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

  1. Olga Martinho1,
  2. António Gouveia2,3,4,
  3. Marta Viana-Pereira1,
  4. Paula Silva2,4,
  5. Amadeu Pimenta2,3,4,
  6. Rui Manuel Reis1,
  7. José Manuel Lopes2,4,5

Article first published online: 9 JUL 2009

DOI: 10.1111/j.1365-2559.2009.03323.x

Issue

Histopathology

Histopathology

Volume 55, Issue 1, pages 53–62, July 2009

Additional Information

How to Cite

Martinho, O., Gouveia, A., Viana-Pereira, M., Silva, P., Pimenta, A., Reis, R. M. and Lopes, J. M. (2009), Low frequency of MAP kinase pathway alterations in KIT and PDGFRA wild-type GISTs. Histopathology, 55: 53–62. doi: 10.1111/j.1365-2559.2009.03323.x

Author Information

  1. 1

    Life and Health Sciences Research Institute (ICVS), School of Health Sciences, University of Minho, Braga

  2. 2

    IPATIMUP, Institute of Molecular Pathology and Immunology of the University of Porto

  3. 3

    Department of Surgery, H.S. João

  4. 4

    Medical Faculty of Porto University

  5. 5

    Department of Pathology, H.S. João, Porto, Portugal

*J M Lopes, Rua Dr Roberto Frias, s/n, 4200-465 Porto, Portugal. e-mail: jmlopes@ipatimup.pt

  1. O.M. and A.G. contributed equally to this work.

Publication History

  1. Issue published online: 9 JUL 2009
  2. Article first published online: 9 JUL 2009
  3. Date of submission 10 July 2008 Accepted for publication 16 December 2008

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Keywords:

  • activation;
  • GISTs;
  • MAP kinase;
  • mutations;
  • wild-type

Aims:  Gastrointestinal stromal tumours (GISTs) are commonly driven by oncogenic mutations in KIT and PDGFRA. However, 10–40% of these patients are wild-type for these genes. The prognostic significance of wild-type GISTs is controversial, and they rarely respond to imatinib. The aim of this study was to elucidate the molecular lesions underlying wild-type GISTs tumorigenesis.

Methods and results:  Twenty-nine KIT and PDGFRA wild-type GISTs were re-assessed for the presence of ‘cryptic’KIT exon 11 duplications. Using a specific polymerase chain reaction assay, three previously undetected mutations were identified. In the remaining 26 wild-type GISTs, KIT, stem cell factor (SCF), phospho-KIT and phospho-ERK expression was evaluated by immunohistochemistry. Samples were screened for gain-of-function mutations in the mitogen-activated protein kinase (MAPK) cascade. KIT and SCF co-expression associated with KIT activation was observed in approximately 30% of cases. Furthermore, phospho-ERK expression showed that MAPK is activated in approximately 30% of cases. None of RAS family (H-, K- and N-RAS) oncogenes exhibited activating mutations, whereas BRAF mutations were found in approximately 4% of cases.

Conclusions:  In the absence of RAS mutations, MAPK could be activated through SCF/KIT autocrine/paracrine mechanisms and/or mutated BRAF in a subset of KIT/PDGFRA wild-type GISTs.

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