. Over the past few decades, significant advances have been made in understanding the regulation of growth and tumorigenesis in adrenocortical cells. Defining the molecular pathomechanisms in inherited tumor syndromes led to the expansion of research to sporadic ACTs. Distinct molecular signatures have been identified in sporadic ACTs and a potential genomic classification of ACT has been proposed. AREAS COVERED In this review, we discuss the various adrenocortical pathologies associated with hereditary syndromes with special focus on their molecular pathomechanisms, the understanding of which is important in the era of precision medicine. EXPERT OPINION Identifying the molecular pathomechanisms of the adrenocortical tumorigenesis in inherited syndromes has led to the understanding of the alterations in different signaling pathways that help explain the wide variations in the biology and behavior of ACTs.
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Affiliation(s)
| | - Paola Concolino
- Dipartimento di Scienze di Laboratorio ed Ematologiche, UOC Chimica, Biochimica e Biologia Molecolare Clinica, Fondazione Policlinico Universitario Agostino Gemelli IRCCS, Roma, Italy
| | - Henrik Falhammar
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
- Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden
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Cicala CM, Matito J, Quindos M, Gómez-Peregrina D, Romero-Lozano P, Fernández-Suárez P, Valverde C, González M, Landolfi S, Pérez-Albert P, Gros L, Vivancos A, Serrano C. Targeted Next-Generation Sequencing in Succinate Dehydrogenase-Deficient GI Stromal Tumor Identifies Actionable Alterations in the PI3K/mTOR Pathway. JCO Precis Oncol 2025; 9:e2400497. [PMID: 39787462 DOI: 10.1200/po-24-00497] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/29/2024] [Accepted: 11/22/2024] [Indexed: 01/12/2025] Open
Abstract
PURPOSE Less than 5% of GI stromal tumors (GISTs) are driven by the loss of the succinate dehydrogenase (SDH) complex, resulting in a pervasive DNA hypermethylation pattern that leads to unique clinical features. Advanced SDH-deficient GISTs are usually treated with the same therapies targeting KIT and PDGFRA receptors as those used in metastatic GIST. However, these treatments display less activity in the absence of alternative therapeutic options. Therefore, it is critical to identify novel actionable alterations in SDH-deficient GIST. PATIENTS AND METHODS We performed a single-center, retrospective analysis of patients with SDH-deficient GIST together with next-generation sequencing (NGS) analysis from their respective tumor samples to identify mutations and copy number alterations and chromosomal alterations. NGS-tailored treatment was implemented whenever possible. RESULTS Seventeen tumor samples from 14 patients with SDH-deficient GIST underwent NGS. Mutational load was low, although three patients (21%) displayed molecular events in relapse samples leading to PI3K/mTOR pathway hyperactivation. mTOR inhibition with everolimus obtained a sustained tumor response in a heavily pretreated patient. Other alterations, largely present in late-stage patients, uncovered genes involved in cell cycle regulation, telomere maintenance, and DNA damage repair. Chromosomal arm-level alterations differed from the canonical cytogenetic progression in KIT/PDGFRA-mutant GIST. CONCLUSION This molecular landscape of SDH-deficient GIST uncovers novel molecular alterations, mostly in relapse and/or previously pretreated patients. The identification of genetic events leading to PI3K/mTOR dysregulation together with the remarkable activity of everolimus in one patient showcases the clinical relevance of this pathway, validates the utility of NGS in this population, and poses everolimus as a novel therapeutic alternative. Several other alterations were found at the genetic and genomic levels, underscoring novel biological processes likely involved during tumor evolution.
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Affiliation(s)
- Carlo María Cicala
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Judit Matito
- Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - María Quindos
- Medical Oncology Department, Complexo Hospitalario Universitario de A Coruña. Biomedical Research Institute (INIBIC), A Coruña, Spain
| | - David Gómez-Peregrina
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
| | - Paula Romero-Lozano
- Vall d'Hebron Institute of Research (VHIR), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - Paula Fernández-Suárez
- Abdominal Imaging, Radiodiagnostic Department, Complexo Hospitalario Universitario de A Coruña, A Coruña, Spain
| | - Claudia Valverde
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Macarena González
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Stefania Landolfi
- Pathology Department, Vall d'Hebron University Hospital, Barcelona, Spain
| | - Paula Pérez-Albert
- Paediatric Oncology and Hematology Department, Vall d'Hebron University Hospital, Barcelona, Spain
- Childhood Cancer and Blood Disorders Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain
| | - Luis Gros
- Paediatric Oncology and Hematology Department, Vall d'Hebron University Hospital, Barcelona, Spain
- Childhood Cancer and Blood Disorders Group, Vall d'Hebron Institute of Research (VHIR), Barcelona, Spain
| | - Ana Vivancos
- Cancer Genomics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain
| | - César Serrano
- Sarcoma Translational Research Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain
- Department of Medical Oncology, Vall d'Hebron University Hospital, Barcelona, Spain
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Beecroft JR, Brar S, Feng X, Hamilton T, Han-Lee C, Henning JW, Josephy PD, Khalili K, Ko YJ, Lemieux C, Liu DM, MacDonald DB, Noujaim J, Pollett A, Salawu A, Saleh R, Smrke A, Warren BE, Zbuk K, Razak AA. Pan-Canadian consensus recommendations for GIST management in high- and low-throughput centres across Canada. Ther Adv Med Oncol 2024; 16:17588359241266179. [PMID: 39386314 PMCID: PMC11461906 DOI: 10.1177/17588359241266179] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2024] [Accepted: 06/18/2024] [Indexed: 10/12/2024] Open
Abstract
Gastrointestinal stromal tumours (GISTs) are mesenchymal tumours that originate from the interstitial cells of Cajal. GISTs are mainly driven by gain-of-function mutations in receptor tyrosine kinase or platelet-derived growth factor receptor alpha. Surgical resection is the only curative treatment for localized tumours and all currently approved medical GIST treatments are based on orally available tyrosine kinase inhibitors. Recent discoveries in the molecular and clinical features of GISTs have greatly impacted GIST management. Due to the provincially rather than nationally administered Canadian healthcare system, there have been inconsistencies in the treatment of GISTs across the country. Therefore, guidance on the latest knowledge, clinical management and treatment of GIST is needed to standardize the approach to GIST management nationwide. To establish pan-Canadian guidance, provide up-to-date data and harmonize the clinical practice of GIST management in high- and low-throughput centres across Canada; a panel of 20 physicians with extensive clinical experience in GIST management reviewed relevant literature. This included radiologists, pathologists, interventional radiologists, surgeons and medical oncologists across Canada. The structured literature focused on seven key domains: molecular profiling, radiological techniques/reporting, targeted localized therapy, intricacies of systemic treatments, emerging tests, multidisciplinary care and patient advocacy. This literature review, along with clinical expertise and opinion, was used to develop this concise and clinically relevant consensus paper to harmonize the knowledge and clinical practice on GIST management across Canada. The content presented here will help guide healthcare providers, especially in Canada, in terms of approaching and managing GIST.
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Affiliation(s)
- J. Robert Beecroft
- Division of Interventional Radiology, Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital, Toronto, ON, Canada
| | - Savtaj Brar
- Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Xiaolan Feng
- Division of Medical Oncology, Tom Baker Cancer Center, Calgary, AB, Canada
| | - Trevor Hamilton
- Department of Surgery, BC Cancer, Vancouver General Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Cheng Han-Lee
- Department of Laboratory Medicine & Pathology, University of Alberta, Edmonton, AB, Canada
| | - Jan-Willem Henning
- Department of Oncology, Tom Baker Cancer Centre, Cuming School of Medicine, University of Calgary, Calgary, AB, Canada
| | | | - Korosh Khalili
- Department of Medical Imaging, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Yoo-Joung Ko
- Department of Medicine, St. Michael’s Hospital, Sunnybrook Odette Cancer Centre, University of Toronto, Toronto, ON, Canada
| | - Christopher Lemieux
- Division of Hematology and Medical Oncology, Centre Hospitalier Universitaire de Québec, Université Laval, Quebec City, QC, Canada
| | - David M. Liu
- Department of Radiology, University of British Columbia, School of Biomedical Engineering, Vancouver, BC, Canada
- Department of Interventional Radiology, Miller School of Medicine, University of Miami, Miami, FL, USA
| | - D. Blair MacDonald
- Department of Medical Radiology, The Ottawa Hospital, University of Ottawa, Ottawa, ON, Canada
| | - Jonathan Noujaim
- Division of Medical Oncology, Hôpital Maisonneuve-Rosemont, University of Montreal, Montreal, QC, Canada
| | - Aaron Pollett
- Pathology and Laboratory Medicine, Division of Diagnostic Medical Genetics, Mount Sinai Hospital, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Abdulazeez Salawu
- Division of Medical Oncology, Princess Margaret Cancer Centre, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Ramy Saleh
- Division of Medical Oncology, McGill University Health Centre, Montreal, Quebec, Canada
| | - Alannah Smrke
- Division of Medical Oncology, BC Cancer, University of British Columbia, Vancouver, BC, Canada
| | - Blair E. Warren
- Department of Medical Imaging, University of Toronto, Toronto, ON, Canada
| | - Kevin Zbuk
- Department of Oncology, McMaster University, Hamilton, ON, Canada
| | - Albiruni Abdul Razak
- Division of Medical Oncology, Princess Margaret Cancer Centre, Mount Sinai Hospital, University of Toronto, 610 University Ave., Toronto, ON M2G 2M9, Canada
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Ramírez-Rentería C, Hernández-Ramírez LC. Genetic diagnosis in acromegaly and gigantism: From research to clinical practice. Best Pract Res Clin Endocrinol Metab 2024; 38:101892. [PMID: 38521632 DOI: 10.1016/j.beem.2024.101892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/25/2024]
Abstract
It is usually considered that only 5% of all pituitary neuroendocrine tumours are due to inheritable causes. Since this estimate was reported, however, multiple genetic defects driving syndromic and nonsyndromic somatotrophinomas have been unveiled. This heterogeneous genetic background results in overlapping phenotypes of GH excess. Genetic tests should be part of the approach to patients with acromegaly and gigantism because they can refine the clinical diagnoses, opening the possibility to tailor the clinical conduct to each patient. Even more, genetic testing and clinical screening of at-risk individuals have a positive impact on disease outcomes, by allowing for the timely detection and treatment of somatotrophinomas at early stages. Future research should focus on determining the actual frequency of novel genetic drivers of somatotrophinomas in the general population, developing up-to-date disease-specific multi-gene panels for clinical use, and finding strategies to improve access to modern genetic testing worldwide.
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Affiliation(s)
- Claudia Ramírez-Rentería
- Unidad de Investigación Médica en Enfermedades Endocrinas, Hospital de Especialidades, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Mexico City, Mexico
| | - Laura C Hernández-Ramírez
- Red de Apoyo a la Investigación, Universidad Nacional Autónoma de México, e Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico City, Mexico.
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Denu RA, Joseph CP, Urquiola ES, Byrd PS, Yang RK, Ratan R, Zarzour MA, Conley AP, Araujo DM, Ravi V, Nassif Haddad EF, Nakazawa MS, Patel S, Wang WL, Lazar AJ, Somaiah N. Utility of Clinical Next Generation Sequencing Tests in KIT/PDGFRA/SDH Wild-Type Gastrointestinal Stromal Tumors. Cancers (Basel) 2024; 16:1707. [PMID: 38730662 PMCID: PMC11083047 DOI: 10.3390/cancers16091707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Revised: 04/18/2024] [Accepted: 04/23/2024] [Indexed: 05/13/2024] Open
Abstract
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.
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Affiliation(s)
- Ryan A. Denu
- Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Cissimol P. Joseph
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Elizabeth S. Urquiola
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Precious S. Byrd
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Richard K. Yang
- Department of Pathology, Division of Pathology & Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Ravin Ratan
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Maria Alejandra Zarzour
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Anthony P. Conley
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Dejka M. Araujo
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Vinod Ravi
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Elise F. Nassif Haddad
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Michael S. Nakazawa
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Shreyaskumar Patel
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Wei-Lien Wang
- Department of Pathology, Division of Pathology & Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Alexander J. Lazar
- Department of Pathology, Division of Pathology & Laboratory Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Neeta Somaiah
- Department of Sarcoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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10
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Fabozzi F, Carrozzo R, Lodi M, Di Giannatale A, Cipri S, Rosignoli C, Giovannoni I, Stracuzzi A, Rizza T, Montante C, Agolini E, Di Nottia M, Galaverna F, Del Baldo G, Del Bufalo F, Mastronuzzi A, De Ioris MA. Case report: A safeguard in the sea of variants of uncertain significance: a case study on child with high risk neuroblastoma and acute myeloid leukemia. Front Oncol 2024; 13:1324013. [PMID: 38260858 PMCID: PMC10800918 DOI: 10.3389/fonc.2023.1324013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2023] [Accepted: 12/11/2023] [Indexed: 01/24/2024] Open
Abstract
The increased availability of genetic technologies has significantly improved the detection of novel germline variants conferring a predisposition to tumor development in patients with malignant disease. The identification of variants of uncertain significance (VUS) represents a challenge for the clinician, leading to difficulties in decision-making regarding medical management, the surveillance program, and genetic counseling. Moreover, it can generate confusion and anxiety for patients and their family members. Herein, we report a 5-year-old girl carrying a VUS in the Succinate Dehydrogenase Complex Subunit C (SHDC) gene who had been previously treated for high-risk neuroblastoma and subsequently followed by the development of secondary acute myeloid leukemia. In this context, we describe how functional studies can provide additional insight on gene function determining whether the variant interferes with normal protein function or stability.
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Affiliation(s)
- Francesco Fabozzi
- Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Rosalba Carrozzo
- Unit of Cell Biology and Diagnosis of Mitochondrial Disorders, Laboratory of Medical Genetics, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Mariachiara Lodi
- Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Angela Di Giannatale
- Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Selene Cipri
- Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Chiara Rosignoli
- Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | | | | | - Teresa Rizza
- Unit of Cell Biology and Diagnosis of Mitochondrial Disorders, Laboratory of Medical Genetics, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Claudio Montante
- Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Emanuele Agolini
- Laboratory of Medical Genetics, Translational Cytogenomics Research Unit, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Michela Di Nottia
- Unit of Cell Biology and Diagnosis of Mitochondrial Disorders, Neuromuscular Disorders Research Unit, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Federica Galaverna
- Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Giada Del Baldo
- Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Francesco Del Bufalo
- Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
| | - Angela Mastronuzzi
- Hematology/Oncology, Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, Rome, Italy
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11
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Lobato EC, Castro FF, Santana LS, Soares IC, Fagundes GFC, Almeida MQ. Three Cases of Carney-Stratakis Syndrome: A Genetically Heterogeneous Disease. JCEM CASE REPORTS 2023; 1:luad139. [PMID: 38021081 PMCID: PMC10675988 DOI: 10.1210/jcemcr/luad139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Indexed: 12/01/2023]
Abstract
Carney-Stratakis syndrome (CSS) is an autosomal dominant rare syndrome, with incomplete penetrance, characterized by the association of paragangliomas and/or pheochromocytomas and gastrointestinal stromal tumors (GISTs). CSS is caused by germline heterozygous loss-of-function pathogenic variants (PVs) in the succinate dehydrogenase subunit genes (SDHB, SDHC, SDHD), with SDHB and SDHD being the most frequent. To date, only 2 germline SDHC PVs (c.43 C > T; c.405 + 1G > A) have been described in 3 patients with CSS. Three patients with CSS and very distinct clinical presentations are reported here: 1 caused by a germline SDHC large deletion and the others with metastatic GIST and negative genetic investigation for SDHx defects. Two cases (1 and 2) presented with pheochromocytoma (case 1 also with abdominal paraganglioma) and metastatic GIST. Although these 2 cases fulfilled the diagnostic criteria for CSS, the genetic investigation for SDHx PVs by next-generation sequencing and multiplex ligation-dependent probe amplification was negative. Case 3 had a large abdominal paraganglioma and a small low-grade GIST not associated with recurrence or metastasis. This case harbored a germline SDHC exon 3 deletion, not previously reported. In conclusion, CSS is a rare and morbid disease with distinct clinical presentations and genetic heterogeneity, which can contribute to underdiagnosis.
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Affiliation(s)
- Eduardo C Lobato
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM/25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Felipe F Castro
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM/25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Lucas S Santana
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM/25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Ibere C Soares
- Divisão de Patologia, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brasil
| | - Gustavo F C Fagundes
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM/25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
| | - Madson Q Almeida
- Unidade de Adrenal, Laboratório de Endocrinologia Molecular e Celular LIM/25, Divisão de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-903, Brasil
- Divisão de Oncologia Clínica, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo 01246-000, Brasil
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12
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Liu C, Zhou D, Yang K, Xu N, Peng J, Zhu Z. Research progress on the pathogenesis of the SDHB mutation and related diseases. Biomed Pharmacother 2023; 167:115500. [PMID: 37734265 DOI: 10.1016/j.biopha.2023.115500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2023] [Revised: 09/01/2023] [Accepted: 09/12/2023] [Indexed: 09/23/2023] Open
Abstract
With the improvement of genetic testing technology in diseases in recent years, researchers have a more detailed and clear understanding of the source of cancers. Succinate dehydrogenase B (SDHB), a mitochondrial gene, is related to the metabolic activities of cells and tissues throughout the body. The mutations of SDHB have been found in pheochromocytoma, paraganglioma and other cancers, and is proved to affect the occurrence and progress of those cancers due to the important structural functions. The importance of SDHB is attracting more and more attention of researchers, however, reviews on the structure and function of SDHB, as well as on the mechanism of its carcinogenesis is inadequate. This paper reviews the relationship between SDHB mutations and related cancers, discusses the molecular mechanism of SDHB mutations that may lead to tumor formation, analyzes the mutation spectrum, structural domains, and penetrance of SDHB and sorts out some of the previously discovered diseases. For the patients with SDHB mutation, it is recommended that people in SDHB mutation families undergo regular genetic testing or SDHB immunohistochemistry (IHC). The purpose of this paper is hopefully to provide some reference and help for follow-up researches on SDHB.
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Affiliation(s)
- Chang Liu
- Ambulatory Surgical Center, First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming 650032, China
| | - Dayang Zhou
- Ambulatory Surgical Center, First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming 650032, China
| | - Kexin Yang
- Department of Surgical oncology, Yunnan Cancer Hospital, 519 Kunzhou Road, Kunming, 650118, China
| | - Ning Xu
- Ambulatory Surgical Center, First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming 650032, China
| | - Jibang Peng
- Department of Surgical oncology, First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming 650032, China
| | - Zhu Zhu
- Ambulatory Surgical Center, First Affiliated Hospital of Kunming Medical University, 295 Xichang Road, Kunming 650032, China.
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13
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Schipani A, Nannini M, Astolfi A, Pantaleo MA. SDHA Germline Mutations in SDH-Deficient GISTs: A Current Update. Genes (Basel) 2023; 14:genes14030646. [PMID: 36980917 PMCID: PMC10048394 DOI: 10.3390/genes14030646] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Revised: 02/17/2023] [Accepted: 03/01/2023] [Indexed: 03/08/2023] Open
Abstract
Loss of function of the succinate dehydrogenase complex characterizes 20–40% of all KIT/PDGFRA-negative GIST. Approximately half of SDH-deficient GIST patients lack SDHx mutations and are caused by a hypermethylation of the SDHC promoter, which causes the repression of SDHC transcription and depletion of SDHC protein levels through a mechanism described as epimutation. The remaining 50% of SDH-deficient GISTs have mutations in one of the SDH subunits and SDHA mutations are the most common (30%), with consequent loss of SDHA and SDHB protein expression immunohistochemically. SDHB, SDHC, and SDHD mutations in GIST occur in only 20–30% of cases and most of these SDH mutations are germline. More recently, germline mutations in SDHA have also been described in several patients with loss of function of the SDH complex. SDHA-mutant patients usually carry two mutational events at the SDHA locus, either the loss of the wild type allele or a second somatic event in compound heterozygosis. This review provides an overview of all data in the literature regarding SDHA-mutated GIST, especially focusing on the prevalence of germline mutations in SDH-deficient GIST populations who harbor SDHA somatic mutations, and offers a view towards understanding the importance of genetic counselling for SDHA-variant carriers and relatives.
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Affiliation(s)
- Angela Schipani
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, 3584 CS Utrecht, The Netherlands
| | - Margherita Nannini
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
| | - Annalisa Astolfi
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Correspondence: ; Tel.: +39-051-2144520
| | - Maria A. Pantaleo
- Department of Medical and Surgical Sciences (DIMEC), University of Bologna, 40138 Bologna, Italy
- Division of Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy
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14
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Würtemberger J, Ripperger T, Vokuhl C, Bauer S, Teichert-von Lüttichau I, Wardelmann E, Niemeyer CM, Kratz CP, Schlegelberger B, Hettmer S. Genetic susceptibility in children, adolescents, and young adults diagnosed with soft-tissue sarcomas. Eur J Med Genet 2023; 66:104718. [PMID: 36764384 DOI: 10.1016/j.ejmg.2023.104718] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/25/2021] [Revised: 10/30/2022] [Accepted: 01/29/2023] [Indexed: 02/11/2023]
Abstract
Soft tissue sarcomas (STS) may arise as a consequence of germline variants in cancer predisposition genes (CPGs). We believe that elucidating germline sarcoma predisposition is critical for understanding disease biology and therapeutic requirements. Participation in surveillance programs may allow for early tumor detection, early initiation of therapy and, ultimately, better outcomes. Among children, adolescents, and adults diagnosed with soft-tissue sarcomas and examined as part of published germline sequencing studies, pathogenic/likely pathogenic (P/LP) variants in CPGs were reported in 7-33% of patients. P/LP germline variants were detected most frequently in TP53, NF1 and BRCA1/2. In this review, we describe reported associations between soft tissue sarcomas and germline variants in CPGs, with mentioning of locally aggressive and benign soft tissue tumors that have important associations with cancer predisposition syndromes. We also discuss recommendations for diagnostic germline genetic testing. Testing for sarcoma-predisposing germline variants should be considered as part of the routine clinical workup and care of any child, adolescent, or adult diagnosed with STS and take into account consequences for the whole family.
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Affiliation(s)
- Julia Würtemberger
- Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Germany
| | - Tim Ripperger
- Department of Human Genetics, Hannover Medical School, Hannover, Germany
| | - Christian Vokuhl
- Institute of Pathology, University Hospital Bonn, 53127, Bonn, Germany
| | - Sebastian Bauer
- Department of Oncology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany
| | - Irene Teichert-von Lüttichau
- Technical University of Munich, School of Medicine, Department of Pediatrics and Children's Cancer Research Center, Kinderklinik München Schwabing, Munich, Germany
| | - Eva Wardelmann
- Gerhard Domagk Institute of Pathology, University Hospital Muenster, Muenster, Germany
| | - Charlotte M Niemeyer
- Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Germany
| | - Christian P Kratz
- Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | | | - Simone Hettmer
- Division of Pediatric Hematology and Oncology, Department of Pediatric and Adolescent Medicine, University Medical Center Freiburg, University of Freiburg, Germany.
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15
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Mandelker D, Marra A, Mehta N, Selenica P, Yelskaya Z, Yang C, Somar J, Mehine M, Misyura M, Basturk O, Latham A, Carlo M, Walsh M, Stadler ZK, Offit K, Bandlamudi C, Hameed M, Chi P, Reis-Filho JS, Ceyhan-Birsoy O. Expanded genetic testing of GIST patients identifies high proportion of non-syndromic patients with germline alterations. NPJ Precis Oncol 2023; 7:1. [PMID: 36593350 PMCID: PMC9807588 DOI: 10.1038/s41698-022-00342-z] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 12/14/2022] [Indexed: 01/03/2023] Open
Abstract
Traditional genetic testing for patients with gastrointestinal stromal tumors (GISTs) focus on those with syndromic features. To assess whether expanded genetic testing of GIST patients could identify hereditary cancer predisposition, we analyzed matched tumor-germline sequencing results from 103 patients with GISTs over a 6-year period. Germline pathogenic/likely pathogenic (P/LP) variants in GIST-associated genes (SDHA, SDHB, SDHC, NF1, KIT) were identified in 69% of patients with KIT/PDGFRA-wildtype GISTs, 63% of whom did not have any personal or family history of syndromic features. To evaluate the frequency of somatic versus germline variants identified in tumor-only sequencing of GISTs, we analyzed 499 de-identified tumor-normal pairs. P/LP variants in certain genes (e.g., BRCA1/2, SDHB) identified in tumor-only sequencing of GISTs were almost exclusively germline in origin. Our results provide guidance for genetic testing of GIST patients and indicate that germline testing should be offered to all patients with KIT/PDGFRA-wildtype GISTs regardless of their history of syndromic features.
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Affiliation(s)
- Diana Mandelker
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Antonio Marra
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nikita Mehta
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Pier Selenica
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zarina Yelskaya
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ciyu Yang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Joshua Somar
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Miika Mehine
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maksym Misyura
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Olca Basturk
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Alicia Latham
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria Carlo
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Michael Walsh
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zsofia K Stadler
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kenneth Offit
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Chaitanya Bandlamudi
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Meera Hameed
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ping Chi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jorge S Reis-Filho
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Ozge Ceyhan-Birsoy
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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16
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Shi Y, Ding L, Mo C, Luo Y, Huang S, Cai S, Xia Y, Zhang X. Bladder paraganglioma, gastrointestinal stromal tumor, and SDHB germline mutation in a patient with Carney-Stratakis syndrome: A case report and literature review. Front Oncol 2022; 12:1030092. [PMID: 36387130 PMCID: PMC9650230 DOI: 10.3389/fonc.2022.1030092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2022] [Accepted: 10/13/2022] [Indexed: 12/02/2022] Open
Abstract
Background Carney-Stratakis syndrome (CSS) is a rare dyad of paraganglioma (PGL)/pheochromocytoma (PHEO) and gastrointestinal stromal tumor (GIST). PGLs are neuroendocrine tumors of neural crest origin which are mostly found in the head, neck, and retroperitoneal space. GISTs are the most common mesenchymal tumors of the digestive tract, usually caused by KIT/PDGFRA mutations. Here, we reported a case of CSS with unusual bladder PGL and succinate dehydrogenase (SDH) deficient GIST due to a germline mutation in SDH-subunit B (SDHB) gene. Case presentation A 39-year-old female patient initially diagnosed with gastric GIST and isolated pelvic metastasis was eventually found to be CSS with bladder PGL and SDH-deficient GIST after surgery. This patient underwent resection of gastric and bladder tumors, and postoperative pathology confirmed the diagnosis of CSS. According to the next-generation sequencing (NGS), the patient carried a germline mutation in the SDHB gene, which was the cause of the disorder. The patient had no tumor recurrence with regular follow-up in 10 months. Conclusions CSS is an autosomal genetic disorder with no gender difference in incidence, and PGLs are more frequent than GISTs. SDH germline mutation is the molecular biological mechanism of CSS while the most common type is SDHB mutation. The unique mechanism of tumorigenesis including hypoxia and hypermethylation caused by SDH deficiency renders target therapy with tyrosine kinase inhibitors ineffective, therefore complete surgical resection is the optimal treatment in the absence of tumor metastases.
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Affiliation(s)
- Yihang Shi
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Li Ding
- Department of Pathology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Chengqiang Mo
- Department of Pharmacy, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanji Luo
- Department of Urology Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shaoqing Huang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shirong Cai
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Yanzhe Xia
- Department of Radiology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Xinhua Zhang, ; Yanzhe Xia,
| | - Xinhua Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- *Correspondence: Xinhua Zhang, ; Yanzhe Xia,
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17
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Metastatic SDH-Deficient GIST Diagnosed during Pregnancy: Approach to a Complex Case. Curr Oncol 2022; 29:5933-5941. [PMID: 36005206 PMCID: PMC9406627 DOI: 10.3390/curroncol29080468] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2022] [Revised: 07/02/2022] [Accepted: 08/17/2022] [Indexed: 02/07/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) account for 1% of GI neoplasms in adults, and epidemiological data suggest an even lower occurrence in pregnant women. The majority of GISTs are caused by KIT and PDGFRA mutations. This is not the case in women of childbearing age. Some GISTs do not have a KIT/PDGFRA mutation and are classified as wild-type (WT) GISTs. WT-GIST includes many molecular subtypes including SDH deficiencies. In this paper, we present the first case report of a metastatic SDH-deficient GIST in a 23-year-old pregnant patient and the challenges encountered given her concurrent pregnancy. Our patient underwent a surgical tumor resection of her gastric GIST as well as a lymphadenectomy a week after induction of labor at 37 + 1 weeks. She received imatinib, sunitinib as well as regorafenib afterward. These drugs were discontinued because of disease progression despite treatment or after side effects were reported. Hence, she is currently under treatment with ripretinib. Her last FDG-PET showed a stable disease. This case highlights the complexity of GI malignancy care during pregnancy, and the presentation and management particularities of metastatic WT-GISTs. This case also emphasizes the need for a multidisciplinary approach and better clinical guidelines for offering optimal management to women in this specific context.
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18
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Abstract
Over the past 20 years, gastrointestinal stromal tumor (GIST) has evolved into an increasingly complex clinical entity with ever more challenges. While surgical resection is the gold standard, advancements in genetic testing, therapeutic options, immunotherapy, and management of metastatic disease necessitate a comprehensive, multimodal approach for these tumors. This chapter highlights the importance of genomic testing of GIST, the use of neoadjuvant and adjuvant therapy for localized disease, surgical principles for GIST, as well as current and new approaches for addressing metastatic disease.
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19
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Dermawan JK, Rubin BP. Molecular Pathogenesis of Gastrointestinal Stromal Tumor: A Paradigm for Personalized Medicine. ANNUAL REVIEW OF PATHOLOGY-MECHANISMS OF DISEASE 2021; 17:323-344. [PMID: 34736340 DOI: 10.1146/annurev-pathol-042220-021510] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Over the past three to four decades, the molecular pathogenesis of gastrointestinal stromal tumors (GISTs) has been elucidated in great detail. In this review, we discuss the biological genesis of GISTs, identification of the various primary activating driver mutations (focusing on KIT and PDGFRA), oncogene addiction and targeted therapies with imatinib and other tyrosine kinase inhibitors, and the subsequent characterization of the various mechanisms of drug resistance. We illustrate how GIST has become a quintessential paradigm for personalized medicine. Expected final online publication date for the Annual Review of Pathology: Mechanisms of Disease, Volume 17 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
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Affiliation(s)
- Josephine K Dermawan
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; ,
| | - Brian P Rubin
- Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA; ,
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20
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Daumova M, Svajdler M, Fabian P, Kren L, Babankova I, Jezova M, Sedivcova M, Vanecek T, Behenska K, Michal M, Daum O. SDHC Methylation Pattern in Patients With Carney Triad. Appl Immunohistochem Mol Morphol 2021; 29:599-605. [PMID: 33624983 DOI: 10.1097/pai.0000000000000920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2020] [Accepted: 01/26/2021] [Indexed: 11/26/2022]
Abstract
Carney triad is a multitumor syndrome affecting almost exclusively young women in a nonfamilial setting, which manifests by multifocal gastric gastrointestinal stromal tumors, paragangliomas, and pulmonary chondroma. The Carney triad-associated tumors are characterized by a deficiency of the mitochondrial succinate dehydrogenase enzymatic complex. Recently, it has been observed that the deficiency results from epigenetic silencing of the SDHC gene by its promoter hypermethylation. To elucidate anatomic distribution of SDHC promoter methylation in Carney triad patients and thus to shed some light on the possible natural development of this epigenetic change, both neoplastic and available non-neoplastic tissues of 3 patients with Carney triad were tested for hypermethylation at the SDHC promoter site. SDHC promoter hypermethylation was proven in all tumors studied. Lack of SDHC epigenetic silencing in the non-neoplastic lymphoid and duodenal tissue (ie, tissues not involved in the development of Carney triad-associated tumors) together with the finding of SDHC promoter hypermethylation in the non-neoplastic gastric wall favors the hypothesis of postzygotic somatic mosaicism as the biological background of Carney triad; it also offers an explanation of the multifocality of gastrointestinal stromal tumors of the stomach occurring in this scenario as well. However, the precise mechanism responsible for the peculiar organ-specific distribution of Carney triad-associated tumors is still unknown.
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Affiliation(s)
- Magdalena Daumova
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University
- Bioptical Laboratory Ltd, Plzen
| | - Marian Svajdler
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University
- Bioptical Laboratory Ltd, Plzen
| | - Pavel Fabian
- Department of Oncological Pathology, Masaryk Memorial Cancer Institute
| | - Leos Kren
- Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Iva Babankova
- Department of Oncological Pathology, Masaryk Memorial Cancer Institute
| | - Marta Jezova
- Department of Pathology, University Hospital Brno and Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | | | - Tomas Vanecek
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University
- Bioptical Laboratory Ltd, Plzen
| | - Kristyna Behenska
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University
| | - Michal Michal
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University
| | - Ondrej Daum
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University
- Bioptical Laboratory Ltd, Plzen
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21
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Zanfardino P, Doccini S, Santorelli FM, Petruzzella V. Tackling Dysfunction of Mitochondrial Bioenergetics in the Brain. Int J Mol Sci 2021; 22:8325. [PMID: 34361091 PMCID: PMC8348117 DOI: 10.3390/ijms22158325] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 07/29/2021] [Accepted: 07/30/2021] [Indexed: 12/15/2022] Open
Abstract
Oxidative phosphorylation (OxPhos) is the basic function of mitochondria, although the landscape of mitochondrial functions is continuously growing to include more aspects of cellular homeostasis. Thanks to the application of -omics technologies to the study of the OxPhos system, novel features emerge from the cataloging of novel proteins as mitochondrial thus adding details to the mitochondrial proteome and defining novel metabolic cellular interrelations, especially in the human brain. We focussed on the diversity of bioenergetics demand and different aspects of mitochondrial structure, functions, and dysfunction in the brain. Definition such as 'mitoexome', 'mitoproteome' and 'mitointeractome' have entered the field of 'mitochondrial medicine'. In this context, we reviewed several genetic defects that hamper the last step of aerobic metabolism, mostly involving the nervous tissue as one of the most prominent energy-dependent tissues and, as consequence, as a primary target of mitochondrial dysfunction. The dual genetic origin of the OxPhos complexes is one of the reasons for the complexity of the genotype-phenotype correlation when facing human diseases associated with mitochondrial defects. Such complexity clinically manifests with extremely heterogeneous symptoms, ranging from organ-specific to multisystemic dysfunction with different clinical courses. Finally, we briefly discuss the future directions of the multi-omics study of human brain disorders.
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Affiliation(s)
- Paola Zanfardino
- Department of Medical Basic Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, 70124 Bari, Italy;
| | - Stefano Doccini
- IRCCS Fondazione Stella Maris, Calambrone, 56128 Pisa, Italy;
| | | | - Vittoria Petruzzella
- Department of Medical Basic Sciences, Neurosciences and Sense Organs, University of Bari Aldo Moro, 70124 Bari, Italy;
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Gastric gastrointestinal stromal tumor (GIST) with co-occurrence of pancreatic neuroendocrine tumor. Radiol Case Rep 2021; 16:1391-1394. [PMID: 33912253 PMCID: PMC8063710 DOI: 10.1016/j.radcr.2021.03.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 03/09/2021] [Accepted: 03/10/2021] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal tumors make up only about 1% of primary GI tumors, with Gastrointestinal Stromal Tumors (GIST) being the most common nonepithelial GI neoplasms. They are derived from the Interstitial cells of Cajal (ICC), and occur predominantly in older individuals, with a mean age of diagnosis of 64 years. Here we discuss the case of a 39-year-old female with atypical thoracic back pain wrapping around to the front and migrating diffuse abdomen pain that sometimes radiates into the chest. Upon imaging, a gastric GIST of the greater curve of the stomach was found incidentally on investigation of a pancreatic mass that was revealed to be a co-occurring pancreatic neuroendocrine tumor. For management of the gastric GIST and pancreatic neuroendocrine tumor, this patient underwent partial gastrectomy with gastrojejunostomy, partial pancreatectomy, splenectomy, and cholecystectomy with no complications.
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Garnier H, Loo C, Czauderna P, Vasudevan SA. Pediatric Gastrointestinal Stromal Tumors and Neuroendocrine Tumors: Advances in Surgical Management. Surg Oncol Clin N Am 2021; 30:219-233. [PMID: 33706897 DOI: 10.1016/j.soc.2020.11.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gastrointestinal stromal tumors and neuroendocrine tumors in adult and pediatric populations differ immensely. Despite these established differences, the extreme rarity of gastrointestinal stromal tumors and neuroendocrine tumors in the pediatric population has resulted in the lack of consensus management guidelines, making optimal surgical approaches unclear. Comprehensive management principles to guide surgical approaches in adult literature are extensive. However, these are still lacking for pediatric patients. International cooperation to develop standardized pediatric-specific guidelines is urgently warranted in the future. This article highlights the vast differences between adult and pediatric parameters and provides recommendations on optimal and novel surgical approaches in children.
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Affiliation(s)
- Hanna Garnier
- Department of Surgery and Urology for Children and Adolescents, Medical University of Gdansk, Marii Skłodowskiej-Curie 3a, Gdańsk 80-210, Poland
| | - Caitlyn Loo
- Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, 7200 Cambridge Street, 7th Floor, Houston, TX 77030, USA; School of Medicine, Royal College of Surgeons in Ireland, 123 St Stephens Green, Saint Peter's, Dublin D02 YN77, Ireland
| | - Piotr Czauderna
- Department of Surgery and Urology for Children and Adolescents, Medical University of Gdansk, Marii Skłodowskiej-Curie 3a, Gdańsk 80-210, Poland
| | - Sanjeev A Vasudevan
- Division of Pediatric Surgery, Michael E. DeBakey Department of Surgery, Texas Children's Surgical Oncology Program, Texas Children's Liver Tumor Program, Dan L. Duncan Cancer Center, Baylor College of Medicine, 7200 Cambridge Street, 7th Floor, Houston, TX 77030, USA.
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Abstract
Gastrointestinal stromal tumours (GIST) have an incidence of ~1.2 per 105 individuals per year in most countries. Around 80% of GIST have varying molecular changes, predominantly mutually exclusive activating KIT or PDGFRA mutations, but other, rare subtypes also exist. Localized GIST are curable, and surgery is their standard treatment. Risk factors for relapse are tumour size, mitotic index, non-gastric site and tumour rupture. Patients with GIST with KIT or PDGFRA mutations sensitive to the tyrosine kinase inhibitor (TKI) imatinib that are at high risk of relapse have improved survival with adjuvant imatinib treatment. In advanced disease, median overall survival has improved from 18 months to >70 months since the introduction of TKIs. The role of surgery in the advanced setting remains unclear. Resistance to TKIs arise mainly from subclonal selection of cells with resistance mutations in KIT or PDGFRA when they are the primary drivers. Advanced resistant GIST respond to second-line sunitinib and third-line regorafenib, as well as to the new broad-spectrum TKI ripretinib. Rare molecular forms of GIST with alterations involving NF1, SDH genes, BRAF or NTRK genes generally show primary resistance to standard TKIs, but some respond to specific inhibitors of the activated genes. Despite major advances, many questions in both advanced and localized disease remain unanswered.
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Affiliation(s)
- Jean-Yves Blay
- Department of Medicine, Centre Leon Berard, UNICANCER & University Lyon I, Lyon, France.
| | - Yoon-Koo Kang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Toshiroo Nishida
- Surgery Department, National Cancer Center Hospital, Chuo-ku, Tokyo, Japan
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Mitochondrial Structure and Bioenergetics in Normal and Disease Conditions. Int J Mol Sci 2021; 22:ijms22020586. [PMID: 33435522 PMCID: PMC7827222 DOI: 10.3390/ijms22020586] [Citation(s) in RCA: 108] [Impact Index Per Article: 27.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/03/2021] [Accepted: 01/04/2021] [Indexed: 02/06/2023] Open
Abstract
Mitochondria are ubiquitous intracellular organelles found in almost all eukaryotes and involved in various aspects of cellular life, with a primary role in energy production. The interest in this organelle has grown stronger with the discovery of their link to various pathologies, including cancer, aging and neurodegenerative diseases. Indeed, dysfunctional mitochondria cannot provide the required energy to tissues with a high-energy demand, such as heart, brain and muscles, leading to a large spectrum of clinical phenotypes. Mitochondrial defects are at the origin of a group of clinically heterogeneous pathologies, called mitochondrial diseases, with an incidence of 1 in 5000 live births. Primary mitochondrial diseases are associated with genetic mutations both in nuclear and mitochondrial DNA (mtDNA), affecting genes involved in every aspect of the organelle function. As a consequence, it is difficult to find a common cause for mitochondrial diseases and, subsequently, to offer a precise clinical definition of the pathology. Moreover, the complexity of this condition makes it challenging to identify possible therapies or drug targets.
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Pitsava G, Settas N, Faucz FR, Stratakis CA. Carney Triad, Carney-Stratakis Syndrome, 3PAS and Other Tumors Due to SDH Deficiency. Front Endocrinol (Lausanne) 2021; 12:680609. [PMID: 34012423 PMCID: PMC8126684 DOI: 10.3389/fendo.2021.680609] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 04/12/2021] [Indexed: 12/20/2022] Open
Abstract
Succinate dehydrogenase (SDH) is a key respiratory enzyme that links Krebs cycle and electron transport chain and is comprised of four subunits SDHA, SDHB, SDHC and SDHD. All SDH-deficient tumors are caused by or secondary to loss of SDH activity. As many as half of the familial cases of paragangliomas (PGLs) and pheochromocytomas (PHEOs) are due to mutations of the SDHx subunits. Gastrointestinal stromal tumors (GISTs) associated with SDH deficiency are negative for KIT/PDGFRA mutations and present with distinctive clinical features such as early onset (usually childhood or adolescence) and almost exclusively gastric location. SDH-deficient GISTs may be part of distinct clinical syndromes, Carney-Stratakis syndrome (CSS) or dyad and Carney triad (CT). CSS is also known as the dyad of GIST and PGL; it affects both genders equally and is inherited in an autosomal dominant manner with incomplete penetrance. CT is a very rare disease; PGL, GIST and pulmonary chondromas constitute CT which shows female predilection and may be a mosaic disorder. Even though there is some overlap between CT and CSS, as both are due to SDH deficiency, CSS is caused by inactivating germline mutations in genes encoding for the SDH subunits, while CT is mostly caused by a specific pattern of methylation of the SDHC gene and may be due to germline mosaicism of the responsible genetic defect.
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Affiliation(s)
- Georgia Pitsava
- Division of Intramural Population Health Research, Eunice Kennedy Shriver National Institutes of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Nikolaos Settas
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
| | - Fabio R. Faucz
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
- *Correspondence: Fabio R. Faucz,
| | - Constantine A. Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD, United States
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Fernandez-Vizarra E, Zeviani M. Mitochondrial disorders of the OXPHOS system. FEBS Lett 2020; 595:1062-1106. [PMID: 33159691 DOI: 10.1002/1873-3468.13995] [Citation(s) in RCA: 151] [Impact Index Per Article: 30.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Revised: 10/21/2020] [Accepted: 11/01/2020] [Indexed: 12/13/2022]
Abstract
Mitochondrial disorders are among the most frequent inborn errors of metabolism, their primary cause being the dysfunction of the oxidative phosphorylation system (OXPHOS). OXPHOS is composed of the electron transport chain (ETC), formed by four multimeric enzymes and two mobile electron carriers, plus an ATP synthase [also called complex V (cV)]. The ETC performs the redox reactions involved in cellular respiration while generating the proton motive force used by cV to synthesize ATP. OXPHOS biogenesis involves multiple steps, starting from the expression of genes encoded in physically separated genomes, namely the mitochondrial and nuclear DNA, to the coordinated assembly of components and cofactors building each individual complex and eventually the supercomplexes. The genetic cause underlying around half of the diagnosed mitochondrial disease cases is currently known. Many of these cases result from pathogenic variants in genes encoding structural subunits or additional factors directly involved in the assembly of the ETC complexes. Here, we review the historical and most recent findings concerning the clinical phenotypes and the molecular pathological mechanisms underlying this particular group of disorders.
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Affiliation(s)
- Erika Fernandez-Vizarra
- Institute of Molecular, Cell and Systems Biology, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK
| | - Massimo Zeviani
- Venetian Institute of Molecular Medicine, Padova, Italy.,Department of Neurosciences, University of Padova, Italy
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Italiano A. New insights into the clinical management of advanced gastrointestinal stromal tumors. Expert Opin Pharmacother 2020; 22:439-447. [PMID: 33307872 DOI: 10.1080/14656566.2020.1828346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
INTRODUCTION 90% of gastrointestinal stromal tumors (GISTs) harbor an activating mutation in the KIT or PDGFRα oncogene, and these are known to confer imatinib sensitivity. AREAS COVERED The author reviews the data regarding the current management of GIST, mechanisms of resistance to imatinib, and new drugs currently in clinical development and provides his unique perspectives on the subject matter. EXPERT OPINION Several studies have shown that the response to imatinib in GIST patients mainly depends on the mutational status of KIT or PDGFRα. Moreover, most, if not all, patients treated with imatinib for advanced GIST will develop a secondary progressive disease under the treatment. In most cases, such progressions are the result of acquired resistance due to the occurrence of secondary c-KIT mutations, especially in GISTs with primary exon 11 mutations. Sunitinib and regorafenib are inhibitors of multiple tyrosine kinases, including KIT, PDGFRα, PDGFRβ, and VEGFRs, and are approved for the management of imatinib- and imatinib/sunitinib-refractory GIST patients, respectively. Clearly, better knowledge of the molecular mechanisms underlying the resistance to imatinib as well as the development of a new class of broad-spectrum tyrosine kinase inhibitors such as avapritinib and ripretinib will provide new individualized therapeutic strategies for GIST patients.
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Recht HS, Fishman EK. Carney-Stratakis syndrome: A dyad of familial paraganglioma and gastrointestinal stromal tumor. Radiol Case Rep 2020; 15:2071-2075. [PMID: 32944103 PMCID: PMC7481509 DOI: 10.1016/j.radcr.2020.08.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 07/29/2020] [Accepted: 08/01/2020] [Indexed: 12/02/2022] Open
Abstract
Carney-Stratakis syndrome is a rare, distinct dyad of familial paraganglioma and gastrointestinal stromal tumor, and is associated with germline mutations in the succinate dehydrogenase genes SDHB, SDHC, and SDHD. We present a unique case of a 45-year-old woman with Carney-Stratakis syndrome who initially presented with a palpable left neck mass. Further workup demonstrated 2 paragangliomas in the neck and multiple SDHB deficient gastrointestinal stromal tumors of the stomach. We describe the imaging findings and clinical course of this rare syndrome.
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De Filpo G, Cilotti A, Rolli L, Pastorino U, Sonzogni A, Pradella S, Cantini G, Ercolino T, Nesi G, Mannelli M, Maggi M, Canu L. SDHx and Non-Chromaffin Tumors: A Mediastinal Germ Cell Tumor Occurring in a Young Man with Germline SDHB Mutation. ACTA ACUST UNITED AC 2020; 56:medicina56110561. [PMID: 33113876 PMCID: PMC7693473 DOI: 10.3390/medicina56110561] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2020] [Revised: 10/22/2020] [Accepted: 10/23/2020] [Indexed: 12/31/2022]
Abstract
Background: Mutations in genes encoding one of the subunits of succinate dehydrogenase (SDH) are involved in pheochromocytoma (PHEO) and paraganglioma (PGL) development. Over the last few years, such mutations have also been associated with non-chromaffin tumors. However, immunohistochemistry (IHC) on the tumor tissue and a study on the loss of heterozygosity (LOH) aimed at demonstrating the pathogenic role of SDHx genes have only been employed in a few cases. Case report: We describe the case of a 19-year-old Caucasian man with a germline SDHB mutation, who presented with acne vulgaris resistant to medical treatment. His follow-up for chromaffin tumors was negative, while hormonal tests revealed suppressed gonadotropins with testosterone in the upper range of normality and elevated β-human chorionic gonadotropin (β-hCG). At the whole-body enhanced CT scan, a mediastinal lesion suggestive of a germ cell tumor (GCT) was detected. 18FDG-PET (fluorodeoxyglucose-positron emission tomography) imaging showed low glucose metabolism at the mediastinal site. Surgical removal of the mass was uneventful. Pathology confirmed the diagnosis of GCT consisting of cystic teratoma (95%) and seminoma (5%). IHC for SDHB showed normal protein expression, and genetic analysis of the tumor tissue revealed the absence of SDHB LOH. Normalization of the hormonal tests and acne attenuation were achieved after surgery. Conclusion: We report an incidental association of a germinal SDHB mutation and mediastinal GCT in a young Caucasian man. Our paper highlights the importance of IHC and genetic analysis in confirming the etiologic role of SDHx genes in nonchromaffin tumors, thus excluding incidental associations.
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Affiliation(s)
- Giuseppina De Filpo
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (G.C.); (M.M.); (M.M.); (L.C.)
- Endocrinology Unit, Careggi University Hospital, 50139 Florence, Italy; (A.C.); (T.E.)
- Correspondence: ; Tel.: +39-55-2758241
| | - Antonio Cilotti
- Endocrinology Unit, Careggi University Hospital, 50139 Florence, Italy; (A.C.); (T.E.)
| | - Luigi Rolli
- Division of Thoracic Surgery, IRCCS Foundation, Istituto Nazionale dei Tumori, 20133 Milan, Italy; (L.R.); (U.P.)
| | - Ugo Pastorino
- Division of Thoracic Surgery, IRCCS Foundation, Istituto Nazionale dei Tumori, 20133 Milan, Italy; (L.R.); (U.P.)
| | - Angelica Sonzogni
- Department of Pathology and Laboratory Medicine, IRCCS Foundation, Istituto Nazionale dei Tumori, 20133 Milan, Italy;
| | - Silvia Pradella
- Department of Radiology, Careggi University Hospital, 50139 Florence, Italy;
| | - Giulia Cantini
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (G.C.); (M.M.); (M.M.); (L.C.)
| | - Tonino Ercolino
- Endocrinology Unit, Careggi University Hospital, 50139 Florence, Italy; (A.C.); (T.E.)
| | - Gabriella Nesi
- Department of Health Sciences, Division of Pathological Anatomy, University of Florence, 50139 Florence, Italy;
| | - Massimo Mannelli
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (G.C.); (M.M.); (M.M.); (L.C.)
| | - Mario Maggi
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (G.C.); (M.M.); (M.M.); (L.C.)
- Endocrinology Unit, Careggi University Hospital, 50139 Florence, Italy; (A.C.); (T.E.)
| | - Letizia Canu
- Department of Experimental and Clinical Biomedical Sciences “Mario Serio”, University of Florence, 50139 Florence, Italy; (G.C.); (M.M.); (M.M.); (L.C.)
- Endocrinology Unit, Careggi University Hospital, 50139 Florence, Italy; (A.C.); (T.E.)
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31
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Wang Y, Call J. Mutational Testing in Gastrointestinal Stromal Tumor. Curr Cancer Drug Targets 2020; 19:688-697. [PMID: 30914028 DOI: 10.2174/1568009619666190326123945] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 02/05/2019] [Accepted: 03/13/2019] [Indexed: 12/14/2022]
Abstract
Targeted treatment has become a major modality in cancer management. Such cancer drugs are generally designed to treat tumors with certain genetic/genomic makeups. Mutational testing prior to prescribing targeted therapy is crucial in identifying who can receive clinical benefit from specific cancer drugs. Over the last two decades, gastrointestinal stromal tumors (GISTs) have evolved from histogenetically obscure to being identified as distinct gastrointestinal mesenchymal tumors with well-defined clinical and molecular characteristics, for which multiple lines of targeted therapies are available. Although the National Comprehensive Cancer Network (NCCN) strongly recommends mutational testing for optimal management of GIST, many GIST patients still have neither a mutation test performed or any mutation-guided cancer management. Here, we review the mutation-guided landscape of GIST, mutational testing methods, and the recent development of new therapies targeting GIST with specific mutations.
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Affiliation(s)
- Yu Wang
- The Life Raft Group, 155 US-46 Wayne, NJ 07470, United States
| | - Jerry Call
- The Life Raft Group, 155 US-46 Wayne, NJ 07470, United States
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Martins RG, Cunha N, Simões H, Matos MJ, Silva J, Torres I, Rodrigues F, Leite V, Teixeira MR, Bugalho MJ. Surveillance of succinate dehydrogenase gene mutation carriers: Insights from a nationwide cohort. Clin Endocrinol (Oxf) 2020; 92:545-553. [PMID: 32181896 DOI: 10.1111/cen.14184] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 03/11/2020] [Accepted: 03/13/2020] [Indexed: 01/22/2023]
Abstract
OBJECTIVE Mutations in the genes coding for succinate dehydrogenase (SDHx) are the most frequent germline alterations in pheochromocytomas and paragangliomas. Evidence for the advantages associated with presymptomatic screening for SDHx mutation carriers is scarce. This study describes a nationwide cohort of these mutation carriers and aims to compare patients with clinical manifestations of the disease and those diagnosed through genetic screening. DESIGN Cross-sectional study. PATIENTS SDHx mutation carriers (n = 118) followed through the Portuguese Oncology referral centres: 41 probands and 77 nonprobands. MEASUREMENTS All participants were subjected to biochemical and body imaging examinations for a complete assessment of the extent and spread of disease. Clinical data obtained this way were further analysed. RESULTS The mean age of this cohort was 44.5 ± 17.4 years, and more than half carried the same founder SDHB mutation. About 50.8% of the mutation carriers developed pheochromocytomas or paragangliomas. Compared to patients diagnosed through genetic screening, those diagnosed clinically were characterized by larger tumours (P < .001), more frequent metastases (P = .024), were more frequently subjected to surgery (P = .011) and radiotherapy (P = .013), and had worse outcomes, such as macroscopic positive margins (P = .034). Persistent and/or unresectable disease and disease-related mortality were also more frequent in symptomatic patients compared to those diagnosed through genetic screening (P = .014). CONCLUSIONS In this nationwide cohort study, a large proportion of mutation carriers were found to develop SDHx-related neoplasia. Genetic testing and subsequent follow-up resulted in the diagnosis of smaller and nonmetastatic tumours, fewer treatment procedures, fewer complications and greater number of disease-free patients.
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Affiliation(s)
- Raquel G Martins
- Endocrinology Department, Portuguese Oncology Institute of Coimbra, Coimbra, Portugal
- Medical Psychology Unit, Department of Clinical Neurosciences and Mental Health, School of Medicine, University of Porto, Porto, Portugal
- Research Centre, Portuguese Oncology Institute of Porto, Porto, Portugal
| | - Nuno Cunha
- Clinical Laboratory Department, Portuguese Oncology Institute of Coimbra, Coimbra, Portugal
| | - Helder Simões
- Endocrinology Department, Portuguese Oncology Institute of Lisbon, Lisbon, Portugal
- Faculty of Medical Sciences, Nova Medical School, NOVA University of Lisbon, Lisbon, Portugal
| | - Maria João Matos
- Endocrinology Department, Portuguese Oncology Institute of Porto, Porto, Portugal
| | - João Silva
- Genetics Department and Research Centre, Portuguese Oncology Institute of Porto, Porto, Portugal
| | - Isabel Torres
- Endocrinology Department, Portuguese Oncology Institute of Porto, Porto, Portugal
| | - Fernando Rodrigues
- Endocrinology Department, Portuguese Oncology Institute of Coimbra, Coimbra, Portugal
| | - Valeriano Leite
- Endocrinology Department, Portuguese Oncology Institute of Lisbon, Lisbon, Portugal
- Faculty of Medical Sciences, Nova Medical School, NOVA University of Lisbon, Lisbon, Portugal
| | - Manuel R Teixeira
- Genetics Department and Research Centre, Portuguese Oncology Institute of Porto, Porto, Portugal
- Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, Portugal
| | - Maria João Bugalho
- Endocrinology, Diabetes and Metabolism Department, CHULN-Hospital Santa Maria, Lisbon, Portugal
- Faculty of Medicine, University of Lisbon, Lisbon, Portugal
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Liu P, Tan F, Liu H, Li B, Lei T, Zhao X. The Use of Molecular Subtypes for Precision Therapy of Recurrent and Metastatic Gastrointestinal Stromal Tumor. Onco Targets Ther 2020; 13:2433-2447. [PMID: 32273716 PMCID: PMC7102917 DOI: 10.2147/ott.s241331] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 03/10/2020] [Indexed: 12/19/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor in the digestive tract. Tyrosine kinase inhibitors (TKIs), represented by imatinib, sunitinib, and regorafenib, have become the main treatment for recurrent and metastatic GISTs. With the wide application of mutation analysis and the precision medicine, molecular characteristics have been determined that not only predict the prognosis of patients with recurrent and metastatic GISTs, but also are closely related to the efficacy of first-, second- and third-line TKIs for GISTs, as well as other TKIs. Despite the significant effects of TKIs, the emergence of primary and secondary resistance ultimately leads to treatment failure and tumor progression. Currently, due to the signal transmission of KIT/PDGFRA during onset and tumor progression, strategies to counteract drug resistance include the replacement of TKIs and the development of new drugs that are directed towards carcinogenic mutations. In addition, it is also the embodiment of precision medicine for GISTs to explore new carcinogenic mechanisms and develop new drugs relying on new biotechnology. Surgery can benefit specific patients but its major purpose is to diminish the resistant clones. However, the prognosis of recurrent and metastatic patients is still unsatisfactory. Therefore, it is worth paying attention to how to maximize the benefits for patients.
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Affiliation(s)
- Peng Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Fengbo Tan
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Heli Liu
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Bin Li
- Department of Oncology, Xiangya Hospital, Central South University, Changsha410008, Hunan, People’s Republic of China
| | - Tianxiang Lei
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
| | - Xianhui Zhao
- Department of Gastrointestinal Surgery, Xiangya Hospital, Central South University, Changsha, Hunan410008, People’s Republic of China
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Djerouni M, Dumont SN. [Wild-type gastroinestinal stromal tumors]. Bull Cancer 2020; 107:499-505. [PMID: 32063345 DOI: 10.1016/j.bulcan.2019.12.007] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 11/29/2019] [Accepted: 12/05/2019] [Indexed: 02/07/2023]
Abstract
Gastrointestinal stromal tumors (GIST) are the most common non-epithelial tumors of the gastrointestinal tract. Wild-type GISTs (WT-GIST) consist of a rare heterogeneous group characterized by the lack of activating mutations in the tyrosine kinase receptor (Kit) and/or platelet derived growth factor receptor A (PDGFRA). However, WT-GIST is characterized by other genomic alterations, including dehydrogenase succinate (SDH) deficiency or mutations in the Ras pathway. Recent studies have reported many mutations in others genes that may be incriminated in the development of WT-GISTs. Moreover, WT-GIST is frequently associated with hereditary cancer syndromes such as the Carney Triad and Type 1 Neurofibromatosis (NF1). WT-GIST affects usually young and pediatric patients. Most WT-GIST subtypes are insensitive to imatinib; therefore, their therapeutic management is somewhat different from usual GISTs. This review resumes the molecular and therapeutic features of this rare entity.
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Affiliation(s)
- Mohamed Djerouni
- Gustave-Roussy Cancer Campus, département d'oncologie médicale, 114, rue Edouard-Vaillant, 94800 Villejuif, France
| | - Sarah N Dumont
- Gustave-Roussy Cancer Campus, département d'oncologie médicale, 114, rue Edouard-Vaillant, 94800 Villejuif, France.
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Glod J, Arnaldez FI, Wiener L, Spencer M, Killian JK, Meltzer P, Dombi E, Derse-Anthony C, Derdak J, Srinivasan R, Linehan WM, Miettinen M, Steinberg SM, Helman L, Widemann BC. A Phase II Trial of Vandetanib in Children and Adults with Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumor. Clin Cancer Res 2019; 25:6302-6308. [PMID: 31439578 PMCID: PMC6825553 DOI: 10.1158/1078-0432.ccr-19-0986] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2019] [Revised: 06/24/2019] [Accepted: 07/30/2019] [Indexed: 01/13/2023]
Abstract
PURPOSE Gastrointestinal stromal tumors (GIST) are resistant to cytotoxic chemotherapy and radiotherapy. Most GIST in children are wild-type for KIT and PDGFRA (WT GIST) and deficient in expression of succinate dehydrogenase (dSDH GIST). We tested the activity of vandetanib, an oral small-molecule inhibitor of VEGFR2, EGFR, and RET, in patients with dSDH GIST. PATIENTS AND METHODS Phase II study of vandetanib (300 mg orally once daily to patients ≥18 years, and 100 mg/m2/dose to patients < 18 years) on a continuous dosing schedule (1 cycle = 28 days) to assess the clinical activity (partial and complete response rate RECIST v1.1) in patients with dSDH GIST. A Simon optimal two-stage design (target response rate 25%, rule out 5%) was used: If ≥1 of 9 patients in stage 1 responded, enrollment would be expanded to 24 patients, and if ≥3 of 24 responded, vandetanib would be considered active. RESULTS Nine patients (7 female and 2 male; median age, 24 years; range, 11-52) with metastatic disease were enrolled. Three of the initial 5 adult patients developed treatment-modifying toxicities. After a protocol amendment, two adults received vandetanib at 200 mg/dose with improved tolerability. The two children (<18 years old) enrolled did not experience treatment-modifying toxicities. No partial or complete responses were observed (median number of cycles, 4; range, 2-18). CONCLUSIONS Vandetanib at a dose of 300 mg daily was not well tolerated by adults with dSDH GIST. Two of 9 patients had prolonged stable disease, but no partial or complete responses were observed, and vandetanib is thus not considered active in dSDH GIST.
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Affiliation(s)
- John Glod
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland.
| | - Fernanda I Arnaldez
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Lori Wiener
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Melissa Spencer
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - J Keith Killian
- Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Paul Meltzer
- Genetics Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Eva Dombi
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Claudia Derse-Anthony
- Clinical Research Directorate, Frederick National Laboratory for Cancer Research, Sponsored by the National Cancer Institute, Bethesda, Maryland
| | - Joanne Derdak
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Ramaprasad Srinivasan
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - W Marston Linehan
- Urologic Oncology Branch, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Markku Miettinen
- Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland
| | - Seth M Steinberg
- Biostatistics and Data Management Section, Office of the Clinical Director, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland
| | - Lee Helman
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Brigitte C Widemann
- Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
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Shi SS, Wang YF, Bao W, Ye SB, Wu N, Wang X, Xia QY, Li R, Shen Q, Zhou XJ. Genetic and epigenetic alterations of SDH genes in patients with sporadic succinate dehydrogenase-deficient gastrointestinal stromal tumors. Pathol Int 2019; 69:350-359. [PMID: 31273876 DOI: 10.1111/pin.12809] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 04/21/2019] [Indexed: 01/28/2023]
Abstract
This study aimed to investigate the association of SDH gene mutations and promoter methylation with succinate dehydrogenase-deficient gastrointestinal stromal tumors (SDH-deficient GISTs) and to further discuss the potential molecular mechanisms underlying SDHB expression loss in these tumors. First, a total of 26 patients with SDH-deficient GISTs were selected by identifying the loss of SDHB protein expression and wild-type for KIT and PDGFRa mutations. Then SDH gene mutations and promoter methylation were detected by DNA sequencing and methylation-specific polymerase chain reaction, respectively, and the clinical and pathological data of SDH-deficient GISTs patients were collected and analyzed accordingly. The results of genetic testing demonstrated that 38.46% (10/26) of these patients harbored mutations in SDHB, SDHC, and SDHD genes (3 cases with double mutations). Besides, aberrant promoter methylation of SDH genes was detected in 10 out of 26 cases (38.46%), including 8 cases in SDHA gene, 3 cases in SDHB gene, 1 case in both SDHA and SDHB genes. It is suggested that SDH gene mutations and promoter methylation may contribute to the loss of SDH protein expression in sporadic SDH-deficient GISTs. This study indicated that the genetic and epigenetic alterations of SDH genes may occur during tumor formation.
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Affiliation(s)
- Shan-Shan Shi
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Yan-Feng Wang
- Department of Pathology, The Affiliated Hospital of Yangzhou University, Yangzhou University, Yangzhou, Jiangsu, P. R. China
| | - Wei Bao
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Sheng-Bin Ye
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Nan Wu
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Xuan Wang
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Qiu-Yuan Xia
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Rui Li
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Qin Shen
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
| | - Xiao-Jun Zhou
- Department of Pathology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, P. R. China
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Xekouki P, Brennand A, Whitelaw B, Pacak K, Stratakis CA. The 3PAs: An Update on the Association of Pheochromocytomas, Paragangliomas, and Pituitary Tumors. Horm Metab Res 2019; 51:419-436. [PMID: 30273935 PMCID: PMC7448524 DOI: 10.1055/a-0661-0341] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Pituitary adenomas (PA) and pheochromocytomas/paragangliomas (PHEO/PGL) are rare tumors. Although they may co-exist by coincidence, there is mounting evidence that genes predisposing in PHEO/PGL development, may play a role in pituitary tumorigenesis. In 2012, we described a GH-secreting PA caused by an SDHD mutation in a patient with familial PGLs and found loss of heterozygosity at the SDHD locus in the pituitary tumor, along with increased hypoxia-inducible factor 1α (HIF-1α) levels. Additional patients with PAs and SDHx defects have since been reported. Overall, prevalence of SDHx mutations in PA is very rare (0.3-1.8% in unselected cases) but we and others have identified several cases of PAs with PHEOs/PGLs, like our original report, a condition which we termed the 3 P association (3PAs). Interestingly, when 3PAs is found in the sporadic setting, no SDHx defects were identified, whereas in familial PGLs, SDHx mutations were identified in 62.5-75% of the reported cases. Hence, pituitary surveillance is recommended among patients with SDHx defects. It is possible that the SDHx germline mutation-negative 3PAs cases may be due to another gene, epigenetic changes, mutations in modifier genes, mosaicism, somatic mutations, pituitary hyperplasia due to ectopic hypothalamic hormone secretion or a coincidence. PA in 3PAs are mainly macroadenomas, more aggressive, more resistant to somatostatin analogues, and often require surgery. Using the Sdhb +/- mouse model, we showed that hyperplasia may be the first abnormality in tumorigenesis as initial response to pseudohypoxia. We also propose surveillance and follow-up approach of patients presenting with this association.
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Affiliation(s)
- Paraskevi Xekouki
- Department of Endocrinology, King’s College Hospital, London, UK
- Division of Diabetes & Nutritional Sciences, King’s College London, London, UK
| | - Ana Brennand
- Division of Diabetes & Nutritional Sciences, King’s College London, London, UK
| | - Ben Whitelaw
- Department of Endocrinology, King’s College Hospital, London, UK
| | - Karel Pacak
- Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
| | - Constantine A. Stratakis
- Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Bethesda, MD, USA
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Abstract
Carney-Stratakis Syndrome (CSS) comprises of paragangliomas (PGLs) and gastrointestinal stromal tumors (GISTs). Several of its features overlap with Carney Triad (CT) - PGLs, GISTs, and pulmonary chondromas. CSS has autosomal dominant inheritance, incomplete penetrance, and greater relative frequency of PGL over GISTs. The PGLs in CSS are multicentric and GISTs are multifocal in all the patients, suggesting an inherited susceptibility and associating the two manifestations. In this review, we highlight the clinical, pathological, and molecular characteristics of CSS, along with its diagnostic and therapeutic implications.
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Affiliation(s)
- Arushi Khurana
- VCU Massey Cancer Center - Hematology Oncology, Richmond, Virginia, USA
| | - Lin Mei
- VCU Massey Cancer Center - Hematology Oncology, Richmond, Virginia, USA
| | - Anthony C Faber
- Virginia Commonwealth University - Philips Institute for Oral Health Research, Richmond, Virginia, USA
| | - Steven C Smith
- Virginia Commonwealth University - Pathology, Richmond, Virginia, USA
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Optimizing Genetic Workup in Pheochromocytoma and Paraganglioma by Integrating Diagnostic and Research Approaches. Cancers (Basel) 2019; 11:cancers11060809. [PMID: 31212687 PMCID: PMC6627084 DOI: 10.3390/cancers11060809] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/01/2019] [Accepted: 06/05/2019] [Indexed: 12/29/2022] Open
Abstract
Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors with a strong hereditary background and a large genetic heterogeneity. Identification of the underlying genetic cause is crucial for the management of patients and their families as it aids differentiation between hereditary and sporadic cases. To improve diagnostics and clinical management we tailored an enrichment based comprehensive multi-gene next generation sequencing panel applicable to both analyses of tumor tissue and blood samples. We applied this panel to tumor samples and compared its performance to our current routine diagnostic approach. Routine diagnostic sequencing of 11 PPGL susceptibility genes was applied to blood samples of 65 unselected PPGL patients at a single center in Dresden, Germany. Predisposing germline mutations were identified in 19 (29.2%) patients. Analyses of 28 PPGL tumor tissues using the dedicated PPGL panel revealed pathogenic or likely pathogenic variants in known PPGL susceptibility genes in 21 (75%) cases, including mutations in IDH2, ATRX and HRAS. These mutations suggest sporadic tumor development. Our results imply a diagnostic benefit from extended molecular tumor testing of PPGLs and consequent improvement of patient management. The approach is promising for determination of prognostic biomarkers that support therapeutic decision-making.
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Ibrahim A, Chopra S. Succinate Dehydrogenase–Deficient Gastrointestinal Stromal Tumors. Arch Pathol Lab Med 2019; 144:655-660. [DOI: 10.5858/arpa.2018-0370-rs] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Succinate dehydrogenase (SDH)–deficient gastrointestinal stromal tumor (GIST) is a subset of wild-type GIST that constitutes approximately 10% of gastric GISTs. SDH-mutated GISTs lack mutations in the proto-oncogene receptor tyrosine kinase (also known as KIT, c-KIT, or CD117) or platelet-derived growth factor receptor α (PDGFR-α). These tumors have female predilection, affect children and young adults, and have a spectrum of behavior from indolent to progressive. These tumors have characteristic morphologic features including multinodular architecture, multiple tumors, lymphovascular involvement, and occasional lymph node metastasis. They can be seen in patients with Carney triad or Carney-Stratakis syndrome. Although a mutation in any one of the SDH subunits can be pathogenic, deficiency of a single subunit leads to loss of detectable SDH subunit B by immunohistochemistry, enabling a convenient, tissue-based screening method. The prognosis and the clinical course of these tumors is different from that of KIT- or PDGFR-α–mutated GISTs. Surgical management is considered the main line of treatment. SDH-mutated GISTs do not respond well to the common targeted therapy, with no objective tumor response to imatinib. The role of the pathologist in diagnosing these cases is imperative in management and subsequent follow-up.
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Affiliation(s)
- Ahmad Ibrahim
- From the Department of Pathology, LAC + USC Medical Center, University of Southern California, Keck School of Medicine, Los Angeles (Dr Ibrahim); and the Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles (Dr Chopra)
| | - Shefali Chopra
- From the Department of Pathology, LAC + USC Medical Center, University of Southern California, Keck School of Medicine, Los Angeles (Dr Ibrahim); and the Department of Pathology, University of Southern California, Keck School of Medicine, Los Angeles (Dr Chopra)
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Cascón A, Remacha L, Calsina B, Robledo M. Pheochromocytomas and Paragangliomas: Bypassing Cellular Respiration. Cancers (Basel) 2019; 11:E683. [PMID: 31100940 PMCID: PMC6562521 DOI: 10.3390/cancers11050683] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2019] [Revised: 05/08/2019] [Accepted: 05/13/2019] [Indexed: 12/14/2022] Open
Abstract
Abstract: Pheochromocytomas and paragangliomas (PPGL) are rare neuroendocrine tumors that show the highest heritability of all human neoplasms and represent a paradoxical example of genetic heterogeneity. Amongst the elevated number of genes involved in the hereditary predisposition to the disease (at least nineteen) there are eleven tricarboxylic acid (TCA) cycle-related genes, some of which are also involved in the development of congenital recessive neurological disorders and other cancers such as cutaneous and uterine leiomyomas, gastrointestinal tumors and renal cancer. Somatic or germline mutation of genes encoding enzymes catalyzing pivotal steps of the TCA cycle not only disrupts cellular respiration, but also causes severe alterations in mitochondrial metabolite pools. These latter alterations lead to aberrant accumulation of "oncometabolites" that, in the end, may lead to deregulation of the metabolic adaptation of cells to hypoxia, inhibition of the DNA repair processes and overall pathological changes in gene expression. In this review, we will address the TCA cycle mutations leading to the development of PPGL, and we will discuss the relevance of these mutations for the transformation of neural crest-derived cells and potential therapeutic approaches based on the emerging knowledge of underlying molecular alterations.
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Affiliation(s)
- Alberto Cascón
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain.
| | - Laura Remacha
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
| | - Bruna Calsina
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
| | - Mercedes Robledo
- Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), 28029 Madrid, Spain.
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Ravegnini G, Ricci R. Succinate Dehydrogenase-Deficient Gastrointestinal Stromal Tumors: Small Steps Toward Personalized Medicine? Epigenet Insights 2019; 12:2516865719842534. [PMID: 31020269 PMCID: PMC6463228 DOI: 10.1177/2516865719842534] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2019] [Accepted: 03/08/2019] [Indexed: 12/12/2022] Open
Abstract
Various molecular triggers define heterogeneous subsets of gastrointestinal stromal tumors (GISTs), differing in clinical behavior and drug sensitivity. KIT/PDGFRA-wild-type GISTs, including those succinate dehydrogenase (SDH)-deficient, are overall unresponsive to the tyrosine kinase inhibitors commonly used, fostering the development of specific alternative therapeutic strategies. Epigenetic inactivation of O6-methylguanine-DNA methyltransferase (MGMT) through promoter methylation leads to effectiveness of alkylating agents in several human cancers. SDH-deficient GISTs typically feature widespread DNA methylation. However, the actual occurrence of MGMT methylation in these tumors, potentially predisposing them to respond to alkylating drugs, has not been investigated so far. Here we discuss the recent findings concerning the occurrence of MGMT methylation in different GIST subgroups, including SDH-deficient ones, as a premise for a possible reappraisal of alkylating agents specifically targeting these small, otherwise overall chemorefractory, GIST subgroups.
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Affiliation(s)
- Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna, Bologna, Italy
| | - Riccardo Ricci
- Department of Pathology, Università Cattolica del Sacro Cuore, Rome, Italy.,UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Rome, Italy
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The loss of succinate dehydrogenase B expression is frequently identified in hemangioblastoma of the central nervous system. Sci Rep 2019; 9:5873. [PMID: 30971719 PMCID: PMC6458311 DOI: 10.1038/s41598-019-42338-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 03/27/2019] [Indexed: 12/23/2022] Open
Abstract
Succinate dehydrogenase (SDH) is a mitochondrial enzyme that plays an important role in both the Krebs cycle and the electron transport chain. SDH inactivation is associated with tumorigenesis in certain types of tumor. SDH consists of subunits A, B, C and D (SDHA, SDHB, SDHC, and SDHD, respectively). Immunohistochemistry for SDHB is a reliable method for detecting the inactivation of SDH by mutations in SDHA, SDHB, SDHC, SDHD and SDH complex assembly factor 2 (SDHAF2) genes with high sensitivity and specificity. SDHB immunohistochemistry has been used to examine the inactivation of SDH in various types of tumors. However, data on central nervous system (CNS) tumors are very limited. In the present study, we investigated the loss of SDHB immunoexpression in 90 cases of CNS tumors. Among the 90 cases of CNS tumors, only three cases of hemangioblastoma showed loss of SDHB immunoexpression. We further investigated SDHB immunoexpression in 35 cases of hemangioblastoma and found that 28 (80%) showed either negative or weak-diffuse pattern of SDHB immunoexpression, which suggests the inactivation of SDH. Our results suggest that SDH inactivation may represent an alternative pathway in the tumorigenesis of hemangioblastoma.
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Ricci R, Martini M, Ravegnini G, Cenci T, Milione M, Lanza P, Pierconti F, Santini D, Angelini S, Biondi A, Rosa F, Alfieri S, Clemente G, Persiani R, Cassano A, Pantaleo MA, Larocca LM. Preferential MGMT methylation could predispose a subset of KIT/PDGFRA-WT GISTs, including SDH-deficient ones, to respond to alkylating agents. Clin Epigenetics 2019; 11:2. [PMID: 30616628 PMCID: PMC6322231 DOI: 10.1186/s13148-018-0594-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 12/03/2018] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Succinate dehydrogenase (SDH)-deficient gastrointestinal stromal tumors (GISTs) constitute a small KIT/PDGFRA-WT GIST subgroup featuring DNA methylation which, although pervasive, appears nevertheless not randomly distributed. Although often indolent, these tumors are mostly chemorefractory in aggressive cases. Promoter methylation-induced O6-methylguanine DNA methyltransferase (MGMT) inactivation improves the efficacy of alkylating agents in gliomas, colorectal cancer and diffuse large B cell lymphoma. MGMT methylation has been found in some GISTs, without determining SDH status. Thirty-six GISTs were enrolled in past sarcoma trials testing alkylating agents, with negative results. Nevertheless, a possible effect on MGMT-methylated GISTs could have escaped detection, since tested GISTs were neither selected by genotype nor investigated for SDH; MGMT was studied in two cases only, revealing baseline activity; these trials were performed prior to the adoption of Choi criteria, the most sensitive for detecting GIST responses to therapy. Under these circumstances, we investigated whether MGMT methylation is preferentially found in SDH-deficient cases (identified by SDHB immunohistochemistry) by analyzing 48 pathogenetically heterogeneous GISTs by methylation-specific PCR, as a premise for possible investigations on the use of alkylating drugs in these tumors. RESULTS Nine GISTs of our series were SDH-deficient, revealing significantly enriched in MGMT-methylated cases (6/9-67%-, vs. 6/39-15%- of SDH-proficient GISTs; p = 0.004). The pathogenetically heterogeneous KIT/PDGFRA-WT GISTs were also significantly MGMT-methylated (11/24-46%-, vs. 1/24-4%- of KIT/PDGFRA-mutant cases, p = 0.002). CONCLUSIONS A subset of KIT/PDGFRA-WT GISTs, including their largest pathogenetically characterized subgroup (i.e., SDH-deficient ones), is preferentially MGMT-methylated. This finding could foster a reappraisal of alkylating agents for treating malignant cases occurring among these overall chemorefractory tumors.
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Affiliation(s)
- Riccardo Ricci
- Department of Pathology, Università Cattolica del Sacro Cuore, Largo F.Vito 1, 00168, Rome, Italy. .,UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.
| | - Maurizio Martini
- Department of Pathology, Università Cattolica del Sacro Cuore, Largo F.Vito 1, 00168, Rome, Italy.,UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Gloria Ravegnini
- Department of Pharmacy and Biotechnology, University of Bologna, via Massarenti 9, 40138, Bologna, Italy
| | - Tonia Cenci
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Massimo Milione
- Department of Pathology and Laboratory Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori, Via Venezian, 20100, Milan, Italy
| | - Paola Lanza
- UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Francesco Pierconti
- Department of Pathology, Università Cattolica del Sacro Cuore, Largo F.Vito 1, 00168, Rome, Italy.,UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Donatella Santini
- Pathology Unit, S.Orsola-Malpighi Hospital, University of Bologna, via Massarenti 9, 40138, Bologna, Italy
| | - Sabrina Angelini
- Department of Pharmacy and Biotechnology, University of Bologna, via Massarenti 9, 40138, Bologna, Italy
| | - Alberto Biondi
- UOC di Chirurgia Generale, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Fausto Rosa
- UOC di Chirurgia Digestiva, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Sergio Alfieri
- UOC di Chirurgia Digestiva, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.,Department of Surgery, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy
| | - Gennaro Clemente
- Department of Surgery, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy.,UOC di Chirurgia Generale ed Epato-Biliare, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Roberto Persiani
- UOC di Chirurgia Generale, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy.,Department of Surgery, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy
| | - Alessandra Cassano
- Department of Internal Medicine, Università Cattolica del Sacro Cuore, Largo F. Vito 1, 00168, Rome, Italy.,UOC di Oncologia Medica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
| | - Maria A Pantaleo
- Department of Experimental, Diagnostic and Specialty Medicine, University of Bologna, via Massarenti 9, 40138, Bologna, Italy
| | - Luigi M Larocca
- Department of Pathology, Università Cattolica del Sacro Cuore, Largo F.Vito 1, 00168, Rome, Italy.,UOC di Anatomia Patologica, Fondazione Policlinico Universitario "A. Gemelli" IRCCS, Largo A. Gemelli 8, 00168, Rome, Italy
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45
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Kamilaris CDC, Stratakis CA. An update on adrenal endocrinology: significant discoveries in the last 10 years and where the field is heading in the next decade. Hormones (Athens) 2018; 17:479-490. [PMID: 30456751 PMCID: PMC6294814 DOI: 10.1007/s42000-018-0072-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Revised: 08/28/2018] [Accepted: 09/20/2018] [Indexed: 02/07/2023]
Abstract
The last 10 years have produced an amazing number of significant discoveries in the field of adrenal endocrinology. The development of the adrenal gland was linked to specific molecules. Cortisol-producing lesions were associated mostly with defects of the cyclic AMP (cAMP) signaling pathway, whereas aldosterone-producing lesions were found to be the result of defects in aldosterone biosynthesis or the potassium channel KCNJ5 and related molecules. Macronodular adrenal hyperplasia was linked to ARMC5 defects and new genes were found to be involved in adrenocortical cancer (ACC). The succinate dehydrogenase (SDH) enzyme was proven to be the most important molecular pathway involved in pheochromocytomas, along with several other genes. Adrenomedullary tumors are now largely molecularly elucidated. Unfortunately, most of these important discoveries have yet to produce new therapeutic tools for our patients with adrenal diseases: ACC in its advanced stages remains largely an untreatable disorder and malignant pheochromocytomas are equally hard to treat. Thus, the challenge for the next 10 years is to translate the important discoveries of the previous decade into substantial advances in the treatment of adrenal disorders and tumors.
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Affiliation(s)
- Crystal D C Kamilaris
- Section on Endocrinology and Genetics & Inter-Institute Endocrinology Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, MD, 20892, USA
| | - Constantine A Stratakis
- Section on Endocrinology and Genetics & Inter-Institute Endocrinology Training Program, Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD), National Institutes of Health (NIH), NIH-Clinical Research Center, 10 Center Drive, Building 10, Room 1-3330, MSC1103, Bethesda, MD, 20892, USA.
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46
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Fite JJ, Maleki Z. Paraganglioma: Cytomorphologic features, radiologic and clinical findings in 12 cases. Diagn Cytopathol 2018; 46:473-481. [PMID: 29575826 DOI: 10.1002/dc.23928] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Revised: 02/28/2018] [Accepted: 03/06/2018] [Indexed: 12/15/2022]
Abstract
BACKGROUND The cytologic diagnosis of paraganglioma can be challenging because of its rarity, wide anatomic distribution, and variable cytomorphological features. DESIGN The Johns Hopkins Hospital pathology archives were searched for fine-needle aspiration (FNA) specimens confirmed as paraganglioma on histology (2003-2015). RESULTS Twelve specimens from 10 patients (6 males and 4 females) with an age range of 16-81 years (mean = 47) were included. Anatomic location included neck (n = 4), paraspinal (n = 2), retroperitoneum (n = 2), and peripancreatic (n = 2). Cellularity of cytological specimens ranged from scant to hypercellular. The cells were arranged in clusters (n = 7), single cells (n = 6), acini (n = 3), and syncytium (n = 1). Plasmacytoid (n = 5) and spindled cells (n = 6) were often present. Nuclear details included anisonucleosis (n = 8), marked pleomorphism (n = 8), scattered binucleation and/or multinucleation, nuclear knobbing (n = 2), speckled (n = 3), coarse (n = 2), hyperchromatic chromatin (n = 3), nuclear grooves (n = 6), intranuclear pseudoinclusions (n = 2), prominent nucleoli (n = 1), naked nuclei (n = 7), and rare nuclear streaking artifact (n = 2). Cytoplasm was delicate, abundant, and granular (n = 9). Necrosis (n = 1) was rare. Synaptophysin, chromogranin, CD56, and S100 (only in sustentacular cells) were positive in tested cases. Three cases showed loss of Succinate Dehydrogenase Subunit B (SDHB). Two patients developed metachronous lesions at different sites. Three patients developed recurrence at the surgical site. Metastatic paraganglioma to the lymph nodes (n = 2), bone (n = 1), and lung (n = 1) also occurred. CONCLUSION An accurate diagnosis of paraganglioma on FNA specimens is crucial for proper treatment. SDH status should be considered for all patients with paraganglioma as it may be important for patients' lifelong follow-up as well as for familial considerations. Paraganglioma is a rare entity with wide age and anatomic distribution and variable cytomorphological features that often overlap with those of malignant neoplasms. Possible aggressive behavior such as recurrence and metastasis to lymph nodes, bone, and lung as well as Succinate Dehydrogenase complex mutations warrant an accurate diagnosis on aspirated material for appropriate clinical management.
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Affiliation(s)
- J Judd Fite
- Department of Pathology, Division of Cytopathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Zahra Maleki
- Department of Pathology, Division of Cytopathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
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47
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Indio V, Astolfi A, Tarantino G, Urbini M, Patterson J, Nannini M, Saponara M, Gatto L, Santini D, do Valle IF, Castellani G, Remondini D, Fiorentino M, von Mehren M, Brandi G, Biasco G, Heinrich MC, Pantaleo MA. Integrated Molecular Characterization of Gastrointestinal Stromal Tumors (GIST) Harboring the Rare D842V Mutation in PDGFRA Gene. Int J Mol Sci 2018; 19:ijms19030732. [PMID: 29510530 PMCID: PMC5877593 DOI: 10.3390/ijms19030732] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 02/14/2018] [Accepted: 02/24/2018] [Indexed: 12/12/2022] Open
Abstract
Gastrointestinal stromal tumors (GIST) carrying the D842V activating mutation in the platelet-derived growth factor receptor alpha (PDGFRA) gene are a very rare subgroup of GIST (about 10%) known to be resistant to conventional tyrosine kinase inhibitors (TKIs) and to show an indolent behavior. In this study, we performed an integrated molecular characterization of D842V mutant GIST by whole-transcriptome and whole-exome sequencing coupled with protein–ligand interaction modelling to identify the molecular signature and any additional recurrent genomic event related to their clinical course. We found a very specific gene expression profile of D842V mutant tumors showing the activation of G-protein-coupled receptor (GPCR) signaling and a relative downregulation of cell cycle processes. Beyond D842V, no recurrently mutated genes were found in our cohort. Nevertheless, many private, clinically relevant alterations were found in each tumor (TP53, IDH1, FBXW7, SDH-complex). Molecular modeling of PDGFRA D842V suggests that the mutant protein binds imatinib with lower affinity with respect to wild-type structure, showing higher stability during the interaction with other type I TKIs (like crenolanib). D842V mutant GIST do not show any actionable recurrent molecular events of therapeutic significance, therefore this study supports the rationale of novel TKIs development that are currently being evaluated in clinical studies for the treatment of D842V mutant GIST.
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Affiliation(s)
- Valentina Indio
- “Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna 40138 Italy; (V.I.); (G.T.); (M.U.); (G.B.); (M.A.P.)
| | - Annalisa Astolfi
- “Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna 40138 Italy; (V.I.); (G.T.); (M.U.); (G.B.); (M.A.P.)
- Correspondence: ; Tel.: +39-051-214-4663; Fax: +39-051-636-4037
| | - Giuseppe Tarantino
- “Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna 40138 Italy; (V.I.); (G.T.); (M.U.); (G.B.); (M.A.P.)
| | - Milena Urbini
- “Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna 40138 Italy; (V.I.); (G.T.); (M.U.); (G.B.); (M.A.P.)
| | - Janice Patterson
- Division of Hematology and Oncology, Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA; (J.P.); (M.C.H.)
| | - Margherita Nannini
- Department of Specialized, Experimental and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy; (M.N.); (M.S.); (L.G.); (G.B.)
| | - Maristella Saponara
- Department of Specialized, Experimental and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy; (M.N.); (M.S.); (L.G.); (G.B.)
| | - Lidia Gatto
- Department of Specialized, Experimental and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy; (M.N.); (M.S.); (L.G.); (G.B.)
| | - Donatella Santini
- Pathology Unit, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy;
| | - Italo F. do Valle
- Department of Physics and Astronomy, L. Galvani Center for Biocomplexity, Biophysics and Systems Biology, University of Bologna, Bologna 40138, Italy; (I.F.d.V.); (G.C.); (D.R.)
| | - Gastone Castellani
- Department of Physics and Astronomy, L. Galvani Center for Biocomplexity, Biophysics and Systems Biology, University of Bologna, Bologna 40138, Italy; (I.F.d.V.); (G.C.); (D.R.)
| | - Daniel Remondini
- Department of Physics and Astronomy, L. Galvani Center for Biocomplexity, Biophysics and Systems Biology, University of Bologna, Bologna 40138, Italy; (I.F.d.V.); (G.C.); (D.R.)
| | - Michelangelo Fiorentino
- Laboratory of Oncological and Transplant Molecular Pathology—Pathology Unit, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy;
| | - Margaret von Mehren
- Department of Hematology and Medical Oncology, Fox Chase Cancer Center, Temple University Philadelphia, PA 19111, USA;
| | - Giovanni Brandi
- Department of Specialized, Experimental and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy; (M.N.); (M.S.); (L.G.); (G.B.)
| | - Guido Biasco
- “Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna 40138 Italy; (V.I.); (G.T.); (M.U.); (G.B.); (M.A.P.)
- Division of Hematology and Oncology, Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA; (J.P.); (M.C.H.)
- Department of Specialized, Experimental and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy; (M.N.); (M.S.); (L.G.); (G.B.)
| | - Michael C. Heinrich
- Division of Hematology and Oncology, Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA; (J.P.); (M.C.H.)
| | - Maria Abbondanza Pantaleo
- “Giorgio Prodi” Cancer Research Center, University of Bologna, Bologna 40138 Italy; (V.I.); (G.T.); (M.U.); (G.B.); (M.A.P.)
- Division of Hematology and Oncology, Portland VA Health Care System and OHSU Knight Cancer Institute, Oregon Health and Science University, Portland, OR 97239, USA; (J.P.); (M.C.H.)
- Department of Specialized, Experimental and Diagnostic Medicine, Sant’Orsola-Malpighi Hospital, University of Bologna, Bologna 40138, Italy; (M.N.); (M.S.); (L.G.); (G.B.)
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48
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Gopie P, Mei L, Faber AC, Grossman SR, Smith SC, Boikos SA. Classification of gastrointestinal stromal tumor syndromes. Endocr Relat Cancer 2018; 25:R49-R58. [PMID: 29170162 DOI: 10.1530/erc-17-0329] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2017] [Accepted: 11/23/2017] [Indexed: 12/12/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract, thought to derive from neoplastic outgrowth of the interstitial cells of Cajal. Building on recent advances in recognition, classification and diagnosis, the past two decades have seen a changing paradigm with molecular diagnostics and targeted therapies. KIT and PDGFRA mutations account for 85-90% of GIST carcinogenesis. However, the remaining 10-15% of GISTs, which until recently were called KIT/PDGFRA wild-type GISTs, have been found to have one of the several mutations, including in the SDHA, B, C, D, BRAF and NF1 genes. Though most of such GISTs are sporadic, a number of families with high incidence rates of GISTs and other associated clinical manifestations have been reported and found to harbor germline mutations in KIT, PDGFRA, SDH subunits and NF1 The goal of this review is to describe the mutations, clinical manifestations and therapeutic implications of syndromic and inherited GISTs in light of recent studies of their clinicopathologic range and pathogenesis.
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Affiliation(s)
- Priya Gopie
- Massey Cancer CenterVCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Lin Mei
- Massey Cancer CenterVCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Anthony C Faber
- Phillips Institute for Oral Health ResearchVCU School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Steven R Grossman
- Massey Cancer CenterVCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Steven C Smith
- Departments of Pathology and SurgeryVCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
| | - Sosipatros A Boikos
- Massey Cancer CenterVCU School of Medicine, Virginia Commonwealth University, Richmond, Virginia, USA
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49
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Mannelli M, Canu L, Ercolino T, Rapizzi E, Martinelli S, Parenti G, De Filpo G, Nesi G. DIAGNOSIS of ENDOCRINE DISEASE: SDHx mutations: beyond pheochromocytomas and paragangliomas. Eur J Endocrinol 2018; 178:R11-R17. [PMID: 28924001 DOI: 10.1530/eje-17-0523] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Revised: 09/06/2017] [Accepted: 09/18/2017] [Indexed: 01/10/2023]
Abstract
Mutations in one of the five genes encoding the succinate dehydrogenase (SDHx) or mitochondrial complex II cause the corresponding family syndromes characterized by the occurrence of pheochromocytomas (PHEO) and paragangliomas (PGL). Recently, other solid growths, such as gastrointestinal stromal tumors (GISTs), renal cell carcinomas (RCCs) and pituitary adenomas (PAs) have been associated with these syndromes. In the absence of prospective studies assessing their frequency, at present, their occurrence seems too infrequent to suggest systematic screening for SDHx mutation carriers. However, SDHB immunohistochemistry (IHC) on tumor tissues or SDHx genetic testing on blood or tumor samples should be performed in patients affected by GISTs, RCCs or PAs with clinicopathologic phenotypes suggesting an etiologic role of SDHx genes.
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Affiliation(s)
| | - Letizia Canu
- Department of Experimental and Clinical Biomedical Sciences
| | | | - Elena Rapizzi
- Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy
| | | | | | | | - Gabriella Nesi
- Department of Surgery and Translational Medicine, University of Florence, Florence, Italy
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50
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Mei L, Smith SC, Faber AC, Trent J, Grossman SR, Stratakis CA, Boikos SA. Gastrointestinal Stromal Tumors: The GIST of Precision Medicine. Trends Cancer 2017; 4:74-91. [PMID: 29413424 DOI: 10.1016/j.trecan.2017.11.006] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2017] [Revised: 11/06/2017] [Accepted: 11/14/2017] [Indexed: 02/07/2023]
Abstract
The discovery of activated KIT mutations in gastrointestinal (GI) stromal tumors (GISTs) in 1998 triggered a sea change in our understanding of these tumors and has ushered in a new paradigm for the use of molecular genetic diagnostics to guide targeted therapies. KIT and PDGFRA mutations account for 85-90% of GISTs; subsequent genetic studies have led to the identification of mutation/epimutation of additional genes, including the succinate dehydrogenase (SDH) subunit A, B, C, and D genes. This review focuses on integrating findings from clinicopathologic, genetic, and epigenetic studies, which classify GISTs into two distinct clusters: an SDH-competent group and an SDH-deficient group. This development is important since it revolutionizes our current management of affected patients and their relatives, fundamentally, based on the GIST genotype.
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Affiliation(s)
- Lin Mei
- VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Steven C Smith
- Departments of Pathology and Surgery, VCU School of Medicine, Richmond, VA, USA
| | - Anthony C Faber
- VCU Phillips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Steven R Grossman
- VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA
| | - Constantine A Stratakis
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, MD, USA
| | - Sosipatros A Boikos
- VCU Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA.
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