Differential expression of neural markers in KIT and PDGFRA wild-type gastrointestinal stromal tumours

Abstract

WT GISTs have different genomic profiles from both mutated GISTs and murine mature ICCs. Considering that IGF1R expression is common to both WT GISTs and putative precursor ICCs, this study suggests that WT GISTs may derive either from ICCs at a different step of differentiation or from a different cell of origin.

An overview on molecular biology of KIT/PDGFRA wild type (WT) gastrointestinal stromal tumours (GIST)

“…Moreover, in a larger series of 30 tumour samples (26 mutant vs 4 KIT/PDGFRA WT GIST), it has been confirmed that the gene expression profiles of KIT/PDGFRA WT and mutated GIST differed profoundly, with a total of 3250 probe sets differentially expressed at a 0.05 p value cut-off level 15. The expression of the top differentially expressed genes at a <0.001 p value cut-off level was restricted mainly to neural tissues, suggesting that neurogenesis-related functions were dominant 15.…”

“…The expression of the top differentially expressed genes at a <0.001 p value cut-off level was restricted mainly to neural tissues, suggesting that neurogenesis-related functions were dominant 15. The differential expression of genes encoding structural protein expressed in neural tissues, such as cadherin-2 (CDH2), neurofilament light polypeptide gene (NEFL) and neural progenitor-specific genes (IGF1R, LHX2, KIRREL3, ELAVL3), was validated by qPCR and IHC analyses, and it has been found that some were selectively expressed in KIT/PDGFRA WT samples 15.…”

“…The expression of the top differentially expressed genes at a <0.001 p value cut-off level was restricted mainly to neural tissues, suggesting that neurogenesis-related functions were dominant 15. The differential expression of genes encoding structural protein expressed in neural tissues, such as cadherin-2 (CDH2), neurofilament light polypeptide gene (NEFL) and neural progenitor-specific genes (IGF1R, LHX2, KIRREL3, ELAVL3), was validated by qPCR and IHC analyses, and it has been found that some were selectively expressed in KIT/PDGFRA WT samples 15. Of note, a subsequent meta-analysis conducted on data in murine ICCs and on data from human GIST and murine ICCs (DMP and MY) showed that mutated GIST co-map with ICCs, and, conversely, the expression profile of KIT/PDGFRA WT GIST was not shared by either mutated tumours or putative precursor ICCs, suggesting that KIT/PDGFRA WT GIST may have a different cellular origin or may derive from ICCs during a different differentiation step, such as from precursors of ICCs 15…”

“…KIT/PDGFRA WT GISTs also differ from mutant GISTs in gene-expression profiling, with the most difference observed in the repressed expression of RTN1, DAAM1 and DACT1 seen in mutant GISTs 10. Differences in the expression of genes that belong to neural tissue were also seen between tissue from mutated GIST and murine mature interstitial cells of Cajal (ICCs), suggesting that KIT/PDGFRA WT GIST may have a different cell of origin 15. Furthermore, several mutations have been described whose pathogenic significance is uncertain.…”

The progressive fragmentation of the KIT/PDGFRA wild-type (WT) gastrointestinal stromal tumors (GIST)

“…Despite their unquestionable GIST morphology, given this marked molecular heterogeneity, quadruple WT GIST could be a different disease than GIST. Otherwise, trusting unquestionable GIST morphology, it could be argued that quadruple WT GIST may arise from a distinct population of pluripotent interstitial cells of Cajal (ICC) [34, 35], or that they may share a molecular driver at the epigenomic level, given their homogeneous gene expression profile.…”