Clinical and molecular characteristics of pediatric gastrointestinal stromal tumors (GISTs)

Price, Victoria; Zieleńska, Maria; Smith, Code; Chilton‐MacNeill, Susan; Malkin, David; Pappo, Alberto S.

doi:10.1200/jco.2004.22.14_suppl.8537

Cited by 9 publications

(18 citation statements)

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“…For this reason, the syndrome is probably under-diagnosed. A similar number of apparently sporadic pediatric GISTs have been reported (18)(19)(20)(21)(22)(23)(24). Based on the clinicopathologic and molecular similarity, it remains possible that some of these apparently sporadic pediatric GISTs may represent either initial manifestation or a forme fruste of Carney triad (20).…”

Section: Introductionmentioning

confidence: 71%

Epithelioid gastric stromal tumours of the antrum in young females with the Carney triad: A report of three new cases with mutational analysis and comparative genomic hybridization

Agaimy¹,

Pelz²,

Corless³

et al. 2007

Oncol Rep

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Carney triad is a rare non-hereditary condition affecting young females and characterized by metachronous or synchronous occurrence of epithelioid gastrointestinal stromal tumours (GISTs), pulmonary chondroma and extraadrenal paraganglioma. The genetic alterations in Carney triad-related GISTs have not been well studied. We evaluated GISTs from three females with incomplete Carney triad for KIT and PDGFRA mutations and studied the DNA by comparative genomic hybridization (CGH). All GISTs originated in the antrum and had a monotonous epithelioid morphology. Two patients had GISTs and pulmonary chondroma and one had GISTs and paraganglioma. Initial manifestation was GIST (n=1), pulmonary chondroma (n=1) and bladder paraganglioma (n=1). Time to the second component was 2-13 years. Two patients were alive at 108 and 168 months (one with metastases) and one died of the disease 3 years later. All cases were wild-type for KIT exons 9, 11, 13, 17 and PDGFRA exons 12 and 18. CGH revealed 14 aberrations (mean, 4.7/tumour) including 11 gains (X, 1q, 5p, 8q, 9p, 12p, 13q, 18p, 19q), 2 amplifications (1q, 19p) and one loss (13q). Carney triad-related GISTs do not only lack conventional KIT and PDGFRA mutations, but they also lack the non-random loss of 14q and 22q characteristic of their sporadic counterparts, suggesting an origin through a distinct pathogenetic pathway.

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Section: Introductionmentioning

confidence: 71%

Epithelioid gastric stromal tumours of the antrum in young females with the Carney triad: A report of three new cases with mutational analysis and comparative genomic hybridization

Agaimy¹,

Pelz²,

Corless³

et al. 2007

Oncol Rep

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“…These tumours lack KIT and PDGFRA mutations, suggesting that other mechanisms of KIT activation or unrelated oncogenic mechanisms are operational 128–133 . A Pro456Ser in KIT exon 9 and nonsense mutation in PDGFRA exon 18 have been reported in two separate paediatric GISTs, 134,135 however, these mutations probably represent random molecular events.…”

Section: Mutations Tumour Location and Demographicsmentioning

confidence: 99%

“…Also, KIT STOP codon/frame‐shift mutations have been reported occasionally in primary and metastatic GISTs 27,90,135,173 . These mutations might reflect secondary changes related to tumour progression.…”

Section: Technical Considerationsmentioning

confidence: 99%

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

2008

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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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“…This suggests that other as yet unidentified gene(s) are responsible for CT. Further support to this notion is provided by the clinical and molecular analysis of KIT mutation‐negative GISTs: KIT mutations are rare in childhood GISTs, tumours that occur predominantly in females, mostly during the second decade of life and with a gastric predilection [23] – all features of GISTs associated with CT [3, 4]. More recent studies show that KIT‐ and PPDFGRA mutation‐negative GISTs have a distinct pattern of gene expression [24, 25].…”

Section: Summary Of the Findings In Ctmentioning

confidence: 99%

The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney–Stratakis syndrome): molecular genetics and clinical implications

Stratakis

Carney

2009

Journal of Internal Medicine

276

232

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Carney triad (CT) describes the association of paragangliomas (PGLs) with gastrointestinal stromal tumours (GISTs) and pulmonary chondromas (PCH). A number of other lesions have been described in the condition including pheochromocytomas, oesophageal leiomyomas and adrenocortical adenomas; CT is a novel form of multiple endocrine neoplasia (MEN), a genetic condition with a female predilection. Inactivating mutations of the mitochondrial complex II succinate dehydrogenase (SDH) enzyme subunits SDHB, SDHC and SDHD have been found in familial and sporadic PGLs, and gain-of-function mutations of the oncogenes c-kit (KIT) and platelet-derived growth factor receptor A (PDGFRA) cause sporadic and familial GISTs. We recently reported an international series of patients with CT, 34 females and three males (median age of presentation 21 years) who did not carry SDHA, SDHB, SDHC, SDHD, KIT or PDGFRA gene mutations. Comparative genomic hybridization revealed a number of DNA copy number changes. The most frequent and greatest contiguous change was a deletion within the 1pcen13-q21 region, which harbours the SDHC gene. Another frequent change was loss of 1p. Although GISTs showed more frequent losses of 1p than PGLs, the pattern of chromosomal changes was similar in the two tumours despite their different tissue origin and histology; the findings were consistent with a common genetic aetiology of these two tumours in CT. In a separate condition, in which the association (or dyad) of GISTs with PGLs is inherited in an autosomal dominant manner (Carney–Stratakis syndrome, CSS), germline mutations of the SDHB, SDHC and SDHD genes (but not KIT or PDFGRA) were found; GISTs in this condition were caused by SDH deficiency. We conclude that CT is a novel MEN syndrome whose genetic defect remains elusive. CSS is caused by SDH defects, suggesting that sarcomas (GISTs) can be caused by defective mitochondrial oxidation, consistent with recent data implicating this enzyme in a variety of endocrine and other tumours. The above have clinical implications (i) for patients with GISTs that are cKIT- and PDGFRA-mutation negative: these tumours are usually resistant to treatment with currently available tyrosine kinase inhibitors and may be part of a syndrome such as CT or CSS; and (ii) for patients with an inherited PGL syndrome, family history should be explored to identify any other tumours in the family, and in particular other endocrine lesions and GISTs.

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Clinical and molecular characteristics of pediatric gastrointestinal stromal tumors (GISTs)

Cited by 9 publications

References 0 publications

Epithelioid gastric stromal tumours of the antrum in young females with the Carney triad: A report of three new cases with mutational analysis and comparative genomic hybridization

Epithelioid gastric stromal tumours of the antrum in young females with the Carney triad: A report of three new cases with mutational analysis and comparative genomic hybridization

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

The triad of paragangliomas, gastric stromal tumours and pulmonary chondromas (Carney triad), and the dyad of paragangliomas and gastric stromal sarcomas (Carney–Stratakis syndrome): molecular genetics and clinical implications

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