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Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors
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Published on: September 20, 2016

KIT and platelet-derived growth factor receptor alpha tyrosine kinase gene mutations and KIT amplifications in human

Harri Sihto1, Maarit Sarlomo-Rikala, Olli Tynninen

  • 1Department of Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 180, FIN-00029 Helsinki, Finland.

Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology
|November 17, 2004
PubMed
Abstract

Insights

Activating mutations in KIT and PDGFRA genes are key targets in GIST treatment. This study found these mutations are rare in most other human cancers, despite KIT protein expression in some.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Gastrointestinal stromal tumors (GISTs) are primarily treated with imatinib mesylate, targeting mutated KIT and platelet-derived growth factor receptor alpha (PDGFRA) tyrosine kinases.
  • The prevalence of activating KIT and PDGFRA gene mutations in other cancer types remains largely unknown.

Purpose of the Study:

  • To investigate the frequency of activating KIT and PDGFRA gene mutations across various human cancer histologic types.
  • To correlate KIT protein expression with gene mutations and chromosomal abnormalities in non-GIST cancers.

Main Methods:

  • Screened KIT and PDGFRA gene exons (KIT: 9, 11, 13, 17, and 9-21; PDGFRA: 11, 17) in 334 human cancers across 32 histologic types using denaturing high-performance liquid chromatography (DHPLC).
  • Sequenced samples with abnormal DHPLC findings and performed KIT protein (CD117) immunostaining on 322 cases.
  • Utilized fluorescence in situ hybridization (FISH) to analyze KIT gene amplification and chromosome 4 aneuploidy in tumors with high KIT expression.

Main Results:

  • Only 17 mutations were found across 3,039 screened exons, all exclusively in GIST tumors (15 KIT, 2 PDGFRA).
  • No KIT or PDGFRA mutations were detected in 316 non-GIST cancer samples.
  • KIT protein expression was frequent in GISTs but also observed in small-cell lung cancer (33%) and testicular teratocarcinoma (24%).
  • Non-GIST tumors with strong KIT expression often showed wild-type KIT gene amplification or chromosome 4 aneuploidy (7 of 12).

Conclusions:

  • Activating KIT and PDGFRA gene mutations are infrequent in the majority of human cancers, with GISTs being the primary exception.
  • KIT protein expression in non-GIST cancers is often associated with amplified wild-type KIT genes rather than activating mutations.

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