Abstract
BackgroundA subset of KIT/PDGFRA wild-type gastrointestinal stromal tumors (WT GIST) have been associated with alteration of the succinate dehydrogenase (SDH) complex II function. A recent report identified four non-syndromic, KIT/PDGFRA WT GIST harboring compound heterozygous or homozygous mutations in SDHA encoding the main subunit of the SDH complex II.MethodsNext generation sequencing was applied on five pediatric and one young adult WT GIST, by whole exome capture and SOLiD 3-plus system sequencing. The putative mutations were first confirmed by Sanger sequencing and then screened on a larger panel of 11 pediatric and young adult WT GIST, including 5 in the context of Carney triad.ResultsA germline p.Arg31X nonsense SDHA mutation was identified in one of the six cases tested by SOLiD platform. An additional p.D38V missense mutation in SDHA exon 2 was identified by Sanger sequencing in the extended KIT/PDGFRA WT GIST patients cohort. Western blotting showed loss of SDHA expression in the two cases harboring SDHA mutations, while expression being retained in the other WT GIST tumors. Results were further confirmed by immunohistochemistry for both SDHA and SDHB, which showed a concurrent loss of expression of both proteins in SDHA-mutant lesions, while the remaining WT tumors showed only loss of SDHB expression.ConclusionsGermline and/or somatic aberrations of SDHA occur in a small subset of KIT/PDGFRA WT GISTs, outside the Carney’s triad and are associated with loss of both SDHA and SDHB protein expression. Mutations of the SDH complex II are more particularly associated with KIT/PDGFRA WT GIST occurring in young adults. Although pediatric GIST consistently display alterations of SDHB protein expression, further molecular studies are needed to identify the crucial genes involved in their tumorigenesis.
Highlights
A subset of KIT/PDGFRA wild-type gastrointestinal stromal tumors (WT GIST) have been associated with alteration of the succinate dehydrogenase (SDH) complex II function
Mutation of SDHA is a recurrent event in young adults with KIT and PDGFRA WT GIST Massive parallel next-generation sequencing of six cases of WT GIST revealed that the GIST from the young adult patient (22 year-old man, with multinodular gastric lesions and multiple liver metastases) carried a C to T transition at nucleotide 206 in SDHA exon 2, a nonsense mutation resulting in the replacement of arginine with a stop codon at residue 31 of SDHA, causing truncation of the peptide chain at residue 30 (p.Arg31X) (Figure 1)
This result was validated by targeted SDHA exon 2 Sanger sequencing from the DNA isolated from both tumor and normal tissue, in keeping with a germline mutation
Summary
A subset of KIT/PDGFRA wild-type gastrointestinal stromal tumors (WT GIST) have been associated with alteration of the succinate dehydrogenase (SDH) complex II function. A subgroup of these GISTs forms a unique clinicopathological entity, defined by negative staining for SDHB in addition to exhibiting distinct morphologic and clinical features [9,10]. Loss of SDHB is seen in WT GIST occuring in the context of CSS with genlius mutation of SDHB or SDHC (II). Such mutations were found in about 10% of sporadic GIST lacking KIT or PDGFRA mutation [11]. One possible explanation is loss of function mutations in the SDHA gene, which have been recently identified in four patients (one pediatric and 3 young adult) with sporadic GIST lacking KIT or PDGFRA mutations [16,17]. The aim of this study was to assess globally by generation sequencing mutations in the SDH-pathway, as well as determine the mutational and expression status of SDHA in a series of syndromic and sporadic GIST without mutations in KIT or PDGFRA
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