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

Katherine A. Janeway, Bernadette Liegl, Amy Harlow, Claudia Le, Antonio Perez-Atayde, Harry Kozakewich, Christopher Corless, Michael Heinrich, Jonathan A. Fletcher

Research output: Contribution to journalArticle

114 Citations (Scopus)

Abstract

Fewer than 15% of gastrointestinal stromal tumors (GIST) in pediatric patients harbor KIT or platelet-derived growth factor receptor α (PDGFRA) mutations in contrast to a mutation rate of 80% in adult GISTs. However, some therapeutic inhibitors of KIT have efficacy in pediatric GIST, suggesting that KIT may, nevertheless, play an important role in oncogenesis. In adult GIST, characteristic cytogenetic changes occur during progression to malignancy. A better understanding of mechanisms of genetic progression and KIT and PDGFRA transforming roles in pediatric GIST might facilitate treatment advances. KIT and PDGFRA mutation analysis was done in 27 pediatric GISTs. The activation status of KIT, PDGFRA, and downstream signaling intermediates was defined, and chromosomal aberrations were determined by single nucleotide polymorphism assays. Mutations in KIT or PDGFRA were identified in 11% of pediatric GISTs. KIT and the signaling intermediates AKT and mitogen-activated protein kinase were activated in pediatric GISTs. In particular, most pediatric KIT-wild-type GISTs displayed levels of KIT activation similar to levels in adult KIT-mutant GISTs. Pediatric KIT-wild-type GISTs lacked the typical cytogenetic deletions seen in adult KIT-mutant GISTs. Notably, most pediatric KIT-wild-type GISTs progress to malignancy without acquiring large-scale chromosomal aberrations, which is a phenomenon not reported previously in malignant solid tumors. KIT activation levels in pediatric KIT-wild-type GISTs are comparable with those in KIT-mutant GISTs. Therapies that inhibit KIT activation, or crucial KIT signaling intermediates, should be explored in pediatric KIT-wild-type GIST.

Original languageEnglish (US)
Pages (from-to)9084-9088
Number of pages5
JournalCancer Research
Volume67
Issue number19
DOIs
StatePublished - Oct 1 2007

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Platelet-Derived Growth Factor Receptors
Gastrointestinal Stromal Tumors
Pediatrics
Cytogenetics
Chromosome Aberrations
Mutation
Neoplasms
Mutation Rate
Mitogen-Activated Protein Kinases
Single Nucleotide Polymorphism
Carcinogenesis
Therapeutics

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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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. / Janeway, Katherine A.; Liegl, Bernadette; Harlow, Amy; Le, Claudia; Perez-Atayde, Antonio; Kozakewich, Harry; Corless, Christopher; Heinrich, Michael; Fletcher, Jonathan A.

In: Cancer Research, Vol. 67, No. 19, 01.10.2007, p. 9084-9088.

Research output: Contribution to journalArticle

Janeway, Katherine A. ; Liegl, Bernadette ; Harlow, Amy ; Le, Claudia ; Perez-Atayde, Antonio ; Kozakewich, Harry ; Corless, Christopher ; Heinrich, Michael ; Fletcher, Jonathan A. / 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. In: Cancer Research. 2007 ; Vol. 67, No. 19. pp. 9084-9088.
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abstract = "Fewer than 15{\%} of gastrointestinal stromal tumors (GIST) in pediatric patients harbor KIT or platelet-derived growth factor receptor α (PDGFRA) mutations in contrast to a mutation rate of 80{\%} in adult GISTs. However, some therapeutic inhibitors of KIT have efficacy in pediatric GIST, suggesting that KIT may, nevertheless, play an important role in oncogenesis. In adult GIST, characteristic cytogenetic changes occur during progression to malignancy. A better understanding of mechanisms of genetic progression and KIT and PDGFRA transforming roles in pediatric GIST might facilitate treatment advances. KIT and PDGFRA mutation analysis was done in 27 pediatric GISTs. The activation status of KIT, PDGFRA, and downstream signaling intermediates was defined, and chromosomal aberrations were determined by single nucleotide polymorphism assays. Mutations in KIT or PDGFRA were identified in 11{\%} of pediatric GISTs. KIT and the signaling intermediates AKT and mitogen-activated protein kinase were activated in pediatric GISTs. In particular, most pediatric KIT-wild-type GISTs displayed levels of KIT activation similar to levels in adult KIT-mutant GISTs. Pediatric KIT-wild-type GISTs lacked the typical cytogenetic deletions seen in adult KIT-mutant GISTs. Notably, most pediatric KIT-wild-type GISTs progress to malignancy without acquiring large-scale chromosomal aberrations, which is a phenomenon not reported previously in malignant solid tumors. KIT activation levels in pediatric KIT-wild-type GISTs are comparable with those in KIT-mutant GISTs. Therapies that inhibit KIT activation, or crucial KIT signaling intermediates, should be explored in pediatric KIT-wild-type GIST.",
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AU - Janeway, Katherine A.

AU - Liegl, Bernadette

AU - Harlow, Amy

AU - Le, Claudia

AU - Perez-Atayde, Antonio

AU - Kozakewich, Harry

AU - Corless, Christopher

AU - Heinrich, Michael

AU - Fletcher, Jonathan A.

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