Pediatric Gastrointestinal Stromal Tumors
Gastrointestinal stromal tumors (GISTs) rarely occur in pediatric patients, but increased recognition of adult GIST has led to better awareness of the existence of this entity in the pediatric population. GIST occurring in pediatric patients has a unique biology and clinical behavior and warrants discussion as an independent entity. The generally accepted definition of pediatric GIST is a tumor that is diagnosed at the age of 18 years or younger. This review highlights the clinical features, molecular biology, and clinical management of this rare pediatric entity.
[Show abstract] [Hide abstract] ABSTRACT: Background: Approximately 10-15 % of gastrointestinal stromal tumors (GISTs) lack gain of function mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. An alternate mechanism of oncogenesis through loss of function of the succinate-dehydrogenase (SDH) enzyme complex has been identified for a subset of these "wild type" GISTs. Methods: Paired tumor and normal DNA from an SDH-intact wild-type GIST case was subjected to whole exome sequencing to identify the pathogenic mechanism(s) in this tumor. Selected findings were further investigated in panels of GIST tumors through Sanger DNA sequencing, quantitative real-time PCR, and immunohistochemical approaches. Results: A hemizygous frameshift mutation (p.His2261Leufs*4), in the neurofibromin 1 (NF1) gene was identified in the patient's GIST; however, no germline NF1 mutation was found. A somatic frameshift mutation (p.Lys54Argfs*31) in the MYC associated factor X (MAX) gene was also identified. Immunohistochemical analysis for MAX on a large panel of GISTs identified loss of MAX expression in the MAX-mutated GIST and in a subset of mainly KIT-mutated tumors. Conclusion: This study suggests that inactivating NF1 mutations outside the context of neurofibromatosis may be the oncogenic mechanism for a subset of sporadic GIST. In addition, loss of function mutation of the MAX gene was identified for the first time in GIST, and a broader role for MAX in GIST progression was suggested.0Comments 1Citation
- "The majority of GISTs exhibit gain of function mutations in KIT or in the related receptor PDGFRA [6, 7]. A subset (~10–15 %) of GISTs in adults lack mutations in the KIT and PDGFRA genes, as do almost all pediatric cases [8, 9]. The commonly used label of " wild type " (WT) GIST belies the epidemiological, clinico-pathological and molecular heterogeneity that define these tumors. "
[Show abstract] [Hide abstract] ABSTRACT: Background: About 10-15% of adult gastrointestinal stromal tumors (GIST) and the vast majority of pediatric GIST do not harbour KIT or platelet-derived growth factor receptor alpha (PDGFRA) mutations (J Clin Oncol 22:3813-3825, 2004; Hematol Oncol Clin North Am 23:15-34, 2009). The molecular biology of these GIST, originally defined as KIT/PDGFRA wild-type (WT), is complex due to the existence of different subgroups with distinct molecular hallmarks, including defects in the succinate dehydrogenase (SDH) complex and mutations of neurofibromatosis type 1 (NF1), BRAF, or KRAS genes (RAS-pathway or RAS-P).In this extremely heterogeneous landscape, the clinical profile and molecular abnormalities of the small subgroup of WT GIST suitably referred to as quadruple wild-type GIST (quadrupleWT or KITWT/PDGFRAWT/SDHWT/RAS-PWT) remains undefined. The aim of this study is to investigate the genomic profile of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, by using a massively parallel sequencing and microarray approach, and compare it with the genomic profile of other GIST subtypes. Methods: We performed a whole genome analysis using a massively parallel sequencing approach on a total of 16 GIST cases (2 KITWT/PDGFRAWT/SDHWT and SDHBIHC+/SDHAIHC+, 2 KITWT/PDGFRAWT/SDHAmut and SDHBIHC-/SDHAIHC- and 12 cases of KITmut or PDGFRAmut GIST). To confirm and extend the results, whole-genome gene expression analysis by microarray was performed on 9 out 16 patients analyzed by RNAseq and an additional 20 GIST patients (1 KITWT/PDGFRAWTSDHAmut GIST and 19 KITmut or PDGFRAmut GIST). The most impressive data were validated by quantitave PCR and Western Blot analysis. Results: We found that both cases of quadrupleWT GIST had a genomic profile profoundly different from both either KIT/PDGFRA mutated or SDHA-mutated GIST. In particular, the quadrupleWT GIST tumors are characterized by the overexpression of molecular markers (CALCRL and COL22A1) and of specific oncogenes including tyrosine and cyclin- dependent kinases (NTRK2 and CDK6) and one member of the ETS-transcription factor family (ERG). Conclusion: We report for the first time an integrated genomic picture of KITWT/PDGFRAWT/SDHWT/RAS-PWT GIST, using massively parallel sequencing and gene expression analyses, and found that quadrupleWT GIST have an expression signature that is distinct from SDH-mutant GIST as well as GIST harbouring mutations in KIT or PDGFRA. Our findings suggest that quadrupleWT GIST represent another unique group within the family of gastrointestintal stromal tumors.0Comments 14Citations
- "These tissues showed strong granular staining in the cytoplasm and mitochondria with both of the antibodies. SDHA gene exons123456789101112131415, SDHB gene exons12345678, SDHC (exon 1–6) and SDHD (exon 1–4) were sequenced on fresh-frozen tumor specimens of KIT WT /PDGFRA WT GIST patients by Sanger Sequencing method. DNA was extracted by the QIAmp DNA Mini kit (Qiagen, Milan, Italy) in accordance with manufacturer's directions. "
[Show abstract] [Hide abstract] ABSTRACT: A subset of GISTs lack mutations in the KIT/PDGFRA or RAS pathways and yet retain an intact succinate dehydrogensase (SDH) complex. We propose that these KIT/PDGFRA/SDH/RAS-P WT GIST tumors be designated as quadruple wild-type (WT) GIST. Further molecular and clinicophatological characterization of quadruple WT GIST will help to determine their prognosis as well as assist in the optimization of medical management, including clinical test of novel therapies.0Comments 11Citations
- "Approximately, 85–90% of gastrointestinal stromal tumors (GISTs) in adults harbor mutant KIT or plateletderived growth factor receptor alpha (PDGFRA) oncopro- teins . The remaining adult cases and the vast majority of pediatric GISTs do not harbor mutations in these receptors and are often referred to as KIT/PDGFRA wildtype (WT) GISTs [1, 2]. Amongst the WT GISTs, at least two other different subgroups with well-defined molecular hallmarks have been described. "