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Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs

Olga Martinho1, António Gouveia, Marta Viana-Pereira

  • 1Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga, Portugal.

Histopathology
|July 21, 2009
PubMed
Abstract

Insights

Molecular analysis of wild-type gastrointestinal stromal tumors (GISTs) revealed that MAPK pathway activation occurs through SCF/KIT mechanisms or BRAF mutations, independent of RAS mutations.

Area of Science:

  • Oncology
  • Molecular Biology
  • Gastroenterology

Background:

  • Gastrointestinal stromal tumors (GISTs) are often driven by KIT or PDGFRA mutations.
  • A significant subset of GISTs (10-40%) lack these common mutations and are considered wild-type.
  • The clinical and molecular characteristics of wild-type GISTs, particularly their response to therapy like imatinib, remain incompletely understood.

Purpose of the Study:

  • To investigate the molecular mechanisms driving tumorigenesis in KIT and PDGFRA wild-type GISTs.
  • To identify alternative oncogenic drivers and signaling pathway activations in these GISTs.
  • To understand the basis for the limited response of wild-type GISTs to imatinib treatment.

Main Methods:

  • Re-evaluation of 29 KIT and PDGFRA wild-type GISTs for cryptic KIT exon 11 duplications using a specific polymerase chain reaction (PCR) assay.
  • Immunohistochemical analysis of KIT, stem cell factor (SCF), phospho-KIT, and phospho-ERK expression in 26 wild-type GISTs.
  • Screening for gain-of-function mutations in the mitogen-activated protein kinase (MAPK) cascade, including RAS family genes and BRAF.

Main Results:

  • Three previously undetected KIT exon 11 duplications were identified.
  • Approximately 30% of wild-type GISTs exhibited co-expression of KIT and SCF, correlating with KIT activation.
  • MAPK pathway activation, indicated by phospho-ERK expression, was observed in approximately 30% of cases.
  • While RAS family oncogenes showed no activating mutations, BRAF mutations were detected in about 4% of cases.

Conclusions:

  • MAPK pathway activation in a subset of KIT/PDGFRA wild-type GISTs can occur independently of RAS mutations.
  • Activation may be mediated by autocrine/paracrine SCF/KIT signaling mechanisms.
  • Mutated BRAF represents another potential driver of MAPK activation in these GISTs.

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