Pediatric <i>KIT</i>–Wild-Type and Platelet-Derived Growth Factor Receptor α–Wild-Type Gastrointestinal Stromal Tumors Share KIT Activation but not Mechanisms of Genetic Progression with Adult Gastrointestinal Stromal Tumors

Janeway, Katherine A.; Liegl, Bernadette; Harlow, Amy; Le, Claudia; Perez‐Atayde, Antonio R.; Kozakewich, Harry; Corless, Christopher L.; Heinrich, Michael C.; Fletcher, Jonathan A.

doi:10.1158/0008-5472.can-07-1938

Cited by 154 publications

(122 citation statements)

References 24 publications

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“…These findings highlight that PKCy pathway therapeutic inhibition warrants clinical evaluation as a novel strategy to downregulate KIT and PDGFRA oncoproteins, including those with imatinib-resistance mutations. PKCy targeting might also be useful therapeutically in pediatric GISTs which coexpress KIT and PKCy (Janeway et al, 2007), and respond poorly to imatinib (K Janeway, personal communication). Further studies are needed to determine whether PKCy inactivation by small-molecule kinase inhibitiors can reproduce the spectrum of findings, demonstrated here, that result from downregulation of PKCy expression in GIST.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors

Zhu

Demetri

et al. 2008

Oncogene

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Section: Discussionmentioning

confidence: 99%

Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors

Zhu

Demetri

et al. 2008

Oncogene

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“…When mutation analysis had not previously been performed, genomic DNA was extracted from the paraffinembedded tumor, and exons 9, 11, 13, and 17 of KIT and exons 12 and 18 of PDGFRA were sequenced as previously described (6). Additional tumor samples, not from participants in the NIH Pediatric and WT GIST Clinic used in this study, have been described previously (4,35,36). Ten additional pediatric GIST cases were collected from the archives and referral cases of one of the authors (M.O.)…”

Section: Methodsmentioning

confidence: 99%

Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations

Janeway

Kim

Lodish

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Carney-Stratakis syndrome, an inherited condition predisposing affected individuals to gastrointestinal stromal tumor (GIST) and paraganglioma, is caused by germline mutations in succinate dehydrogenase (SDH) subunits B, C, or D, leading to dysfunction of complex II of the electron transport chain. We evaluated the role of defective cellular respiration in sporadic GIST lacking mutations in KIT or PDGFRA (WT). Thirty-four patients with WT GIST without a personal or family history of paraganglioma were tested for SDH germline mutations. WT GISTs lacking demonstrable SDH genetic inactivation were evaluated for SDHB expression by immunohistochemistry and Western blotting and for complex II activity. For comparison, SDHB expression was also determined in KIT mutant and neurofibromatosis-1-associated GIST, and complex II activity was also measured in SDH-deficient paraganglioma and KIT mutant GIST; 4 of 34 patients (12%) with WT GIST without a personal or family history of paraganglioma had germline mutations in SDHB or SDHC. WT GISTs lacking somatic mutations or deletions in SDH subunits had either complete loss of or substantial reduction in SDHB protein expression, whereas most KIT mutant GISTs had strong SDHB expression. Complex II activity was substantially decreased in WT GISTs. WT GISTs, particularly those in younger patients, have defects in SDH mitochondrial complex II, and in a subset of these patients, GIST seems to arise from germline-inactivating SDH mutations. Testing for germline mutations in SDH is recommended in patients with WT GIST. These findings highlight a potential central role of SDH dysregulation in WT GIST oncogenesis.genetic predisposition | sarcoma | pediatric

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“…These tumors, which often metastasize but tend to grow slowly, have a different gene expression signature from KIT/PDGFRA-mutant GISTs. [69][70][71] Some pediatric-type GISTs are accompanied by pulmonary chondromas and/or paragangliomas, referred to as Carney triad, a non-heritable syndrome, the genetic cause for which has yet to be determined. 72 The origin of GISTs…”

Section: Sdh-deficient Gistsmentioning

confidence: 99%

Gastrointestinal stromal tumors: what do we know now?

2014

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Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the GI tract, arising from the interstitial cells of Cajal, primarily in the stomach and small intestine. They manifest a wide range of morphologies, from spindle cell to epithelioid, but are immunopositive for KIT (CD117) and/or DOG1 in essentially all cases. Although most tumors are localized at presentation, up to half will recur in the abdomen or spread to the liver. The growth of most GISTs is driven by oncogenic mutations in either of two receptor tyrosine kinases: KIT (75% of cases) or PDGFRA (10%). Treatment with tyrosine kinase inhibitors (TKIs) such as imatinib, sunitinib, and regorafenib is effective in controlling unresectable disease; however, drug resistance caused by secondary KIT or PDGFRA mutations eventually develops in 90% of cases. Adjuvant therapy with imatinib is commonly used to reduce the likelihood of disease recurrence after primary surgery, and for this reason assessing the prognosis of newly resected tumors is one of the most important roles for pathologists. Approximately 15% of GISTs are negative for mutations in KIT and PDGFRA. Recent studies of these so-called wild-type GISTs have uncovered a number of other oncogenic drivers, including mutations in neurofibromatosis type I, RAS genes, BRAF, and subunits of the succinate dehydrogenase complex. Routine genotyping is strongly recommended for optimal management of GISTs, as the type and dose of TKI used for treatment is dependent on the mutation identified.

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Pediatric KIT–Wild-Type and Platelet-Derived Growth Factor Receptor α–Wild-Type Gastrointestinal Stromal Tumors Share KIT Activation but not Mechanisms of Genetic Progression with Adult Gastrointestinal Stromal Tumors

Abstract: Fewer than 15% of gastrointestinal stromal tumors (GIST) in pediatric patients harbor KIT or platelet-derived growth factor receptor A (PDGFRA) mutations in contrast to a mutation rate of 80% in adult GISTs. However, some

Cited by 154 publications

References 24 publications

Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors

Protein kinase C-θ regulates KIT expression and proliferation in gastrointestinal stromal tumors

Defects in succinate dehydrogenase in gastrointestinal stromal tumors lacking KIT and PDGFRA mutations

Gastrointestinal stromal tumors: what do we know now?

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