Novel oncogene and tumor suppressor mutations in KIT and PDGFRA wild type gastrointestinal stromal tumors revealed by next generation sequencing Journal Article


Authors: Hechtman, J. F.; Zehir, A.; Mitchell, T.; Borsu, L.; Singer, S.; Tap, W.; Oultache, A.; Ladanyi, M.; Nafa, K.
Article Title: Novel oncogene and tumor suppressor mutations in KIT and PDGFRA wild type gastrointestinal stromal tumors revealed by next generation sequencing
Abstract: Among gastrointestinal stromal tumors (GISTs) of 10-15% are negative for KIT and PDGFRA, and most of these cases are SDH deficient. Recent studies have provided data on additional molecular alterations such as KRAS in KIT mutant GISTs. We aimed to assess the frequency and spectrum of somatic mutations in common oncogenes as well as copy number variations in GISTs negative for KIT and PDGFRA mutations. GISTs with wild type KIT/PDGFRA were tested via next generation sequencing for somatic mutations in 341 genes. SDHB immunohistochemistry to evaluate for SDH deficiency was also performed. Of 267 GISTs tested for KIT and PDGFRA mutations, 15 were wild type, of which eight cases had material available for further testing. All eight cases had loss of SDHB expression and had various molecular alterations involving ARID1A, TP53, and other genes. One case had a KRAS G12V (c.35G>T) mutation in both the primary gastric tumor and a post-imatinib recurrence. This tumor had anaplastic features and was resistant to multiple tyrosine kinase inhibitors, ultimately resulting in cancer-related mortality within 2 years of diagnosis. In conclusion, KRAS mutations occur in rare GISTs with wild type KIT and PDGFRA. These tumors may display immunohistochemical positivity for KIT and primary resistance to tyrosine kinase inhibitors.
Keywords: immunohistochemistry; adult; clinical article; aged; middle aged; gene mutation; gene sequence; gastrointestinal stromal tumor; imatinib; wild type; oncogene; tumor suppressor gene; kit gene; kras gene; pdgfra gene; tp53 gene; human; male; female; priority journal; article; aridia gene
Journal Title: Genes Chromosomes and Cancer
Volume: 54
Issue: 3
ISSN: 1045-2257
Publisher: Wiley Periodicals, Inc  
Date Published: 2015-03-01
Start Page: 177
End Page: 184
Language: English
DOI: 10.1002/gcc.22230
PROVIDER: scopus
PUBMED: 25427437
PMCID: PMC6452627
DOI/URL:
Notes: Export Date: 2 March 2015 -- Source: Scopus
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MSK Authors
  1. Khedoudja Nafa
    244 Nafa
  2. Marc Ladanyi
    1332 Ladanyi
  3. Samuel Singer
    337 Singer
  4. Ahmet Zehir
    344 Zehir
  5. William Douglas Tap
    377 Tap
  6. Jaclyn Frances Hechtman
    212 Hechtman