GEIS 2013 guidelines for gastrointestinal sarcomas (GIST)

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Abstract

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal soft tissue sarcoma of the gastrointestinal tract. Correct diagnosis with thorough use of pathologic and molecular tools of GIST mutations has been of the foremost importance. GIST are usually (95 %) KIT positive and harbor frequent KIT or platelet-derived growth factor receptor α-activating mutations. This deep molecular understanding has allowed the correct classification into risk groups with implications regarding prognosis, essential use in the development of targeted therapies and even response prediction to this drugs. Treatment has been evolving and an update to include lessons learned from recent trials in advanced disease as well as controversies in the adjuvant setting that are changing daily practice, is reviewed here. An effort from the Spanish Group for Sarcoma Research with investigators from the group has been undertaken to launch this third version of the GIST guidelines and provide a practical means for the different disciplines that treat this complex disease.

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Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours.

Jerzy Lasota, Markku Miettinen (2008)

Gastrointestinal stromal tumours (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract. Despite clinicopathological differences, GISTs share oncogenic KIT or platelet-derived growth factor-alpha (PDGFRA) mutations. Imatinib, KIT and PDGFRA inhibitor, has been successfully used in the treatment of metastatic GISTs. There are primary KIT or PDGFRA mutations diagnosed before imatinib treatment, linked to GIST pathogenesis, and secondary mutations detected during treatment, causing drug resistance. KIT exon 11 mutations are the most common. Gastric GISTs with exon 11 deletions are more aggressive than those with substitutions. KIT exon 11 mutants respond well to imatinib. Less common KIT exon 9 Ala502_Tyr503dup mutants occur predominantly in intestinal GISTs and are less sensitive to imatinib. An Asp842Val substitution in exon 18 is the most common PDGFRA mutation. GISTs with such mutation are resistant to imatinib. PDGFRA mutations are associated with gastric GISTs, epithelioid morphology and a less malignant course of disease. GISTs in neurofibromatosis 1, Carney triad and paediatric tumours generally lack KIT and PDGFRA mutations. Secondary KIT mutations affect exons 13-17. GISTs with secondary mutations in exon 13 and 14 are sensitive to sunitinib, another tyrosine kinase inhibitor. KIT and PDGFRA genotyping is important for GIST diagnosis and assessment of sensitivity to tyrosine kinase inhibitors.

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Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.

Barbara Pasini, Sarah R. McWhinney, Thalia Bei … (2008)

Gastrointestinal stromal tumors (GISTs) may be caused by germline mutations of the KIT and platelet-derived growth factor receptor-alpha (PDGFRA) genes and treated by Imatinib mesylate (STI571) or other protein tyrosine kinase inhibitors. However, not all GISTs harbor these genetic defects and several do not respond to STI571 suggesting that other molecular mechanisms may be implicated in GIST pathogenesis. In a subset of patients with GISTs, the lesions are associated with paragangliomas; the condition is familial and transmitted as an autosomal-dominant trait. We investigated 11 patients with the dyad of 'paraganglioma and gastric stromal sarcoma'; in eight (from seven unrelated families), the GISTs were caused by germline mutations of the genes encoding subunits B, C, or D (the SDHB, SDHC and SDHD genes, respectively). In this report, we present the molecular effects of these mutations on these genes and the clinical information on the patients. We conclude that succinate dehydrogenase deficiency may be the cause of a subgroup of GISTs and this offers a therapeutic target for GISTs that may not respond to STI571 and its analogs.

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Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors.

Seiichi Hirota, Akiko Ohashi, Toshirou Nishida … (2003)

Most gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of c-kit receptor tyrosine kinase (KIT) gene, but some GISTs do not. We investigated the cause of GISTs without KIT mutations. Because GISTs apparently expressed platelet-derived growth factor receptor (PDGFR) alpha, we examined whether GISTs without KIT mutations had a mutation of PDGFR alpha. Whole coding region of PDGFR alpha complementary DNA (cDNA) was sequenced in GISTs with or without KIT mutations. Mutant PDGFR alpha cDNA was transfected into 293T human embryonic kidney cells, and autophosphorylation of PDGFR alpha was examined. Proliferation of Ba/F3 murine lymphoid cells stably transfected with mutant PDGFR alpha cDNA was estimated by tritium thymidine incorporation. Wild-type KIT cDNA was cotransfected with mutant PDGFR alpha cDNA, and immunoprecipitation by anti-KIT antibody was performed. Inhibitory effect of Imatinib mesylate on activated PDGFR alpha was examined. We found 2 types of constitutively activated mutations of PDGFR alpha, Val-561 to Asp or Asp-842 to Val, in 5 of 8 GISTs without KIT mutations but not in 10 GISTs with KIT mutations. Stable transfection of each mutation induced autonomous proliferation of Ba/F3 cells. Constitutively activated mutant PDGFR alpha bound and activated the cotransfected wild-type KIT. The constitutive activation of PDGFR alpha with Val-561 to Asp was inhibited effectively by Imatinib mesylate but that of PDGFR alpha with Asp-842 to Val was inhibited only weakly, even at the concentration of 10 micromol/L. The gain-of-function mutations of PDGFR alpha appear to play an important role in development of GISTs without KIT mutations.

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Author and article information

Contributors

Andrés Poveda: (+34) 96 110 4647 , apoveda@fivo.org

Journal

Journal ID (nlm-ta): Cancer Chemother Pharmacol

Journal ID (iso-abbrev): Cancer Chemother. Pharmacol

Title: Cancer Chemotherapy and Pharmacology

Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )

ISSN (Print): 0344-5704

ISSN (Electronic): 1432-0843

Publication date (Electronic): 6 September 2014

Publication date PMC-release: 6 September 2014

Publication date (Print): 2014

Volume: 74

Issue: 5

Pages: 883-898

Affiliations

[ ]Instituto Valenciano de Oncología, Calle del Profesor Beltrán Bàguena, 8, 46009 Valencia, Spain

[ ]Institut Català d’Oncologia, Avinguda de la Granvia de l’Hospitalet, 199-203, 08907 L’Hospitalet de Llobregat, Barcelona, Spain

[ ]Fundación Instituto Valenciano de Oncología, C/Prof Baguena, 19, 46009 Valencia, Spain

[ ]Hospital La Paz, Paseo de la Castellana, 261, 28046 Madrid, Spain

[ ]Hospital Vall d’Hebrón, Passeig de la Vall d’Hebrón 119-129, 08035 Barcelona, Spain

[ ]Hospital Puerta de Hierro, Calle Manuel de Falla, 1, 28222 Majadahonda, Madrid, Spain

[ ]Hospital Virgen del Rocío, Avda. Manuel Siurot s/n, 41013 Sevilla, Spain

Article

Publisher ID: 2547

DOI: 10.1007/s00280-014-2547-0

PMC ID: 4209233

PubMed ID: 25193432

SO-VID: 1aac5cb4-01a3-494e-825f-144ea992c692

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Open AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

History

Date received : 7 July 2014

Date accepted : 19 July 2014

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: gist,imatinib,sunitinib,cd117,c-kit,pdfgra

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: gist, imatinib, sunitinib, cd117, c-kit, pdfgra

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GEIS 2013 guidelines for gastrointestinal sarcomas (GIST)

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Most cited references 18

Clinical significance of oncogenic KIT and PDGFRA mutations in gastrointestinal stromal tumours.

Clinical and molecular genetics of patients with the Carney-Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD.

Gain-of-function mutations of platelet-derived growth factor receptor alpha gene in gastrointestinal stromal tumors.

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Cited by 23

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