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1
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Savad S, Modarressi MH, Younesi S, Seifi-Alan M, Samadaian N, Masoomy M, Dianatpour M, Norouzi S, Amidi S, Boroumand A, Ashrafi MR, Ronagh A, Eslami M, Hashemnejad M, Nourian S, Mohammadi S, Taheri Amin MM, Heidari M, Seifi-Alan M, Shojaaldini Ardakani H, Aghamahdi F, Khalilian S, Ghafouri-Fard S. A Comprehensive Overview of NF1 Mutations in Iranian Patients. Neuromolecular Med 2024; 26:28. [PMID: 38954284 DOI: 10.1007/s12017-024-08790-5] [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: 03/16/2024] [Accepted: 04/30/2024] [Indexed: 07/04/2024]
Abstract
Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations in the NF1 gene. This disorder shows nearly complete penetrance and high phenotypic variability. We used the whole-exome sequencing technique to identify mutations in 32 NF1 cases from 22 Iranian families. A total of 31 variants, including 30 point mutations and one large deletion, were detected. In eight cases, variants were inherited, while they were sporadic in the remaining. Seven novel variants, including c.5576 T > G, c.6658_6659insC, c.2322dupT, c.92_93insAA, c.4360C > T, c.3814C > T, and c.4565_4566delinsC, were identified. The current study is the largest in terms of the sample size of Iranian NF1 cases with identified mutations. The results can broaden the spectrum of NF1 mutations and facilitate the process of genetic counseling in the affected families.
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Affiliation(s)
| | | | - Sarang Younesi
- Prenatal Screening Department, Nilou Laboratory, Tehran, Iran
| | - Mahnaz Seifi-Alan
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | | | - Mona Masoomy
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Mehdi Dianatpour
- Stem Cell and Transgenic Technology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Human Genetic, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | | | | | - Mahmoud Reza Ashrafi
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Ronagh
- Department of Pediatrics Neurologists, Shahid Bahonar Hospital, Alborz University of Medical Sciences, Karaj, Iran
| | - Maryam Eslami
- Applied Biotechnology Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- Department of Genetics, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
| | - Maryam Hashemnejad
- Department of Obstetrics and Gynecology, School of Medicine, Kamali Hospital, Alborz University of Medical Sciences, Karaj, Iran
| | - Shahab Nourian
- Department of Pediatrics Endocrinology and Metabolisms, Emam Ali Hospital, Alborz University of Medical Sciences and Health Services, Karaj, Iran
| | - Sanaz Mohammadi
- Comprehensive Medical Genetics Center, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | | | - Morteza Heidari
- Pediatric Neurology Division, Children's Medical Center, Pediatrics Center of Excellence, Ataxia Clinic, Tehran University of Medical Sciences, Tehran, Iran
| | - Mahin Seifi-Alan
- Cardiovascular Research Center, Alborz University of Medical Sciences, Karaj, Iran
| | | | - Fatemeh Aghamahdi
- Department of Pediatrics, Alborz University of Medical Sciences, Karaj, Iran
| | - Sheyda Khalilian
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soudeh Ghafouri-Fard
- Department of Medical Genetics, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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2
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Nagano H, Ohyama S, Sato A, Igarashi J, Yamamoto T, Kadoya M, Kobayashi M. Jejunal gastrointestinal stromal tumor that developed in a patient with neurofibromatosis type 1: a case report. Diagn Pathol 2023; 18:110. [PMID: 37789344 PMCID: PMC10546696 DOI: 10.1186/s13000-023-01398-6] [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: 08/14/2023] [Accepted: 09/28/2023] [Indexed: 10/05/2023] Open
Abstract
BACKGROUND Neurofibromatosis type 1 (NF1) is known to be associated with the frequent occurrence of unique gastrointestinal stromal tumors (GISTs), preferably occurring in the small intestine, with no mutations in the c-kit proto-oncogene or platelet-derived growth factor receptor-alpha (PDGFRA), with a high tendency for multifocal development, indolent nature, with low proliferation activity and favorable prognosis. CASE PRESENTATION A woman in her forties visited her local doctor complaining of menstrual pain; a large mass was detected in her lower abdomen, and she was referred to our hospital. The patient had hundreds of skin warts and café au lait spots. The patient's mother had been diagnosed with type 1 neurofibromatosis. The patient met the diagnostic criteria for NF1 and was diagnosed with NF1. Ultrasonography showed a large heterogeneous cystic mass with various echo patterns, solid compartments and multiple septations. Magnetic resonance imaging showed a multilocular cystic mass with liquid content exhibiting various intensities, including that of blood. A small round solid mass was also observed close to the cystic tumor. Contrast-enhanced computed tomography showed that the round solid mass showed strong enhancement in the early phase, unlike the cystic tumor component. Open laparotomy revealed a multicystic exophytic tumor measuring 11.5 cm originating from the jejunal wall, 20 cm distal to the duodenojejunal flexure. A solid tumor measuring 2.1 cm was also found on the anal side of the large tumor. We resected the short segment of the jejunum, including the two lesions. Microscopic findings revealed that the cystic and solid tumors consisted of spindle-shaped tumor cells showing little atypia with a fascicular or bundle arrangement. Nuclear mitosis was scarce. Immunostaining of the tumor cells showed positive staining for KIT and DOG1 and negative staining for S100 and desmin. The NF1 patient was diagnosed with multiple GISTs accompanied by intratumoral hemorrhagic denaturation arising from the jejunum. The TNM staging was pT4N0M0, stage IIIA. CONCLUSION We report a case of GISTs associated with NF1 that showed a jejunal origin, multifocal development and few mitotic figures. The recurrence risk, survival prognosis and need for adjuvant chemotherapy, particularly in cases where the initial GIST exhibits a very indolent pathology in NF1-related GISTs, remain to be elucidated.
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Affiliation(s)
- Hideki Nagano
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan.
| | - Shigekazu Ohyama
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Atsushi Sato
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Jun Igarashi
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Tomoko Yamamoto
- Department of Surgery, Marunouchi Hospital, 1-7-45, Nagisa Matsumoto, Nagano, 390-0841, Japan
| | - Masumi Kadoya
- Department of Radiology, Marunouchi Hospital, Matsumoto Nagano, Japan
| | - Mikiko Kobayashi
- Department of Pathology, Marunouchi Hospital, Matsumoto Nagano, Japan
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Serrano C, Martín-Broto J, Asencio-Pascual JM, López-Guerrero JA, Rubió-Casadevall J, Bagué S, García-del-Muro X, Fernández-Hernández JÁ, Herrero L, López-Pousa A, Poveda A, Martínez-Marín V. 2023 GEIS Guidelines for gastrointestinal stromal tumors. Ther Adv Med Oncol 2023; 15:17588359231192388. [PMID: 37655207 PMCID: PMC10467260 DOI: 10.1177/17588359231192388] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 07/19/2023] [Indexed: 09/02/2023] Open
Abstract
Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. GIST spans a wide clinical spectrum that ranges from tumors with essentially no metastatic potential to malignant and life-threatening spread diseases. Gain-of-function mutations in KIT or PDGFRA receptor tyrosine kinases are the crucial drivers of most GISTs, responsible for tumor initiation and evolution throughout the entire course of the disease. The introduction of tyrosine kinase inhibitors targeting these receptors has substantially improved the outcomes in this formerly chemoresistant cancer. As of today, five agents hold regulatory approval for the treatment of GIST: imatinib, sunitinib, regorafenib, ripretinib, and avapritinib. This, in turn, represents a success for a rare neoplasm. During the past two decades, GIST has become a paradigmatic model in cancer for multidisciplinary work, given the disease-specific particularities regarding tumor biology and tumor evolution. Herein, we review currently available evidence for the management of GIST. This clinical practice guideline has been developed by a multidisciplinary expert panel (oncologist, pathologist, surgeon, molecular biologist, radiologist, and representative of patients' advocacy groups) from the Spanish Group for Sarcoma Research, and it is conceived to provide, from a critical perspective, the standard approach for diagnosis, treatment, and follow-up.
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Affiliation(s)
- César Serrano
- Sarcoma Translational Research Group, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron University Hospital, Vall d’Hebron Barcelona Hospital Campus, Carrer de Natzaret, 115-117, Barcelona 08035, Spain
| | - Javier Martín-Broto
- Medical Oncology Department, Fundación Jimenez Diaz University Hospital, Madrid, Spain
- University Hospital General de Villalba, Madrid, Spain Instituto de investigación Sanitaria Fundación Jimenez Diaz (IIS/FJD; UAM), Madrid, Spain
| | - José Manuel Asencio-Pascual
- Department of General Surgery, Gregorio Marañón University Hospital, Madrid, Spain
- Department of Surgery, Universidad Complutense de Madrid, Madrid, Spain
| | | | - Jordi Rubió-Casadevall
- Department of Medical Oncology, Catalan Institute of Oncology, Girona Biomedical Research Institute (IDIBGI), Girona, Spain
| | - Silvia Bagué
- Department of Pathology, Santa Creu i Sant Pau University Hospital, Barcelona, Spain
| | - Xavier García-del-Muro
- Department of Medical Oncology, Institut Català d’Oncologia, IDIBELL and University of Barcelona, Barcelona, Spain
| | | | - Luís Herrero
- GIST advocacy group – Colectivo GIST, Valladolid, Spain
| | - Antonio López-Pousa
- Department of Pathology, Santa Creu i Sant Pau University Hospital, Barcelona, Spain
| | - Andrés Poveda
- Initia Oncologia, Hospital Quironsalud, Valencia, Spain
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Tang Y, Gutmann DH. Neurofibromatosis Type 1-Associated Optic Pathway Gliomas: Current Challenges and Future Prospects. Cancer Manag Res 2023; 15:667-681. [PMID: 37465080 PMCID: PMC10351533 DOI: 10.2147/cmar.s362678] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 06/06/2023] [Indexed: 07/20/2023] Open
Abstract
Optic pathway glioma (OPG) occurs in as many as one-fifth of individuals with the neurofibromatosis type 1 (NF1) cancer predisposition syndrome. Generally considered low-grade and slow growing, many children with NF1-OPGs remain asymptomatic. However, due to their location within the optic pathway, ~20-30% of those harboring NF1-OPGs will experience symptoms, including progressive vision loss, proptosis, diplopia, and precocious puberty. While treatment with conventional chemotherapy is largely effective at attenuating tumor growth, it is not clear whether there is much long-term recovery of visual function. Additionally, because these tumors predominantly affect young children, there are unique challenges to NF1-OPG diagnosis, monitoring, and longitudinal management. Over the past two decades, the employment of authenticated genetically engineered Nf1-OPG mouse models have provided key insights into the function of the NF1 protein, neurofibromin, as well as the molecular and cellular pathways that contribute to optic gliomagenesis. Findings from these studies have resulted in the identification of new molecular targets whose inhibition blocks murine Nf1-OPG growth in preclinical studies. Some of these promising compounds have now entered into early clinical trials. Future research focused on defining the determinants that underlie optic glioma initiation, expansion, and tumor-induced optic nerve injury will pave the way to personalized risk assessment strategies, improved tumor monitoring, and optimized treatment plans for children with NF1-OPG.
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Affiliation(s)
- Yunshuo Tang
- Department of Ophthalmology, Washington University School of Medicine, St. Louis, MO, USA
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
| | - David H Gutmann
- Department of Neurology, Washington University School of Medicine, St. Louis, MO, USA
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Masucci MT, Motti ML, Minopoli M, Di Carluccio G, Carriero MV. Emerging Targeted Therapeutic Strategies to Overcome Imatinib Resistance of Gastrointestinal Stromal Tumors. Int J Mol Sci 2023; 24:6026. [PMID: 37046997 PMCID: PMC10094678 DOI: 10.3390/ijms24076026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2023] [Revised: 03/17/2023] [Accepted: 03/19/2023] [Indexed: 04/14/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common malignant mesenchymal neoplasms of the gastrointestinal tract. The gold standard for the diagnosis of GISTs is morphologic analysis with an immunohistochemical evaluation plus genomic profiling to assess the mutational status of lesions. The majority of GISTs are driven by gain-of-function mutations in the proto-oncogene c-KIT encoding the tyrosine kinase receptor (TKR) known as KIT and in the platelet-derived growth factor-alpha receptor (PDGFRA) genes. Approved therapeutics are orally available as tyrosine kinase inhibitors (TKIs) targeting KIT and/or PDGFRA oncogenic activation. Among these, imatinib has changed the management of patients with unresectable or metastatic GISTs, improving their survival time and delaying disease progression. Nevertheless, the majority of patients with GISTs experience disease progression after 2-3 years of imatinib therapy due to the development of secondary KIT mutations. Today, based on the identification of new driving oncogenic mutations, targeted therapy and precision medicine are regarded as the new frontiers for GISTs. This article reviews the most important mutations in GISTs and highlights their importance in the current understanding and treatment options of GISTs, with an emphasis on the most recent clinical trials.
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Affiliation(s)
- Maria Teresa Masucci
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
| | - Maria Letizia Motti
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
- Department of Movement Sciences and Wellbeing, University “Parthenope”, 80133 Naples, Italy
| | - Michele Minopoli
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
| | - Gioconda Di Carluccio
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
| | - Maria Vincenza Carriero
- Preclinical Models of Tumor Progression Unit, Istituto Nazionale Tumori IRCCS ‘Fondazione G. Pascale’, 80131 Naples, Italy
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6
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Unk M, Jezeršek Novaković B, Novaković S. Molecular Mechanisms of Gastrointestinal Stromal Tumors and Their Impact on Systemic Therapy Decision. Cancers (Basel) 2023; 15:1498. [PMID: 36900287 PMCID: PMC10001062 DOI: 10.3390/cancers15051498] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2023] [Revised: 02/23/2023] [Accepted: 02/24/2023] [Indexed: 03/08/2023] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are soft tissue sarcomas that mostly derive from Cajal cell precursors. They are by far the most common soft tissue sarcomas. Clinically, they present as gastrointestinal malignancies, most often with bleeding, pain, or intestinal obstruction. They are identified using characteristic immunohistochemical staining for CD117 and DOG1. Improved understanding of the molecular biology of these tumors and identification of oncogenic drivers have altered the systemic treatment of primarily disseminated disease, which is becoming increasingly complex. Gain-of-function mutations in KIT or PDGFRA genes represent the driving mutations in more than 90% of all GISTs. These patients exhibit good responses to targeted therapy with tyrosine kinase inhibitors (TKIs). Gastrointestinal stromal tumors lacking the KIT/PDGFRA mutations, however, represent distinct clinico-pathological entities with diverse molecular mechanisms of oncogenesis. In these patients, therapy with TKIs is hardly ever as effective as for KIT/PDGFRA-mutated GISTs. This review provides an outline of current diagnostics aimed at identifying clinically relevant driver alterations and a comprehensive summary of current treatments with targeted therapies for patients with GISTs in both adjuvant and metastatic settings. The role of molecular testing and the selection of the optimal targeted therapy according to the identified oncogenic driver are reviewed and some future directions are proposed.
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Affiliation(s)
- Mojca Unk
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
- Division of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia
| | - Barbara Jezeršek Novaković
- Faculty of Medicine, University of Ljubljana, Vrazov trg 2, 1000 Ljubljana, Slovenia
- Division of Medical Oncology, Institute of Oncology Ljubljana, Zaloška 2, 1000 Ljubljana, Slovenia
| | - Srdjan Novaković
- Department of Molecular Diagnostics, Institute of Oncology Ljubljana, 1000 Ljubljana, Slovenia
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7
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Muacevic A, Adler JR, Kananeh S, Aldookhi A. A Rare Association Between Gastrointestinal Stromal Tumor and Neurofibromatosis Type 1: A Case Report. Cureus 2023; 15:e34148. [PMID: 36843795 PMCID: PMC9949750 DOI: 10.7759/cureus.34148] [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] [Accepted: 01/23/2023] [Indexed: 01/26/2023] Open
Abstract
The association between gastrointestinal stromal tumor (GIST) and neurofibromatosis type 1 (NF1) has been documented in medical literature but remains rare. We report a 53-year-old male patient who was investigated extensively for months for lower gastrointestinal tract (GIT) bleeding that remained obscure despite upper and lower endoscopies as well as a barium follow-through. His past medical history is significant for NF1 with numerous cutaneous neurofibromas as well as café au lait spots and bilateral functional pheochromocytoma status post-bilateral adrenalectomy. However, the progression of his bleeding as well as iron deficiency anemia prompted more aggressive investigations. These have revealed a small bowel mass that proved to be GIST on histological and immunohistochemical staining examination. This case helps remind clinicians of the important association between NF1 and GIST, and the clinical pearl that most GISTs in NF1 are located in the small intestine and may not be apparent on endoscopy with barium follow-through and require push enteroscopy to allow for better localization.
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Affiliation(s)
| | - John R Adler
- Internal Medicine, Capital Health Regional Medical Center, Trenton, USA
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8
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Zhang W, Hu X, Chen Z, Lai C. Case report: Neurofibromatosis type 1 gastrointestinal stromal tumor and small bowel adenocarcinoma with a novel germline NF1 frameshift mutation. Front Oncol 2022; 12:1052799. [PMID: 36620543 PMCID: PMC9815498 DOI: 10.3389/fonc.2022.1052799] [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: 09/24/2022] [Accepted: 12/08/2022] [Indexed: 12/24/2022] Open
Abstract
A synchronous case of small bowel adenocarcinoma(SAB) is reported, accompanied with gastrointestinal stromal tumor(GIST),and gangliocytomain in an elderly woman with neurofibromatosis type 1 (NF-1). A 67-year-old female was hospitalized with the chief complaint of abdominal pain, the computed tomography scan indicated a large bowel mass. Multiple tumors were found in the small intestine, through which two larger tumors (7 cm and 1.5 cm) were resected. A novel germline NF1 mutation and a PMS2 mutation were identified after genetic testing, followed by the exploration of possible relationship between them in promoting tumorigenesis. Our results suggest multiple gastrointestinal tumors emerging in NF1 patients, and genetic testing can better guide postoperative treatment in a more efficient way.
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Affiliation(s)
- Wuming Zhang
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China,Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital of Central South University, Changsha, Hunan, China,International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xianqin Hu
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China,Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital of Central South University, Changsha, Hunan, China,International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Zhikang Chen
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China,Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital of Central South University, Changsha, Hunan, China,International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Chen Lai
- Department of General Surgery, Xiangya Hospital of Central South University, Changsha, Hunan, China,Hunan Key Laboratory of Precise Diagnosis and Treatment of Gastrointestinal Tumor, Xiangya Hospital of Central South University, Changsha, Hunan, China,International Joint Research Center of Minimally Invasive Endoscopic Technology Equipment & Standardization, Xiangya Hospital of Central South University, Changsha, Hunan, China,*Correspondence: Chen Lai,
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9
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Gunawardene A, Fischer J. Obscure gastrointestinal bleeding in a patient with neurofibromatosis type 1. ANZ J Surg 2022; 92:3105-3106. [PMID: 35212097 PMCID: PMC9790566 DOI: 10.1111/ans.17573] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 02/08/2022] [Accepted: 02/09/2022] [Indexed: 12/30/2022]
Affiliation(s)
- Ashok Gunawardene
- Department of General SurgeryWaikato District Health BoardHamiltonNew Zealand,Department of SurgeryUniversity of AucklandAucklandNew Zealand
| | - Jesse Fischer
- Department of General SurgeryWaikato District Health BoardHamiltonNew Zealand,Department of SurgeryUniversity of AucklandAucklandNew Zealand
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von Mehren M, Kane JM, Riedel RF, Sicklick JK, Pollack SM, Agulnik M, Bui MM, Carr-Ascher J, Choy E, Connelly M, Dry S, Ganjoo KN, Gonzalez RJ, Holder A, Homsi J, Keedy V, Kelly CM, Kim E, Liebner D, McCarter M, McGarry SV, Mesko NW, Meyer C, Pappo AS, Parkes AM, Petersen IA, Poppe M, Schuetze S, Shabason J, Spraker MB, Zimel M, Bergman MA, Sundar H, Hang LE. NCCN Guidelines® Insights: Gastrointestinal Stromal Tumors, Version 2.2022. J Natl Compr Canc Netw 2022; 20:1204-1214. [PMID: 36351335 PMCID: PMC10245542 DOI: 10.6004/jnccn.2022.0058] [Citation(s) in RCA: 49] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
Abstract
Gastrointestinal stromal tumors (GIST) are the most common type of soft tissue sarcoma that occur throughout the gastrointestinal tract. Most of these tumors are caused by oncogenic activating mutations in the KIT or PDGFRA genes. The NCCN Guidelines for GIST provide recommendations for the diagnosis, evaluation, treatment, and follow-up of patients with these tumors. These NCCN Guidelines Insights summarize the panel discussion behind recent important updates to the guidelines, including revised systemic therapy options for unresectable, progressive, or metastatic GIST based on mutational status, and updated recommendations for the management of GIST that develop resistance to specific tyrosine kinase inhibitors.
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Affiliation(s)
| | | | | | | | - Seth M Pollack
- 5Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | - Edwin Choy
- 9Massachusetts General Hospital Cancer Center
| | - Mary Connelly
- 10The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | - Sarah Dry
- 11UCLA Jonsson Comprehensive Cancer Center
| | | | | | | | - Jade Homsi
- 14UT Southwestern Simmons Comprehensive Cancer Center
| | | | | | | | - David Liebner
- 10The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | - Nathan W Mesko
- 20Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | - Christian Meyer
- 21The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | - Alberto S Pappo
- 22St. Jude Children's Research Hospital/University of Tennessee Health Science Center
| | | | | | - Matthew Poppe
- 25Huntsman Cancer Institute at the University of Utah
| | | | - Jacob Shabason
- 27Abramson Cancer Center at the University of Pennsylvania
| | - Matthew B Spraker
- 28Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | - Melissa Zimel
- 29UCSF Helen Diller Family Comprehensive Cancer Center; and
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11
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Inoue A, Ota S, Yamasaki M, Batsaikhan B, Furukawa A, Watanabe Y. Gastrointestinal stromal tumors: a comprehensive radiological review. Jpn J Radiol 2022; 40:1105-1120. [PMID: 35809209 DOI: 10.1007/s11604-022-01305-x] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2022] [Accepted: 06/08/2022] [Indexed: 11/29/2022]
Abstract
Gastrointestinal stromal tumors (GISTs) originating from the interstitial cells of Cajal in the muscularis propria are the most common mesenchymal tumor of the gastrointestinal tract. Multiple modalities, including computed tomography (CT), magnetic resonance imaging (MRI), fluorodeoxyglucose positron emission tomography, ultrasonography, digital subtraction angiography, and endoscopy, have been performed to evaluate GISTs. CT is most frequently used for diagnosis, staging, surveillance, and response monitoring during molecularly targeted therapy in clinical practice. The diagnosis of GISTs is sometimes challenging because of the diverse imaging findings, such as anatomical location (esophagus, stomach, duodenum, small bowel, colorectum, appendix, and peritoneum), growth pattern, and enhancement pattern as well as the presence of necrosis, calcification, ulceration, early venous return, and metastasis. Imaging findings of GISTs treated with antineoplastic agents are quite different from those of other neoplasms (e.g. adenocarcinomas) because only subtle changes in size are seen even in responsive lesions. Furthermore, the recurrence pattern of GISTs is different from that of other neoplasms. This review discusses the advantages and disadvantages of each imaging modality, describes imaging findings obtained before and after treatment, presents a few cases of complicated GISTs, and discusses recent investigations performed using CT and MRI to predict histological risk grade, gene mutations, and patient outcomes.
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Affiliation(s)
- Akitoshi Inoue
- Department of Radiology, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan. .,Department of Radiology, Mayo Clinic, Rochester, MN, USA.
| | - Shinichi Ota
- Department of Radiology, Nagahama Red Cross Hospital, Shiga, Japan
| | - Michio Yamasaki
- Department of Radiology, Kohka Public Hospital, Shiga, Japan
| | - Bolorkhand Batsaikhan
- Graduate School of Human Health Sciences, Department of Radiological Science, Tokyo Metropolitan University, Tokyo, Japan
| | - Akira Furukawa
- Graduate School of Human Health Sciences, Department of Radiological Science, Tokyo Metropolitan University, Tokyo, Japan
| | - Yoshiyuki Watanabe
- Department of Radiology, Shiga University of Medical Science, Seta, Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan
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Klug LR, Khosroyani HM, Kent JD, Heinrich MC. New treatment strategies for advanced-stage gastrointestinal stromal tumours. Nat Rev Clin Oncol 2022; 19:328-341. [PMID: 35217782 PMCID: PMC11488293 DOI: 10.1038/s41571-022-00606-4] [Citation(s) in RCA: 70] [Impact Index Per Article: 23.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/08/2022] [Indexed: 02/06/2023]
Abstract
When gastrointestinal stromal tumour (GIST), the most common form of sarcoma, was first recognized as a distinct pathological entity in the 1990s, patients with advanced-stage disease had a very poor prognosis owing to a lack of effective medical therapies. The discovery of KIT mutations as the first and most prevalent drivers of GIST and the subsequent development of the first KIT tyrosine kinase inhibitor (TKI), imatinib, revolutionized the treatment of patients with this disease. We can now identify the driver mutation in 99% of patients with GIST via molecular diagnostic testing, and therapies have been developed to treat many, but not all, molecular subtypes of the disease. At present, seven drugs are approved by the FDA for the treatment of advanced-stage GIST (imatinib, sunitinib, regorafenib, ripretinib, avapritinib, larotrectinib and entrectinib), all of which are TKIs. Although these agents can be very effective for treating certain GIST subtypes, challenges remain and new therapeutic approaches are needed. In this Review, we discuss the molecular subtypes of GIST and the evolution of current treatments, as well as their therapeutic limitations. We also highlight emerging therapeutic approaches that might overcome clinical challenges through novel strategies predicated on the biological features of the distinct GIST molecular subtypes.
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Affiliation(s)
- Lillian R Klug
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Homma M Khosroyani
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Jason D Kent
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Michael C Heinrich
- Portland VA Health Care System and Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
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13
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Giant composite pheochromocytoma and gastrointestinal stromal tumor in a patient with neurofibromatosis: A case report. North Clin Istanb 2022; 8:629-633. [PMID: 35284800 PMCID: PMC8848499 DOI: 10.14744/nci.2020.37431] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2020] [Indexed: 12/14/2022] Open
Abstract
A 54-year-old male was admitted to our department with neurofibromatosis and hypertension. During his examination, a mass was detected in the abdomen, and he was transferred to a surgical clinic. At the first examination of the patient, extensive café-au-lait spots and granulomas were detected on the body and the mass occupying right abdomen quadrant was palpable. The patient’s medical history indicated that he had hypertension for almost a decade. The patient also stated that nodules on the body existed from his earliest recollection and he had relatives with neurofibromatosis. The patient was taken to a surgical operation. A mass with 30×23 cm in size was removed. The area of the nodular structure, with 0.5 cm in diameter, in the stomach serosa was also removed. The tumor was composed of phaeochromocytoma in the larger spaces and ganglioneuromas in the relatively narrow spaces. The nodular area removed in gastric serosa was reported as a very low-risk gastrointestinal stromal tumor. Apart from this rare combination, adrenal mass removed from the patient was considerably larger than the masses in the literature until now. Therefore, we aimed to present this rare case with a literature background.
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14
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Torrence D, Xie Z, Zhang L, Chi P, Antonescu CR. Gastrointestinal stromal tumors with BRAF gene fusions. A report of two cases showing low or absent KIT expression resulting in diagnostic pitfalls. Genes Chromosomes Cancer 2021; 60:789-795. [PMID: 34398495 DOI: 10.1002/gcc.22991] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 08/12/2021] [Accepted: 08/13/2021] [Indexed: 01/02/2023] Open
Abstract
Although most gastrointestinal stromal tumors (GISTs) exhibit activating mutations in either KIT or PDGFRA, rare cases have shown to be driven by gene fusions involving kinases, mainly involving NTRK3, and rarely BRAF or FGFR1. BRAF gene rearrangements have been described in only two patients to date, as separate case reports. In addition, BRAF V600E mutation is an uncommon but established oncogenic pathway in GIST. In this report, we describe two new GIST cases harboring novel BRAF fusion genes, arising in two young-adult women (37 and 40 years of age) in the small bowel and distal esophagus, both with a spindle cell phenotype. The small bowel GIST measured 2.8 cm and showed a high cellularity and a mitotic rate of 20/50 HPFs, while the esophageal lesion measured 7 cm and 1/50 HPFs. Immunohistochemically, both tumors showed diffuse reactivity for DOG1, while KIT/CD117 was weakly positive in the small bowel GIST and completely negative in the esophageal tumor. Based on these findings, the latter case was misinterpreted as a low-grade myxoid leiomyosarcoma, as it showed a myxoid stroma, reactivity for SMA and focal positivity for desmin. Archer FusionPlex revealed a fusion between BRAF with either AGAP3 or MKRN1 gene partners. Moreover, MSK-IMPACT DNA targeted sequencing confirmed both fusions but did not identify additional mutations. In one case with available material, the BRAF gene rearrangement was also validated by FISH. The recognition of BRAF fusion-positive GISTs is critical as it may be associated with a low level of KIT expression and may result in diagnostic challenges with significant impact on therapeutic management. The clinical benefit with KIT inhibitors, such as imatinib, remains to be determined.
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Affiliation(s)
- Dianne Torrence
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ziyu Xie
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Lei Zhang
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
| | - Ping Chi
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.,Department of Medicine, Weill Cornell Medical College, New York, New York, USA
| | - Cristina R Antonescu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York, USA
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15
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Mishra A, Gyawali S, Kharel S, Mishra A, Pathak N, Subedi N, Gaire P. Multiple jejunal gastrointestinal stromal tumors and Neurofibromatosis type 1: A rare association. Int J Surg Case Rep 2021; 85:106178. [PMID: 34274754 PMCID: PMC8319367 DOI: 10.1016/j.ijscr.2021.106178] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 07/04/2021] [Accepted: 07/06/2021] [Indexed: 11/17/2022] Open
Abstract
INTRODUCTION AND IMPORTANCE The association between gastrointestinal stromal tumor (GIST), mesenchymal tumor arising from the interstitial cells of cajal and Neurofibromatosis type 1 (NF1), an autosomal dominant disease has been reported in the literature. GIST in NF1 patients are multiple and located in the small intestine. Tumorigenesis in NF1 associated GIST is different to that of sporadic GIST and hence the treatment. Here we report a rare case of an NF1 patient with multiple jejunal GISTs. CASE PRESENTATION We here present a rare case of a 57-year-old male diagnosed with NF1 30 years back, presented in our emergency department with complaints of black, tarry stools later diagnosed to have multiple GIST in jejunum. Contrast enhanced computed tomography (CECT) of the abdomen showed a large 10.1 × 7.33 × 6.2 cm heterogeneous, exophytic, solid mass with cystic areas originating from the jejunum. The microscopic examination of the specimen showed spindle shaped tumor cells while immunohistochemistry showed CD117 (c-KIT) and DOG-1 positivity. The primary treatment was complete surgical excision of the tumor. CLINICAL DISCUSSION The incidence of GISTs in NF1 patient is around 6-7%; however, concomitant presence of multiple GISTs is rare. CECT of abdomen along with histopathological and immunohistochemistry studies are diagnostic. The management of GIST includes surgical and adjuvant therapy methods based on the tumorigenesis and recurrent risk stratification. CONCLUSION Early clinical suspicion and imaging aids in early detection of the tumor in patients with NF1 presenting with gastrointestinal symptoms. Postoperatively, screening for recurrence with radiology is of utmost importance.
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Affiliation(s)
- Aakash Mishra
- Kathmandu Medical College Teaching Hospital, Kathmandu, Nepal.
| | - Sandesh Gyawali
- Department of General Surgery, National Academy of Medical Sciences, Bir Hospital, Kathmandu, Nepal
| | - Sanjeev Kharel
- Maharajgunj Medical Campus, Institute of Medicine, Maharajgunj, Kathmandu, Nepal.
| | - Aman Mishra
- Maharajgunj Medical Campus, Institute of Medicine, Maharajgunj, Kathmandu, Nepal.
| | - Nibesh Pathak
- Maharajgunj Medical Campus, Institute of Medicine, Maharajgunj, Kathmandu, Nepal.
| | - Nirajan Subedi
- Department of GI and General Surgery, Maharajgunj Medical Campus, Institute of Medicine, Kathmandu, Nepal
| | - Prabin Gaire
- Department of Pathology, Maharajgunj Medical Campus, Institute of Medicine, Kathmandu, Nepal
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16
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Vargas Ávila AL, Jiménez Leyva A, Vargas Flores J, Reyes Garcia VG, de Alba Cruz I, Narváez González HF, Galicia Gómez TDJ. GIST associated with von recklinghausen disease: Report of two cases and review of literature. Ann Med Surg (Lond) 2021; 62:365-368. [PMID: 33552495 PMCID: PMC7848713 DOI: 10.1016/j.amsu.2021.01.033] [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: 12/12/2020] [Revised: 01/11/2021] [Accepted: 01/12/2021] [Indexed: 11/01/2022] Open
Abstract
INTRODUCTION AND IMPORTANCE Neurofibromatosis type 1 (NF1), or Von Recklinghausen's disease, is an autosomal dominant condition that affects the central nervous system. Gastrointestinal stromal tumor (GIST) refers to non-epithelial tumors of the gastrointestinal tract lacking smooth muscle structural features and schwann cell immunohistochemical characteristics. The risk of patients with NF1 to develop a GIST is 7%. CASE PRESENTATION GIST is a soft tissue sarcoma that probably arises from the interstitial Cajal cells of the intestine. GIST associated with NF1 syndrome appears to have a distinct phenotype, occurring in younger patients compared to sporadic GIST. CLINICAL DISCUSSION The clinical presentation can be highly variable, the association of gastrointestinal tumors associated with Von Recklinghausen's disease is up to 7%, postoperative treatment with imatinib is reserved for patients with a high risk of recurrence. CONCLUSION The treatment of primary GIST is complete surgical resection with free microscopic margins and an intact pseudocapsule.
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Affiliation(s)
- Arcenio Luis Vargas Ávila
- Department of Surgery, Hospital Regional “General Ignacio Zaragoza” ISSSTE, Ciudad de México, México
| | - Amador Jiménez Leyva
- Department of Surgery, Hospital Regional “General Ignacio Zaragoza” ISSSTE, Ciudad de México, México
| | - Julián Vargas Flores
- Department of Surgery, Hospital Regional “General Ignacio Zaragoza” ISSSTE, Ciudad de México, México
| | | | - Israel de Alba Cruz
- Department of Surgery, Hospital Regional “General Ignacio Zaragoza” ISSSTE, Ciudad de México, México
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17
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Li C, Yang KL, Wang Q, Tian JH, Li Y, Gao ZD, Yang XD, Ye YJ, Jiang KW. Clinical features of multiple gastrointestinal stromal tumors: A pooling analysis combined with evidence and gap map. World J Gastroenterol 2020; 26:7550-7567. [PMID: 33384554 PMCID: PMC7754550 DOI: 10.3748/wjg.v26.i47.7550] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Revised: 11/09/2020] [Accepted: 11/21/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Multiple gastrointestinal stromal tumors (MGISTs) are a very rare type of gastrointestinal stromal tumor (GIST) and are usually observed in syndrome.
AIM The paper aimed to describe the clinical and oncological features of MGISTs and to offer evidence for the diagnosis and treatment.
METHODS Data of consecutive patients with MGISTs who were diagnosed at Peking University People’s Hospital (PKUPH) from 2008 to 2019 were retrospectively evaluated. Further, a literature search was conducted by retrieving data from PubMed, EMBASE, and the Cochrane library databases from inception up to November 30, 2019.
RESULTS In all, 12 patients were diagnosed with MGISTs at PKUPH, and 43 published records were ultimately included following the literature review. Combined analysis of the whole individual patient data showed that female (59.30%), young (14.45%), and syndromic GIST (63.95%) patients comprised a large proportion of the total patient population. Tumors were mainly located in the small intestine (58.92%), and both CD117 and CD34 were generally positive. After a mean 78.32-mo follow-up, the estimated median overall survival duration (11.5 years) was similar to single GISTs, but recurrence-free survival was relatively poorer.
CONCLUSION The clinical and oncological features are potentially different between MGISTs and single GIST. Further studies are needed to explore appropriate surgical approach and adjuvant therapy.
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Affiliation(s)
- Chen Li
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Ke-Lu Yang
- Evidence-Based Nursing Center, School of Nursing, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Quan Wang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Jin-Hui Tian
- Evidence Based Medicine Center, School of Basic Medical Science of Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Yang Li
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Zhi-Dong Gao
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Xiao-Dong Yang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Ying-Jiang Ye
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
| | - Ke-Wei Jiang
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing 100044, China
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18
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Vanden Bempt I, Vander Borght S, Sciot R, Spans L, Claerhout S, Brems H, Lehnert S, Dehaspe L, Fransis S, Neuville B, Topal B, Schöffski P, Legius E, Debiec-Rychter M. Comprehensive targeted next-generation sequencing approach in the molecular diagnosis of gastrointestinal stromal tumor. Genes Chromosomes Cancer 2020; 60:239-249. [PMID: 33258138 DOI: 10.1002/gcc.22923] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2020] [Revised: 11/25/2020] [Accepted: 11/28/2020] [Indexed: 12/26/2022] Open
Abstract
Mutational analysis guides therapeutic decision making in patients with advanced-stage gastrointestinal stromal tumors (GISTs). We evaluated three targeted next-generation sequencing (NGS) assays, consecutively used over 4 years in our laboratory for mutational analysis of 162 primary GISTs: Agilent GIST MASTR, Illumina TruSight 26 and an in-house developed 96 gene panels. In addition, we investigated the feasibility of a more comprehensive approach by adding targeted RNA sequencing (Archer FusionPlex, 11 genes) in an attempt to reduce the number of Wild Type GISTs. We found KIT or PDGFRA mutations in 149 out of 162 GISTs (92.0%). Challenging KIT exon 11 alterations were initially missed by different assays in seven GISTs and typically represented deletions at the KIT intron 10-exon 11 boundary or large insertions/deletions (>24 base pairs). Comprehensive analysis led to the additional identification of driver alterations in 8/162 GISTs (4.9%): apart from BRAF and SDHA mutations (one case each), we found five GISTs harboring somatic neurofibromatosis type 1 (NF1) alterations (3.1%) and one case with an in-frame TRIM4-BRAF fusion not reported in GIST before. Eventually, no driver alteration was found in two out of 162 GISTs (1.2%) and three samples (1.9%) failed analysis. Our study shows that a comprehensive targeted NGS approach is feasible for routine mutational analysis of GIST, thereby substantially reducing the number of Wild Type GISTs, and highlights the need to optimize assays for challenging KIT exon 11 alterations.
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Affiliation(s)
- Isabelle Vanden Bempt
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Sara Vander Borght
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium.,Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Raf Sciot
- Department of Pathology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Lien Spans
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Sofie Claerhout
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Hilde Brems
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Stefan Lehnert
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Luc Dehaspe
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Sabine Fransis
- Department of Pathology, Ziekenhuis Oost Limburg, Genk, Belgium
| | - Bart Neuville
- Department of Gastroenterology and Hepatology, Ziekenhuis Oost-Limburg, Genk, Belgium
| | - Baki Topal
- Department of Abdominal Surgery, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Patrick Schöffski
- Department of General Medical Oncology, University Hospitals Leuven, Leuven Cancer Institute, and Department of Oncology, KU Leuven, Laboratory of Experimental Oncology, Leuven, Belgium.,Department of Oncology, KU Leuven, Laboratory of Experimental Oncology, Leuven, Belgium
| | - Eric Legius
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
| | - Maria Debiec-Rychter
- Department for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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19
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Vongsumran N, Kongkarnka S, Watanawittawas P, Manosroi W. Pheochromocytoma and gastrointestinal stromal tumours in an adult neurofibromatosis type 1 patient: a rare co-occurrence. BMJ Case Rep 2020; 13:13/6/e235129. [PMID: 32595117 DOI: 10.1136/bcr-2020-235129] [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: 11/03/2022] Open
Abstract
The risk of tumours including pheochromocytoma and gastrointestinal stromal tumour (GIST) has been reported to be higher in neurofibromatosis type 1 (NF1) patients. The concomitant occurrence of these two tumours was rare in NF1 patient and most were symptomatic. In this case report, we describe the case of a 47-year-old man with NF1 who presented with microscopic haematuria. Neither hypertension nor any gastrointestinal symptoms were reported by the patient. While investigating for haematuria, left adrenal mass and arterial enhancing lesions in the small bowel were incidentally documented during computerised urography. The patient subsequently underwent a left adrenalectomy and small bowel resection. The pheochromocytoma and multiple GIST tumours were diagnosed based on pathology. Here, we discuss the rare association of pheochromocytoma and GIST and the asymptomatic presentation of those tumours in an NF1 patient. We further suggest that in NF1 patients a heightened level of vigilance can help identify this infrequent combination.
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Affiliation(s)
- Nuttawut Vongsumran
- Endocrine and Metabolism Unit, Internal Medicine Department, Faculty of Medicine, Chiang Mai University, Muang Chiang Mai, Chiang Mai, Thailand
| | - Sarawut Kongkarnka
- Department of Pathology, Faculty of Medicine, Chiang Mai University, Muang Chiang Mai, Chiang Mai, Thailand
| | - Pittaporn Watanawittawas
- Endocrine and Metabolism Unit, Internal Medicine Department, Faculty of Medicine, Chiang Mai University, Muang Chiang Mai, Chiang Mai, Thailand.,Endocrine and Metabolism Unit, Sriphat Medical Center, Faculty of Medicine, Chiang Mai University, Muang Chiang Mai, Chiang Mai, Thailand
| | - Worapaka Manosroi
- Endocrine and Metabolism Unit, Internal Medicine Department, Faculty of Medicine, Chiang Mai University, Muang Chiang Mai, Chiang Mai, Thailand
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20
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Vankova B, Behenska K, Bauer M, Sedivcova M, Daumova M, Agaimy A, Michal M, Daum O. Morphological features useful in the differential diagnosis between undifferentiated carcinoma and gastrointestinal stromal tumor. Ann Diagn Pathol 2020; 46:151527. [PMID: 32388398 DOI: 10.1016/j.anndiagpath.2020.151527] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Accepted: 04/16/2020] [Indexed: 12/15/2022]
Abstract
Undifferentiated (sarcomatoid) carcinomas may closely mimic gastrointestinal stromal tumors (GISTs) due to possible histological and immunohistochemical overlap between these two entities. To avoid unnecessary employment of a wide spectrum of immunohistochemical stainings and molecular genetics and thus decrease costs, finding simple morphological features to target further investigation of such neoplasms of the gastrointestinal tract would be helpful. Five cases classified as undifferentiated (sarcomatoid) carcinomas with a definite proof of the diagnosis, i. e. the presence of a differentiated carcinomatous component, were retrieved from archives of several institutions. For comparison, 84 cases of GIST mutated in KIT or PDGFRA genes served as the control group. Hematoxylin and eosin stained slides were evaluated for the presence of patterns which might discriminate between sarcomatoid carcinoma and GIST. Lymphatic invasion and entrapment of fat tissue strongly favor the diagnosis of undifferentiated carcinoma, as it was found in all or almost all cases of undifferentiated carcinoma, but in no GIST. Alternation of low- and high- grade areas, formation of angiosarcomatous-like spaces, and the presence of yolk sac-like areas were also detected in all cases of undifferentiated carcinoma, but only in 1.2%, 2.4% and 7.2% of the GISTs, respectively. Furthermore, DOG1 was negative in all cases of undifferentiated carcinoma. According to this study, the presence of the histological findings listed above should prompt extensive tumor sampling in order to find a differentiated carcinomatous component. However, due to the small number of cases of undifferentiated carcinoma available for the study, a larger multi-institutional study is warranted.
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Affiliation(s)
- Bohuslava Vankova
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic; Bioptical Laboratory, Ltd., Plzen, Czech Republic
| | - Kristyna Behenska
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic
| | - Meret Bauer
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic
| | | | - Magdalena Daumova
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic; Bioptical Laboratory, Ltd., Plzen, Czech Republic
| | - Abbas Agaimy
- Institute of Pathology, University Hospital, Friedrich-Alexander University Erlangen-Nürnberg, Erlangen, Germany
| | - Michal Michal
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic
| | - Ondrej Daum
- Sikl's Institute of Pathology, Faculty of Medicine and Teaching Hospital in Plzen, Charles University, Plzen, Czech Republic; Bioptical Laboratory, Ltd., Plzen, Czech Republic.
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21
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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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22
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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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Ylä-Outinen H, Loponen N, Kallionpää RA, Peltonen S, Peltonen J. Intestinal tumors in neurofibromatosis 1 with special reference to fatal gastrointestinal stromal tumors (GIST). Mol Genet Genomic Med 2019; 7:e927. [PMID: 31397088 PMCID: PMC6732307 DOI: 10.1002/mgg3.927] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2019] [Revised: 07/23/2019] [Accepted: 07/26/2019] [Indexed: 12/18/2022] Open
Abstract
Background Type 1 neurofibromatosis (NF1) is a genetic tumor predisposing Rasopathy. NF1 patients have an increased risk for developing benign and malignant tumors, but the occurrence of intestinal tumors has not been investigated at the population level. Methods In this retrospective register‐based total population study, diagnoses of gastrointestinal tract tumors were retrieved from the Finnish Care Register for Health Care for 1,410 NF1 patients and 14,030 reference persons. We also reviewed the death certificates of 232 NF1 patients who died during years 1987–2013, and specifically searched for diagnosis of gastrointestinal stromal tumor (GIST). Results The register analysis revealed an increased overall hazard ratio (HR) of 2.6 (95% CI 1.9–3.6) for intestinal tumors in NF1 compared to general population. The highest HR of 15.6 (95% CI 6.9–35.1) was observed in the small intestine. The focused analysis of NF1 death certificates and GISTs demonstrated that the GIST was the primary cause of death in seven patients. Conclusion This study emphasizes the need for careful evaluation of NF1 patients with gastrointestinal complaints. The challenge in diagnosis is that the tumors preferably occur at the small intestine, which is difficult target for diagnostic procedures. We also show that the NF1 GISTs may lead to fatal outcome despite of benign histopathological findings at the time of the diagnosis.
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Affiliation(s)
- Heli Ylä-Outinen
- Department of Cell Biology and Anatomy, University of Turku, Turku, Finland.,Department of Pulmonary Diseases, Turku University Hospital, Turku, Finland
| | - Niina Loponen
- Department of Cell Biology and Anatomy, University of Turku, Turku, Finland
| | - Roope A Kallionpää
- Department of Cell Biology and Anatomy, University of Turku, Turku, Finland
| | - Sirkku Peltonen
- Department of Dermatology, Turku University Hospital, Turku, Finland
| | - Juha Peltonen
- Department of Cell Biology and Anatomy, University of Turku, Turku, Finland
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Fujimi A, Nagamachi Y, Yamauchi N, Tamura F, Kimura T, Miyajima N, Inomata H, Nishisato T, Yoshida M, Takada K, Kobayashi K, Kato J. Gastrointestinal Stromal Tumor in a Patient with Neurofibromatosis Type 1 That Was Successfully Treated with Regorafenib. Intern Med 2019; 58:1865-1870. [PMID: 30918185 PMCID: PMC6663552 DOI: 10.2169/internalmedicine.2321-18] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 01/07/2019] [Indexed: 12/29/2022] Open
Abstract
An unconscious 55-year-old man with a history of neurofibromatosis type 1 (NF1) was transported to the emergency department and was diagnosed with acute renal failure owing to a large bladder tumor. A submucosal tumor was also identified in the duodenum. The patient was diagnosed with a primary gastrointestinal stromal tumor (GIST) of the bladder and duodenum. After six cycles of regorafenib therapy, 18F-fluorodeoxyglucose accumulation in the duodenal GIST on positron emission tomography-computed tomography (PET-CT) showed a partial metabolic response. Currently, no standard drug therapy for unresectable or relapsed NF1-associated GIST has been established. Regorafenib may thus be considered as and appropriate initial therapy.
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Affiliation(s)
- Akihito Fujimi
- Department of Hematology, Sapporo Kiyota Hospital, Japan
| | | | | | - Fumito Tamura
- Department of Internal Medicine, Sapporo Kiyota Hospital, Japan
| | - Tomohiro Kimura
- Department of Internal Medicine, Sapporo Kiyota Hospital, Japan
| | - Naoya Miyajima
- Department of Internal Medicine, Sapporo Kiyota Hospital, Japan
| | | | | | - Makoto Yoshida
- Department of Medical Oncology, Sapporo Medical University, Japan
| | - Kohichi Takada
- Department of Medical Oncology, Sapporo Medical University, Japan
| | - Ko Kobayashi
- Department of Urology, Sapporo Medical University, Japan
| | - Junji Kato
- Department of Medical Oncology, Sapporo Medical University, Japan
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Thavaraputta S, Graham S, Rivas Mejia AM, Lado-Abeal J. Duodenal somatostatinoma presenting as obstructive jaundice with the coexistence of a gastrointestinal stromal tumour in neurofibromatosis type 1: a case with review of the literature. BMJ Case Rep 2019; 12:12/1/bcr-2018-226702. [PMID: 30635305 DOI: 10.1136/bcr-2018-226702] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Somatostatinomas are rare neuroendocrine tumours, mostly located in the pancreas or duodenum, with an estimated incidence of 1 in 40 million. Duodenal somatostatinomas (DSs) are usually found in association with neurofibromatosis type 1 (NF1), tuberous sclerosis and Von Hippel-Lindau syndrome. Gastrointestinal stromal tumours (GIST) have also been described in NF1, but the association with somatostatinoma is very uncommon. We report the case of a patient with NF1 who presented with obstructive jaundice due to multiple firm nodules around the ampulla of Vater. A pancreaticoduodenectomy was performed and revealed a 1 cm duodenal/ampullary mass which stained positive for somatostatin, together with a GIST also found on the duodenal wall. Despite its rarity, ampullary somatostatinomas should be considered in the differential diagnosis of biliary tract dilation in patients with NF1.
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Affiliation(s)
- Subhanudh Thavaraputta
- Department of Internal Medicine, Texas Tech University Health Sciences Center, Lubbock, Texas, USA
| | - Suzanne Graham
- Department of Pathology, Texas Tech Univeristy Health Sciences Center, Lubbock, Texas, USA
| | - Ana M Rivas Mejia
- Division of Endocrinology, Department of Internal Medicine, Texas Tech University Health Science Center School of Medicine, Lubbock, Texas, USA
| | - Joaquin Lado-Abeal
- Division of Endocrinology, Department of Internal Medicine, Texas Tech University Health Science Center School of Medicine, Lubbock, Texas, USA
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26
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Noë M, Pea A, Luchini C, Felsenstein M, Barbi S, Bhaijee F, Yonescu R, Ning Y, Adsay NV, Zamboni G, Lawlor RT, Scarpa A, Offerhaus GJA, Brosens LAA, Hruban RH, Roberts NJ, Wood LD. Whole-exome sequencing of duodenal neuroendocrine tumors in patients with neurofibromatosis type 1. Mod Pathol 2018; 31:1532-1538. [PMID: 29849115 PMCID: PMC6168403 DOI: 10.1038/s41379-018-0082-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2018] [Revised: 04/30/2018] [Accepted: 05/03/2018] [Indexed: 02/08/2023]
Abstract
Neurofibromatosis type 1 (NF1) is a hereditary cancer predisposition syndrome characterized by frequent cutaneous and nervous system abnormalities. Patients with NF1 also have an increased prevalence of multiple gastrointestinal and peripancreatic neoplasms-neuroendocrine tumors of the ampulla that express somatostatin are particularly characteristic of NF1. In this study, we characterize the genetic alterations of a clinically well-characterized cohort of six NF1-associated duodenal neuroendocrine tumors using whole-exome sequencing. We identified inactivating somatic mutations in the NF1 gene in three of six tumors; the only other gene altered in more than one tumor was IFNB1. Copy number analysis revealed deletion/loss of heterozygosity of chromosome 22 in three of six patients. Analysis of germline variants revealed germline deleterious NF1 variants in four of six patients, as well as deleterious variants in other tumor suppressor genes in two of four patients with deleterious NF1 variants. Taken together, these data confirm the importance of somatic inactivation of the wild-type NF1 allele in the formation of NF1-associated duodenal neuroendocrine tumors and suggest that loss of chromosome 22 is important in at least a subset of cases. However, we did not identify any genes altered in the majority of NF1-associated duodenal neuroendocrine tumors that uniquely characterize the genomic landscape of this tumor. Still, the genetic alterations in these tumors are distinct from sporadic neuroendocrine tumors occurring at these sites, highlighting that unique genetic alterations drive syndromic tumors.
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Affiliation(s)
- Michaël Noë
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA,Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Antonio Pea
- Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA,Department of Surgery, University and Hospital Trust of Verona, Verona, Italy
| | - Claudio Luchini
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA,Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Matthäus Felsenstein
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Stefano Barbi
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy
| | - Feriyl Bhaijee
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Raluca Yonescu
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yi Ning
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | | | - Giuseppe Zamboni
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy,Sacro Cuore Don Calabria Hospital, 37024 Negrar, Verona, Italy
| | - Rita T. Lawlor
- ARC-Net Research Center, University of Verona, Verona, Italy
| | - Aldo Scarpa
- Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy,ARC-Net Research Center, University of Verona, Verona, Italy
| | - G. Johan A. Offerhaus
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Lodewijk A. A. Brosens
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA,Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands,Department of Pathology, Radboud University Medical Center, PO Box 9101, 6500 HB, Nijmegen, The Netherlands
| | - Ralph H. Hruban
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA,Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Nicholas J. Roberts
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA,Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Laura D. Wood
- Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA,Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
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28
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Integrated genetic and epigenetic analysis of myxofibrosarcoma. Nat Commun 2018; 9:2765. [PMID: 30018380 PMCID: PMC6050269 DOI: 10.1038/s41467-018-03891-9] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 03/20/2018] [Indexed: 12/27/2022] Open
Abstract
Myxofibrosarcoma (MFS) is a common adult soft tissue sarcoma characterized by an infiltrative growth pattern and a high local recurrence rate. Here we report the genetic and epigenetic landscape of MFS based on the results of whole-exome sequencing (N = 41), RNA sequencing (N = 29), and methylation analysis (N = 41), using 41 MFSs as a discovery set, and subsequent targeted sequencing of 140 genes in the entire cohort of 99 MFSs and 17 MFSs' data from TCGA. Fourteen driver genes are identified, including potentially actionable therapeutic targets seen in 37% of cases. There are frequent alterations in p53 signaling (51%) and cell cycle checkpoint genes (43%). Other conceivably actionable driver genes including ATRX, JAK1, NF1, NTRK1, and novel oncogenic BRAF fusion gene are identified. Methylation patterns cluster into three subtypes associated with unique combinations of driver mutations, clinical outcomes, and immune cell compositions. Our results provide a valuable genomic resource to enable the design of precision medicine for MFS. Myxofibrosarcoma occurs in adults and is associated with high local relapse. Here, based on exome/transcriptome sequencing and DNA methylation analysis, the authors identify driver genes and methylation clusters associated with unique combinations of mutations, outcomes, and immune cell compositions.
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29
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Palma Milla C, Lezana Rosales JM, López Montiel J, Andrés Garrido LD, Sánchez Linares C, Carmona Tamajón S, Torres Fernández C, Sánchez González P, Franco Freire S, Benito López C, López Siles J. Neurofibromatosis type I: mutation spectrum of NF1 in spanish patients. Ann Hum Genet 2018; 82:425-436. [PMID: 30014477 DOI: 10.1111/ahg.12272] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2018] [Revised: 05/19/2018] [Accepted: 06/18/2018] [Indexed: 01/07/2023]
Abstract
Neurofibromatosis type I (NF1) is one of the most common genetic disorders in humans. NF1, a tumor predisposition syndrome, is caused by heterozygous pathogenic variants in the NF1 gene. Molecular genetic testing of NF1 is complex, especially because of the presence of a high number of partial pseudogenes, some of them with a high percentage of sequence identity. In this study, we have analyzed the largest cohort of NF1 Spanish patients (150 unrelated individuals suspected of having NF1 and 53 relatives, making a total of 203 individuals). Mutation analysis of the entire coding region was performed in all unrelated index patients. Additionally, the Multiplex Ligation-dependent Probe Amplification (MLPA) test of the NF1 gene and SPRED1 gene analysis (sequencing and MLPA test) was performed in some of the negative patients for NF1 point mutations. When fulfilling the National Institutes of Health (NIH) criterion for the clinical diagnosis of NF1, the detection rate was 79%. Among the 80 genetically confirmed NF1 probands, we detected 69 different pathogenic variants. Two mutations (3%) were gross deletions of the whole gene, the remaining 78 mutations (97%) were small changes spread among all NF1 exons. Among these 69 different mutations detected, 42 mutations were described elsewhere, and 27 mutations were novel mutations. When segregation was studied, 67% of mutations resulted de novo variants. No genetic mosaicism was detected on patients' parents.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Sara Franco Freire
- Hospital Regional Universitario de Málaga. U.G.C. de Laboratorio. Sección de Genética
| | - Carmen Benito López
- Hospital Regional Universitario de Málaga. U.G.C. de Laboratorio. Sección de Genética
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30
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Freret ME, Gutmann DH. Insights into optic pathway glioma vision loss from mouse models of neurofibromatosis type 1. J Neurosci Res 2018; 97:45-56. [PMID: 29704429 DOI: 10.1002/jnr.24250] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 04/09/2018] [Indexed: 12/12/2022]
Abstract
Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 gene. The NF1-encoded protein (neurofibromin) is an inhibitor of the oncoprotein RAS and controls cell growth and survival. Individuals with NF1 are prone to developing low-grade tumors of the optic nerves, chiasm, tracts, and radiations, termed optic pathway gliomas (OPGs), which can cause vision loss. A paucity of surgical tumor specimens and of patient-derived xenografts for investigative studies has limited our understanding of human NF1-associated OPG (NF1-OPG). However, mice genetically engineered to harbor Nf1 gene mutations develop optic gliomas that share many features of their human counterparts. These genetically engineered mouse (GEM) strains have provided important insights into the cellular and molecular determinants that underlie mouse Nf1 optic glioma development, maintenance, and associated vision loss, with relevance by extension to human NF1-OPG disease. Herein, we review our current understanding of NF1-OPG pathobiology and describe the mechanisms responsible for tumor initiation, growth, and associated vision loss in Nf1 GEM models. We also discuss how Nf1 GEM and other preclinical models can be deployed to identify and evaluate molecularly targeted therapies for OPG, particularly as they pertain to future strategies aimed at preventing or improving tumor-associated vision loss in children with NF1.
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Affiliation(s)
- Morgan E Freret
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
| | - David H Gutmann
- Department of Neurology, Washington University School of Medicine, St. Louis, Missouri
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31
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Suarez-Kelly LP, Akagi K, Reeser JW, Samorodnitsky E, Reeder M, Smith A, Roychowdhury S, Symer DE, Carson WE. Metaplastic breast cancer in a patient with neurofibromatosis type 1 and somatic loss of heterozygosity. Cold Spring Harb Mol Case Stud 2018; 4:mcs.a002352. [PMID: 29449315 PMCID: PMC5880258 DOI: 10.1101/mcs.a002352] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2017] [Accepted: 01/30/2018] [Indexed: 01/06/2023] Open
Abstract
Metaplastic breast carcinoma (MBC) is rare and has a poor prognosis. Here we describe genetic analysis of a 41-yr-old female patient with MBC and neurofibromatosis type I (NF1). She initially presented with pT3N1a, grade 3 MBC, but lung metastases were discovered subsequently. To identify the molecular cause of her NF1, we screened for germline mutations disrupting NF1 or SPRED1, revealing a heterozygous germline single-nucleotide variant (SNV) in exon 21 of NF1 at c.2709G>A, Chr 17: 29556342. By report, this variant disrupts pre-mRNA splicing of NF1 transcripts. No pathogenic mutations were identified in SPRED1. A potential association between MBC and NF1 was reported in eight previous cases, but none underwent detailed genomics analysis. To identify additional candidate germline variants potentially predisposing to MBC, we conducted targeted exome sequencing of 279 established cancer-causing genes in a control blood sample, disclosing four rare SNVs. Analysis of her breast tumor showed markedly altered variant allelic fractions (VAFs) for two (50%) of them, revealing somatic loss of heterozygosity (LOH) at germline SNVs. Of these, only the VAF of the pathogenic SNV in NF1 was increased in the tumor. Tumor sequencing demonstrated five somatic mutations altering TP53, BRCA1, and other genes potentially contributing to cancer formation. Because somatic LOH at certain germline SNVs can enhance their impacts, we conclude that increased allelic imbalance of the pathogenic SNV in NF1 likely contributed to tumorigenesis. Our results highlight a need to assess predisposing genetic factors and LOH that can cause rare, aggressive diseases such as MBC in NF1.
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Affiliation(s)
- Lorena P Suarez-Kelly
- The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA
| | - Keiko Akagi
- The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
| | - Julie W Reeser
- The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA
| | - Eric Samorodnitsky
- The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA
| | - Matthew Reeder
- The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA
| | - Amy Smith
- The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA
| | - Sameek Roychowdhury
- The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA
| | - David E Symer
- The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA.,Department of Cancer Biology and Genetics, The Ohio State University, Columbus, Ohio 43210, USA
| | - William E Carson
- The Arthur G. James Comprehensive Cancer Center and Richard J. Solove Research Institute, The Ohio State University, Columbus, Ohio 43210, USA.,Division of Surgical Oncology, Department of Surgery, The Ohio State University, Columbus, Ohio 43210, USA
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32
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Hammami A, Hasnaoui B, Guerfala M, Mabrouk MB, Farhat W, Ksiaa M, Jaziri H, Elleuch N, Brahem A, Ajmi S, Ali AB, Sriha B, Slama AB, Jmaa A. Gastrointestinal stromal tumor (GIST) inpatient with Von Recklinghausen's disease. Presse Med 2018; 47:404-408. [PMID: 29588106 DOI: 10.1016/j.lpm.2018.02.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/16/2017] [Revised: 01/16/2018] [Accepted: 02/19/2018] [Indexed: 10/17/2022] Open
Affiliation(s)
- Aya Hammami
- Departement of Gastroenterology, Sahloul City, Tunisia.
| | | | | | | | - Waad Farhat
- Departement of Surgery, Sahloul City, Tunisia
| | - Mehdi Ksiaa
- Departement of Gastroenterology, Sahloul City, Tunisia
| | - Hanen Jaziri
- Departement of Gastroenterology, Sahloul City, Tunisia
| | - Nour Elleuch
- Departement of Gastroenterology, Sahloul City, Tunisia
| | - Ahlem Brahem
- Departement of Gastroenterology, Sahloul City, Tunisia
| | - Salem Ajmi
- Departement of Gastroenterology, Sahloul City, Tunisia
| | - Ali Ben Ali
- Departement of Surgery, Sahloul City, Tunisia
| | | | | | - Ali Jmaa
- Departement of Gastroenterology, Sahloul City, Tunisia
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Norris EJ, Jones WD, Surleac MD, Petrescu AJ, Destephanis D, Zhang Q, Hamadeh I, Kneisl JS, Livasy CA, Ganapathi RN, Tait DL, Ganapathi MK. Clonal lineage of high grade serous ovarian cancer in a patient with neurofibromatosis type 1. Gynecol Oncol Rep 2018; 23:41-44. [PMID: 29892687 PMCID: PMC5993517 DOI: 10.1016/j.gore.2018.01.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2017] [Revised: 01/05/2018] [Accepted: 01/13/2018] [Indexed: 10/25/2022] Open
Abstract
Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene encoding neurofibromin, which negatively regulates Ras signaling. NF1 patients have an increased risk of developing early onset breast cancer, however, the association between NF1 and high grade serous ovarian cancer (HGSOC) is unclear. Since most NF1-related tumors exhibit early biallelic inactivation of NF1, we evaluated the evolution of genetic alterations in HGSOC in an NF1 patient. Somatic variation analysis of whole exome sequencing of tumor samples from both ovaries and a peritoneal metastasis showed a clonal lineage originating from an ancestral clone within the left adnexa, which exhibited copy number (CN) loss of heterozygosity (LOH) in the region of chromosome 17 containing TP53, NF1, and BRCA1 and mutation of the other TP53 allele. This event led to biallelic inactivation of NF1 and TP53 and LOH for the BRCA1 germline mutation. Subsequent CN alterations were found in the dominant tumor clone in the left ovary and nearly 100% of tumor at other sites. Neurofibromin modeling studies suggested that the germline NF1 mutation could potentially alter protein function. These results demonstrate early, biallelic inactivation of neurofibromin in HGSOC and highlight the potential of targeting RAS signaling in NF1 patients.
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Affiliation(s)
- Eric J Norris
- Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Drive, Charlotte, NC 28204, USA
| | - Wendell D Jones
- Q Solutions-EA Genomics, 5827 South Miami Boulevard, Morrisville, NC 27560, USA
| | - Marius D Surleac
- Department of Bioinformatics, Institute of Biochemistry of the Romanian Academy, Splaiul Independenței 296, Bucharest 060031, Romania
| | - Andrei J Petrescu
- Department of Bioinformatics, Institute of Biochemistry of the Romanian Academy, Splaiul Independenței 296, Bucharest 060031, Romania
| | - Darla Destephanis
- Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Drive, Charlotte, NC 28204, USA
| | - Qing Zhang
- Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Drive, Charlotte, NC 28204, USA
| | - Issam Hamadeh
- Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Drive, Charlotte, NC 28204, USA
| | - Jeffrey S Kneisl
- Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Drive, Charlotte, NC 28204, USA
| | - Chad A Livasy
- Carolinas Pathology Group, 2001 Vail Avenue, Charlotte, NC 28207, USA
| | - Ram N Ganapathi
- Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Drive, Charlotte, NC 28204, USA
| | - David L Tait
- Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Drive, Charlotte, NC 28204, USA
| | - Mahrukh K Ganapathi
- Levine Cancer Institute, Carolinas HealthCare System, 1021 Morehead Medical Drive, Charlotte, NC 28204, USA
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Niinuma T, Suzuki H, Sugai T. Molecular characterization and pathogenesis of gastrointestinal stromal tumor. Transl Gastroenterol Hepatol 2018; 3:2. [PMID: 29441367 DOI: 10.21037/tgh.2018.01.02] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2017] [Accepted: 01/04/2018] [Indexed: 12/11/2022] Open
Abstract
Most gastrointestinal stromal tumors (GISTs) harbor activating mutations in the receptor tyrosine kinase gene KIT or platelet-derived growth factor receptor alpha (PDGFRA), and the resultant activation of downstream signals plays a pivotal role in the development of GISTs. The sites of the tyrosine kinase gene mutations are associated with the biological behavior of GISTs, including risk category, clinical outcome and drug response. Mutations in RAS signaling pathway genes, including KRAS and BRAF, have also been reported in KIT/PDGFRA wild-type GISTs, though they are rare. Neurofibromin 1 (NF1) is a tumor suppressor gene mutated in neurofibromatosis type 1. Patients with NF1 mutations are at high risk of developing GISTs. Recent findings suggest that altered expression or mutation of members of succinate dehydrogenase (SDH) heterotetramer are causally associated with GIST development through induction of aberrant DNA methylation. At present, GISTs with no alterations in KIT, PDGFRA, RAS signaling genes or SDH family genes are referred to as true wild-type GISTs. KIT and PDGFRA mutations are thought as the earliest events in GIST development, and subsequent accumulation of chromosomal aberrations and other molecular alterations are required for malignant progression. In addition, recent studies have shown that epigenetic alterations and noncoding RNAs also play key roles in the pathogenesis of GISTs.
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Affiliation(s)
- Takeshi Niinuma
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, Sapporo Medical University School of Medicine, Sapporo, Japan
| | - Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Morioka, Japan
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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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Segawa K, Sugita S, Sugawara T, Ito Y, Tsujiwaki M, Fujita H, Ono Y, Kobayashi K, Hirobe M, Yoshida M, Hasegawa T. Multiple gastrointestinal stromal tumors involving extragastrointestinal sites in neurofibromatosis type 1. Pathol Int 2017; 68:142-144. [PMID: 29222828 DOI: 10.1111/pin.12620] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 11/21/2017] [Indexed: 12/30/2022]
Affiliation(s)
- Keiko Segawa
- Department of Surgical Pathology, Sapporo Medical University, School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Shintaro Sugita
- Department of Surgical Pathology, Sapporo Medical University, School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Taro Sugawara
- Department of Surgical Pathology, Sapporo Medical University, School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Yumika Ito
- Department of Surgical Pathology, Sapporo Medical University, School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Mitsuhiro Tsujiwaki
- Department of Surgical Pathology, Sapporo Medical University, School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Hiromi Fujita
- Department of Surgical Pathology, Sapporo Medical University, School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Yusuke Ono
- Department of Surgical Pathology, Sapporo Medical University, School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Kou Kobayashi
- Department of Urology, Sapporo Medical University, School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Megumi Hirobe
- Department of Urology, Sapporo Medical University, School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Makoto Yoshida
- Department of Medical Oncology, Sapporo Medical University, School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
| | - Tadashi Hasegawa
- Department of Surgical Pathology, Sapporo Medical University, School of Medicine, South 1, West 16, Chuo-ku, Sapporo, Hokkaido 060-8543, Japan
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Burgoyne AM, De Siena M, Alkhuziem M, Tang CM, Medina B, Fanta PT, Belinsky MG, von Mehren M, Thorson JA, Madlensky L, Bowler T, D'Angelo F, Stupack DG, Harismendy O, DeMatteo RP, Sicklick JK. Duodenal-Jejunal Flexure GI Stromal Tumor Frequently Heralds Somatic NF1 and Notch Pathway Mutations. JCO Precis Oncol 2017; 2017. [PMID: 29938249 DOI: 10.1200/po.17.00014] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Purpose GI stromal tumors (GISTs) are commonly associated with somatic mutations in KIT and PDGFRA. However, a subset arises from mutations in NF1, most commonly associated with neurofibromatosis type 1. We define the anatomic distribution of NF1 alterations in GIST. Methods We describe the demographic/clinicopathologic features of 177 patients from two institutions whose GISTs underwent next-generation sequencing of ≥315 cancer-related genes. Results We initially identified six (9.7%) of 62 GISTs with NF1 genomic alterations from the first cohort. Of these six patients, five (83.3%) had unifocal tumors at the duodenal-jejunal flexure (DJF). Two additional patients with DJF GISTs had non-NF1 (KIT and BRAF) genomic alterations. After excluding one DJF GIST with an NF1 single nucleotide polymorphism, four (57.1%) of seven sequenced DJF tumors demonstrated deleterious NF1 alterations, whereas only one (1.8%) of 55 sequenced non-DJF GISTs had a deleterious NF1 somatic mutation (P < .001). One patient with DJF GIST had a germline NF1 variant that was associated with incomplete penetrance of clinical neurofibromatosis type 1 features along with a somatic NF1 mutation. Of the five DJF GISTs with any NF1 alteration, three (60%) had KIT mutations, and three (60%) had Notch pathway mutations (NOTCH2, MAML2, CDC73). We validated these findings in a second cohort of 115 GISTs, where two (40%) of five unifocal NF1-mutated GISTs arose at the DJF, and one of these also had a Notch pathway mutation (EP300). Conclusion Broad genomic profiling of adult GISTs has revealed that NF1 alterations are enriched in DJF GISTs. These tumors also may harbor concurrent activating KIT and/or inactivating Notch pathway mutations. In some cases, germline NF1 genetic testing may be appropriate for patients with DJF GISTs.
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Affiliation(s)
| | - Martina De Siena
- University of California, San Diego, La Jolla, CA; Sapienza e Università di Roma, Rome, Italy
| | | | | | | | - Paul T Fanta
- University of California, San Diego, La Jolla, CA
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Namløs HM, Zaikova O, Bjerkehagen B, Vodák D, Hovig E, Myklebost O, Boye K, Meza-Zepeda LA. Use of liquid biopsies to monitor disease progression in a sarcoma patient: a case report. BMC Cancer 2017; 17:29. [PMID: 28061772 PMCID: PMC5219677 DOI: 10.1186/s12885-016-2992-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2015] [Accepted: 12/13/2016] [Indexed: 01/16/2023] Open
Abstract
BACKGROUND Many patients experience local recurrence or metastases after receiving potentially curative treatment, and early detection of these events is important for disease control. Recent technological advances make it possible to use blood plasma containing circulating cell-free tumour DNA (ctDNA) as a liquid biopsy. In this case report we show how serial liquid biopsies can be used to monitor the disease course and detect disease recurrence in a sarcoma patient. CASE PRESENTATION A 55-year-old male presented with a rapidly growing, painful palpable mass in the left groin region, and a biopsy revealed a high-grade malignant spindle cell sarcoma. No metastases were detected on radiologic imaging scans. Using targeted resequencing with a custom 900 cancer gene panel, eight somatic mutations among them KRAS and NF1, were identified in the primary tumour. Targeted resequencing of plasma cell-free DNA (ctDNA) collected before and after surgery and at disease progression confirmed the presence of six of eight mutations at all three time points. The ctDNA level, estimated from the somatic allele frequencies of these six mutations, was high in plasma taken at the time of surgery, at levels similar to the primary tumour. Detection of low levels of ctDNA three days after surgery indicated persistent microscopic disease. Repeated radiologic imaging six weeks postoperatively showed widespread metastatic disease in the lungs, skeleton and the pelvic region. At this time point there was a dramatic increase in the ctDNA level, reflecting the disease progression of the patient. The patient had an unusually aggressive cancer, and succumbed to the disease 13 weeks after surgery. CONCLUSIONS This case report demonstrated that targeted resequencing of ctDNA from longitudinal collected plasma can be used to monitor disease progression in a soft tissue sarcoma patient, including manifestation of metastatic disease. The ctDNA represented the genomic profile of the tumour, supporting clinical use of liquid biopsies to identify tumour-specific mutations as well as recurrent disease.
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Affiliation(s)
- Heidi M Namløs
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
| | - Olga Zaikova
- Department of Surgery, Oslo University Hospital, Oslo, Norway
| | | | - Daniel Vodák
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Eivind Hovig
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Institute of Cancer Genetics and Informatics, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Norwegian Cancer Genomics Consortium (CancerGenomics.no), Oslo, Norway
| | - Ola Myklebost
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Norwegian Cancer Genomics Consortium (CancerGenomics.no), Oslo, Norway
| | - Kjetil Boye
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.,Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Leonardo A Meza-Zepeda
- Department of Tumor Biology, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway. .,Norwegian Cancer Genomics Consortium (CancerGenomics.no), Oslo, Norway. .,Genomics Core Facility, Department of Core Facilities, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway.
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de Gouvea ACRC, Garber JE. Breast Cancer Genetics. Breast Cancer 2017. [DOI: 10.1007/978-3-319-48848-6_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Li J, Ye Y, Wang J, Zhang B, Qin S, Shi Y, He Y, Liang X, Liu X, Zhou Y, Wu X, Zhang X, Wang M, Gao Z, Lin T, Cao H, Shen L, Chinese Society Of Clinical Oncology Csco Expert Committee On Gastrointestinal Stromal Tumor. Chinese consensus guidelines for diagnosis and management of gastrointestinal stromal tumor. Chin J Cancer Res 2017; 29:281-293. [PMID: 28947860 PMCID: PMC5592117 DOI: 10.21147/j.issn.1000-9604.2017.04.01] [Citation(s) in RCA: 131] [Impact Index Per Article: 16.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
In order to further promote the standardization of diagnosis and treatment of gastrointestinal stromal tumor (GIST) in China, the members of Chinese Society of Clinical Oncology (CSCO) Expert Committee on GIST thoroughly discussed the key contents of the consensus guidelines, and voted on the controversial issue. In final, the Chinese consensus guidelines for the diagnosis and management of GIST (2017 edition) was formed on the basis of 2013 edition consensus guidelines, which is hereby announced. The consensus included the pathological diagnosis, recurrence risk classification evaluation, targeted agent therapy, surgery and principles of surveillance of GIST.
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Affiliation(s)
- Jian Li
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yingjiang Ye
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Jian Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Bo Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Shukui Qin
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yingqiang Shi
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Yulong He
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xiaobo Liang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xiufeng Liu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Ye Zhou
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xin Wu
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Xinhua Zhang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Ming Wang
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Zhidong Gao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Tianlong Lin
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Hui Cao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
| | - Lin Shen
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China
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Breast cancer in neurofibromatosis type 1: overrepresentation of unfavourable prognostic factors. Br J Cancer 2016; 116:211-217. [PMID: 27931045 PMCID: PMC5243991 DOI: 10.1038/bjc.2016.403] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2016] [Revised: 10/21/2016] [Accepted: 11/11/2016] [Indexed: 01/05/2023] Open
Abstract
Background: An increased breast cancer incidence and poor survival have been reported for women with neurofibromatosis 1 (NF1). To explain the poor survival, we aimed to link the histopathology and clinical characteristics of NF1-associated breast cancers. Methods: The Finnish Cancer Registry and the Finnish NF Registry were cross-referenced to identify the NF1 patients with breast cancer. Archival NF1 breast cancer specimens were retrieved for histopathological typing and compared with matched controls. Results: A total of 32 breast cancers were diagnosed in 1404 NF1 patients during the follow-up. Women with NF1 had an estimated lifetime risk of 18.0% for breast cancer, and this is nearly two-fold compared with that of the general Finnish female population (9.74%). The 26 successfully retrieved archival NF1 breast tumours were more often associated with unfavourable prognostic factors, such as oestrogen and progesterone receptor negativity and HER2 amplification. However, survival was worse in the NF1 group (P=0.053) even when compared with the control group matched for age, diagnosis year, gender and oestrogen receptor status. Scrutiny of The Cancer Genome Atlas data set showed that NF1 mutations and deletions were associated with similar characteristics in the breast cancers of the general population. Conclusions: These results emphasise the role of the NF1 gene in the pathogenesis of breast cancer and a need for active follow-up for breast cancer in women with NF1.
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Wang S, Ma G, Zhu H, Lv C, Chu H, Tong N, Wu D, Qiang F, Gong W, Zhao Q, Tao G, Zhou J, Zhang Z, Wang M. miR-107 regulates tumor progression by targeting NF1 in gastric cancer. Sci Rep 2016; 6:36531. [PMID: 27827403 PMCID: PMC5101511 DOI: 10.1038/srep36531] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Accepted: 10/17/2016] [Indexed: 12/20/2022] Open
Abstract
Our previous genome-wide miRNA microarray study revealed that miR-107 was upregulated in gastric cancer (GC). In this study we aimed to explore its biological role in the pathogenesis of GC. Integrating in silico prediction algorithms with western blotting assays revealed that miR-107 inhibition enhanced NF1 (neurofibromin 1) mRNA and protein levels, suggesting that NF1 is one of miR-107 targets in GC. Luciferase reporter assay revealed that miR-107 suppressed NF1 expression by binding to the first potential binding site within the 3′-UTR of NF1 mRNA. mRNA stable assay indicated this binding could result in NF1 mRNA instability, which might contribute to its abnormal protein expression. Functional analyses such as cell growth, transwell migration and invasion assays were used to investigate the role of interaction between miR-107 and its target on GC development and progression. Moreover, We investigated the association between the clinical phenotype and the status of miR-107 expression in 55 GC tissues, and found the high expression contributed to the tumor size and depth of invasion. The results exhibited that down regulation of miR-107 opposed cell growth, migration, and invasion, whereas NF1 repression promoted these phenotypes. Our findings provide a mechanism by which miR-107 regulates NF1 in GC, as well as highlight the importance of interaction between miR-107 and NF1 in GC development and progression.
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Affiliation(s)
- Shizhi Wang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China.,Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Gaoxiang Ma
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Haixia Zhu
- Core Laboratory, Nantong Tumor Hospital, Nantong, China
| | - Chunye Lv
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of General Surgery, The Affiliated Jiangning Hospital of Nanjing Medical University, Nanjing, China
| | - Haiyan Chu
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Na Tong
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Dongmei Wu
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Fulin Qiang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Core Laboratory, Nantong Tumor Hospital, Nantong, China
| | - Weida Gong
- Department of General Surgery, Yixing Cancer Hospital, Yixing, China
| | - Qinghong Zhao
- Department of General Surgery, The Second Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Guoquan Tao
- Department of General Surgery, Huai-An First People's Hospital Affiliated to Nanjing Medical University, Huai-An, China
| | - Jianwei Zhou
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Zhengdong Zhang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Meilin Wang
- Department of Environmental Genomics, Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center For Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China.,Department of Genetic Toxicology, the Key Laboratory of Modern Toxicology of Ministry of Education, School of Public Health, Nanjing Medical University, Nanjing, China
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Rodriquenz MG, Rossi S, Ricci R, Martini M, Larocca M, Dipasquale A, Quirino M, Schinzari G, Basso M, D’Argento E, Strippoli A, Barone C, Cassano A. Gastrointestinal stromal tumors (GISTs) and second malignancies: A novel "sentinel tumor"? A monoinstitutional, STROBE-compliant observational analysis. Medicine (Baltimore) 2016; 95:e4718. [PMID: 27661019 PMCID: PMC5044889 DOI: 10.1097/md.0000000000004718] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Several evidences showed that patients with gastrointestinal stromal tumors (GISTs) develop additional malignancies. However, thorough incidence of second tumors remains uncertain as the possibility of a common molecular pathogenesis.A retrospective series of 128 patients with histologically proven GIST treated at our institution was evaluated. Molecular analysis of KIT and PDGFR-α genes was performed in all patients. Following the involvement of KRAS mutation in many tumors' pathogenesis, analysis of KRAS was performed in patients with also second neoplasms.Forty-six out of 128 GIST patients (35.9%) had a second neoplasm. Most second tumors (52%) raised from gastrointestinal tract and 19.6% from genitourinary tract. Benign neoplasms were also included (21.7%). Molecular analysis was available for 29/46 patients with a second tumor: wild-type GISTs (n. 5), exon 11 (n. 16), exon 13 (n. 1), exon 9 (n. 1) KIT mutations, exon 14 PDGFR-α mutation (n. 2) and exon 18 PDGFR-α mutation (n. 4). KIT exon 11 mutations were more frequent between patients who developed a second tumor (P = 0.0003). Mutational analysis of KRAS showed a wild-type sequence in all cases. In metachronous cases, the median time interval between GIST and second tumor was 21.5 months.The high frequency of second tumors suggests that an unknown common molecular mechanism might play a role, but it is not likely that KRAS is involved in this common pathogenesis. The short interval between GIST diagnosis and the onset of second neoplasms asks for a careful follow-up, particularly in the first 3 years after diagnosis.
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Affiliation(s)
| | - Sabrina Rossi
- Department of Medical Oncology, Humanitas Clinical and Research Center, Rozzano (MI)
- Correspondence: Sabrina Rossi, Humanitas Clinical and Research Center, Via Manzoni, 56, 20089 Rozzano (MI), Italy (e-mail: )
| | - Riccardo Ricci
- Department of Pathology, Catholic University of Sacred Heart, Rome
| | - Maurizio Martini
- Department of Pathology, Catholic University of Sacred Heart, Rome
| | - Mario Larocca
- Department of Medical Oncology, Catholic University of Sacred Heart, Rome, Italy
| | - Angelo Dipasquale
- Department of Medical Oncology, Catholic University of Sacred Heart, Rome, Italy
| | - Michela Quirino
- Department of Medical Oncology, Catholic University of Sacred Heart, Rome, Italy
| | - Giovanni Schinzari
- Department of Medical Oncology, Catholic University of Sacred Heart, Rome, Italy
| | - Michele Basso
- Department of Medical Oncology, Catholic University of Sacred Heart, Rome, Italy
| | - Ettore D’Argento
- Department of Medical Oncology, Catholic University of Sacred Heart, Rome, Italy
| | - Antonia Strippoli
- Department of Medical Oncology, Catholic University of Sacred Heart, Rome, Italy
| | - Carlo Barone
- Department of Medical Oncology, Catholic University of Sacred Heart, Rome, Italy
| | - Alessandra Cassano
- Department of Medical Oncology, Catholic University of Sacred Heart, Rome, Italy
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Abstract
The first 15 years of management of gastrointestinal stromal tumor (GIST) have led to 3 lines of therapy for metastatic disease: imatinib, sunitinib, and regorafenib. In the adjuvant setting, imatinib is usually given for 3 years postoperatively to patients with higher-risk primary tumors that are completely resected. In this review, issues regarding GIST adjuvant therapy are discussed. It is hoped this review will help the reader understand the present standard of care to improve upon it in years to come.
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Pancreaticoduodenectomy in patients with type 1 Neurofibromatosis: Report of two cases and literature review. Int J Surg Case Rep 2016; 27:36-40. [PMID: 27529834 PMCID: PMC4987505 DOI: 10.1016/j.ijscr.2016.08.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Revised: 08/07/2016] [Accepted: 08/08/2016] [Indexed: 02/08/2023] Open
Abstract
Type 1 Neurofibromatosis is an autosomal disorder associated with gastrointestinal tumors in almost one quarter of the cases. The presence of synchronous malignant gastrintestinal tumor in patients with type 1 Neurofibromatosis is rarely reported in the literature. Patients with type 1 Neurofibromatosis with gastrointestinal complaints should be thoroughly evaluated to rule out malignancy. Optimal management of patients with synchronous neoplasms is single-stage surgical resection. Introduction Type 1 Neurofibromatosis (NF1) is one of the most common autosomal dominantly inherited multisystem disorders. It is associated with an increased risk of developing neurologic and gastrointestinal (GI) malignant neoplasms. The incidence of GI involvement is reported in 10–25% of patients. Less than 5% of NF1 patients with GI neoplasms manifest symptoms. The presence of synchronic gastrointestinal stromal and neuroendocrine tumors is rare in these patients. Presentation of cases The first case is a 37 year-old male patient with a history of abdominal pain for a few months. Imaging study showed a periampullary mass and a solid lesion at the third duodenal portion. He was submitted to a pancreatoduodenectomy and histological anaylisis showed two low-grade neuroendocrine tumors and a gastrointestinal stromal tumor. The second case is a 47 year-old female patient with a routine computed tomography scan showing a duodenal and a jejunal lesion. Duodenopancreatectomy was performed and histological analysis showed a neuroendocrine adenocarcinoma of the duodenum and two jejunal lesions compatible with GI tumors. Discussion GI symptoms such as jaundice, pain and bleeding in NF1 patients should prompt urgent admission Occasionally, associated gastrointestinal tumors may be incidentally found in asymptomatic NF1 patients. The presence of a periampullary or duodenal neoplasia such as neuroendocrine tumors should be evaluated. Conclusion Although rare, the synchronic presentation of gastrointestinal tumors in patients with NF1 should be ruled out since it can lead to higher morbidity and mortality rates. Single-stage surgical management is feasable and yields satisfactory results.
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Ricci R. Syndromic gastrointestinal stromal tumors. Hered Cancer Clin Pract 2016; 14:15. [PMID: 27437068 PMCID: PMC4950812 DOI: 10.1186/s13053-016-0055-4] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2016] [Accepted: 06/09/2016] [Indexed: 12/28/2022] Open
Abstract
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of gastrointestinal tract. They feature heterogeneous triggering mechanisms, implying relevant clinical differences. The vast majority of GISTs are sporadic tumors. Rarely, however, GIST-prone syndromes occur, mostly depending on heritable GIST predisposing molecular defects involving the entire organism. These conditions need to be properly identified in order to plan appropriate diagnostic, prognostic and therapeutic procedures. Clinically, GIST-prone syndromes must be thought of whenever GISTs are multiple and/or associated with accompanying signs peculiar to the background tumorigenic trigger, either in single individuals or in kindreds. Moreover, syndromic GISTs, individually considered, tend to show distinctive features depending on the underlying condition. When applicable, genotyping is usually confirmatory. In GIST-prone conditions, the prognostic features of each GIST, defined according to the criteria routinely applied to sporadic GISTs, combine with the characters proper to the background syndromes, defining peculiar clinical settings which challenge physicians to undertake complex decisions. The latter concern preventive therapy and single tumor therapy, implying possible surgical and molecularly targeted options. In the absence of specific comprehensive guidelines, this review will highlight the traits characteristic of GIST-predisposing syndromes, with particular emphasis on diagnostic, prognostic and therapeutic implications, which can help the clinical management of these rare diseases.
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Affiliation(s)
- Riccardo Ricci
- Department of Pathology, Università Cattolica del S. Cuore, Largo Agostino Gemelli, 8, I-00168 Rome, Italy
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Concomitant Nonfunctional Pancreatic Neuroendocrine Tumor and Gastric GIST in a Patient Without Neurofibromatosis Type 1. J Gastrointest Cancer 2016; 43 Suppl 1:S171-4. [PMID: 22083533 DOI: 10.1007/s12029-011-9344-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
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Pan D, Liang P, Xiao H. Neurofibromatosis type 1 associated with pheochromocytoma and gastrointestinal stromal tumors: A case report and literature review. Oncol Lett 2016; 12:637-643. [PMID: 27347193 DOI: 10.3892/ol.2016.4670] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2015] [Accepted: 02/01/2016] [Indexed: 12/16/2022] Open
Abstract
Neurofibromatosis type 1 (NF1) is a genetic disorder associated with neurofibromin 1 (NF1) gene mutation, which generates an increased risk of variety of tumor types. The current study reports a case involving NF1, pheochromocytoma (PHEO) and gastrointestinal stromal tumors (GIST). A 56-year-old man presented with abdominal pain and polypnea. Clinical investigation revealed multiple diffuse soft-tissue lesions throughout his body, and pigmented macules on the skin. Imaging analyses revealed thoracic scoliosis, multiple subcutaneous nodules in the abdomen and trunk, and a 7.0×7.7×8.9-cm oval-shaped, cystic mass in the left upper abdominal cavity. Immunohistochemical staining indicated that S-100 protein and synaptophysin were highly expressed in adrenal gland neoplasm, whilst CD117 and CD34 were highly expressed in small intestine tumors. The overall clinical and pathological finding suggested a diagnosis of NF1, giant PHEO and small intestinal stromal tumor. In addition, a literature review was conducted to identify the specific clinical features of patients with this condition. Only 11 similar cases have been reported worldwide. In the present study, paroxysmal hypertension occurred in the majority of patients, and GISTs tended to be located in the small intestine. In addition, the present study demonstrated that many of the patients had a poor prognosis. Therefore, the present study indicates that NF1-PHEO-GIST is a special type tumor with varied clinical symptoms, which may be associated with an increased risk for poor prognosis; however, more studies are required to confirm this.
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Affiliation(s)
- Dongfeng Pan
- Emergency Department, The People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia Hui Autonomous Region 750021, P.R. China
| | - Peifeng Liang
- Department of Medical Statistics, The People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia Hui Autonomous Region 750021, P.R. China; Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, P.R. China
| | - Hongyan Xiao
- Department of Pathology, The People's Hospital of Ningxia Hui Autonomous Region, Yinchuan, Ningxia Hui Autonomous Region 750002, P.R. China
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Kang Y, Choi JW, Kim Y, Oh HE, Lee JH, Kim YS. Goblet Cell Carcinoid of the Rectum in a Patient with Neurofibromatosis Type 1. J Pathol Transl Med 2016; 50:482-485. [PMID: 27237132 PMCID: PMC5122723 DOI: 10.4132/jptm.2016.02.27] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2016] [Revised: 02/24/2016] [Accepted: 02/27/2016] [Indexed: 11/18/2022] Open
Affiliation(s)
- Youngjin Kang
- Department of Pathology, Korea University Ansan Hospital, Ansan, Korea
| | - Jung-Woo Choi
- Department of Pathology, Korea University Ansan Hospital, Ansan, Korea
| | - Younghye Kim
- Department of Pathology, Korea University Ansan Hospital, Ansan, Korea
| | - Hwa Eun Oh
- Department of Pathology, Korea University Ansan Hospital, Ansan, Korea
| | - Ju-Han Lee
- Department of Pathology, Korea University Ansan Hospital, Ansan, Korea
| | - Young-Sik Kim
- Department of Pathology, Korea University Ansan Hospital, Ansan, Korea
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Yap P, Super L, Qin J, Burgess T, Prodanovic Z, Edwards C, Thomas R, Carpenter K, Tan TY. Congenital Retroperitoneal Teratoma in Neurofibromatosis Type 1. Pediatr Blood Cancer 2016; 63:706-8. [PMID: 26514327 DOI: 10.1002/pbc.25812] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2015] [Revised: 09/29/2015] [Accepted: 09/30/2015] [Indexed: 12/11/2022]
Abstract
Neurofibromatosis type 1 (NF1) is caused by mutations in the tumor suppressor gene NF1. The increased tumor risk in affected individuals is well established, caused by somatic biallelic inactivation of NF1 due to loss of heterozygosity. Pediatric teratoma has not been reported in individuals with NF1 previously. We report a case of congenital teratoma in an infant with a heterozygous maternally inherited pathogenic NF1 mutation (c.[1756_1759delACTA] and p.[Thr586Valfs*18]). We detected a "second hit" in the form of mosaic whole NF1 deletion in the tumor tissue using multiplex ligation-dependent probe amplification, as a proof to support the hypothesis of NF1 involvement in the pathogenesis of teratoma.
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Affiliation(s)
- Patrick Yap
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia
| | - Leanne Super
- Monash Children's Cancer Centre, Monash Medical Centre, Clayton, Victoria, Australia
| | - Jinyi Qin
- Department of Diagnostic Genomics, PathWest Laboratory Medicine, Western Australia, Australia
| | - Trent Burgess
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia
- Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, Australia
| | | | - Caitlin Edwards
- Department of Diagnostic Genomics, PathWest Laboratory Medicine, Western Australia, Australia
| | - Rosemary Thomas
- Monash Children's Cancer Centre, Monash Medical Centre, Clayton, Victoria, Australia
| | - Karen Carpenter
- Department of Diagnostic Genomics, PathWest Laboratory Medicine, Western Australia, Australia
| | - Tiong Yang Tan
- Victorian Clinical Genetics Services, Murdoch Children's Research Institute, Melbourne, Australia
- Department of Paediatrics, Royal Children's Hospital, University of Melbourne, Melbourne, Australia
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