Novel oncogene and tumor suppressor mutations in KIT and PDGFRA wild type gastrointestinal stromal tumors revealed by next generation sequencing. Issue 3 (27th November 2014)

• Record Type: Journal Article
• Authors: Hechtman, Jaclyn Frances; Zehir, Ahmet; Mitchell, Talia; Borsu, Laetitia; Singer, Samuel; Tap, William; Oultache, Alifya; Ladanyi, Marc; Nafa, Khedoudja
• Is Part Of: Genes, chromosomes & cancer. Volume 54:Issue 3(2015:Mar.)
• Page Start: 177
• Page End: 184
• Publication Date: 2014-11-27
• Subjects: Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22230
• Languages: English
• ISSNs: 1045-2257

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Among gastrointestinal stromal tumors (GISTs) of 10–15% are negative for <italic>KIT</italic> and <italic>PDGFRA</italic>, and most of these cases are SDH deficient. Recent studies have provided data on additional molecular alterations such as <italic>KRAS</italic> in <italic>KIT</italic> 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 <italic>KIT</italic> and <italic>PDGFRA</italic> mutations. GISTs with wild type <italic>KIT</italic>/<italic>PDGFRA</italic> 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 <italic>KIT</italic> and <italic>PDGFRA</italic> 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 <italic>ARID1A</italic>, <italic>TP53</italic>, and other genes. One case had a <italic>KRAS</italic> 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, <italic>KRAS</italic> mutations occur in rare GISTs with wild type <italic>KIT</italic> and <italic>PDGFRA</italic>. These tumors may display immunohistochemical positivity for KIT and primary resistance to tyrosine kinase inhibitors. © 2014 Wiley Periodicals, Inc.</p> </abstract>