Abstract
BackgroundApproximately 10–15 % of gastrointestinal stromal tumors (GISTs) lack gain of function mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. An alternate mechanism of oncogenesis through loss of function of the succinate-dehydrogenase (SDH) enzyme complex has been identified for a subset of these “wild type” GISTs.MethodsPaired tumor and normal DNA from an SDH-intact wild-type GIST case was subjected to whole exome sequencing to identify the pathogenic mechanism(s) in this tumor. Selected findings were further investigated in panels of GIST tumors through Sanger DNA sequencing, quantitative real-time PCR, and immunohistochemical approaches.ResultsA hemizygous frameshift mutation (p.His2261Leufs*4), in the neurofibromin 1 (NF1) gene was identified in the patient’s GIST; however, no germline NF1 mutation was found. A somatic frameshift mutation (p.Lys54Argfs*31) in the MYC associated factor X (MAX) gene was also identified. Immunohistochemical analysis for MAX on a large panel of GISTs identified loss of MAX expression in the MAX-mutated GIST and in a subset of mainly KIT-mutated tumors.ConclusionThis study suggests that inactivating NF1 mutations outside the context of neurofibromatosis may be the oncogenic mechanism for a subset of sporadic GIST. In addition, loss of function mutation of the MAX gene was identified for the first time in GIST, and a broader role for MAX in GIST progression was suggested.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1872-y) contains supplementary material, which is available to authorized users.
Highlights
10–15 % of gastrointestinal stromal tumors (GISTs) lack gain of function mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes
These analyses suggested that the case belonged to the small subset of SDH-intact and KIT, PDGFA, BRAF wild-type GIST, for which no clear molecular pathogenic mechanism has been established
In a recent transcriptome-sequencing study [51], no neurofibromin 1 (NF1) mutations were identified in two SDH intact wild-type GIST, it has been shown that only a portion of exonic variants are typically captured by RNA-seq approaches [52]
Summary
10–15 % of gastrointestinal stromal tumors (GISTs) lack gain of function mutations in the KIT and platelet-derived growth factor receptor alpha (PDGFRA) genes. An alternate mechanism of oncogenesis through loss of function of the succinate-dehydrogenase (SDH) enzyme complex has been identified for a subset of these “wild type” GISTs. Gastrointestinal stromal tumor (GIST) is a mesenchymal neoplasm that originates throughout the GI tract, primarily in the stomach (>50 %) and small intestine (~30 %) [1]. ICC and the majority (95 %) of GIST express the type III receptor tyrosine kinase KIT (CD117), and variably exhibit myoid or neural features. The majority of GISTs exhibit gain of function mutations in KIT or in the related receptor PDGFRA [6, 7]. A subset (~10–15 %) of GISTs in adults lack mutations in the KIT and PDGFRA genes, as do almost all pediatric cases [8, 9].
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