Abstract
Gastrointestinal stromal tumours that are wild type for KIT and PDGFRA are referred to as WT GISTs. Of these tumours, SDH-deficient (characterized by the loss of SDHB) and quadruple WT GIST (KIT/PDGFRA/SDH/RAS-P WT) subgroups were reported to display a marked overexpression of FGF4, identifying a putative common therapeutic target for the first time. In SDH-deficient GISTs, methylation of an FGF insulator region was found to be responsible for the induction of FGF4 expression. In quadruple WT, recurrent focal duplication of FGF3/FGF4 was reported; however, how it induced FGF4 expression was not investigated. To assess whether overexpression of FGF4 in quadruple WT could be driven by similar epigenetic mechanisms as in SDH-deficient GISTs, we performed global and locus-specific (on FGF4 and FGF insulator) methylation analyses. However, no epigenetic alterations were detected. Conversely, we demonstrated that in quadruple WT GISTs, FGF4 expression and the structure of the duplication were intimately connected, with the copy of FGF4 closer to the ANO1 super-enhancer being preferentially expressed. In conclusion, we demonstrated that in quadruple WT GISTs, FGF4 overexpression is not due to an epigenetic mechanism but rather to the specific genomic structure of the duplication. Even if FGF4 overexpression is driven by different molecular mechanisms, these findings support an increasing biologic relevance of the FGFR pathway in WT GISTs, both in SDH-deficient and quadruple WT GISTs, suggesting that it may be a common therapeutic target.
Highlights
Gastrointestinal stromal tumours that are wild type for KIT and PDGFRA are referred to as WT gastrointestinal stromal tumours (GISTs)
Since it was shown that the hypermethylator phenotype of SDH-deficient GISTs was responsible for FGF4 transcriptional a ctivation[8], we investigated for the first time the global DNA methylation profile of quadruple WT GISTs to uncover whether overexpression of FGF4 could be regulated by the same epigenetic mechanism as SDH-deficient cases
Focusing on the FGF4 locus, we showed that neither gene methylation was responsible for FGF4 upregulation in quadruple WT GIST
Summary
The hypermethylator phenotype of SDH-deficient GISTs9 was associated with the methylation of an insulator region (referred to as the “FGF insulator”) located in the upstream region of FGF4 (between FGF3 and AP003555.2) This epigenetic alteration caused genome topology changes, allowing ANO1 (which has super-enhancer activity) to induce the expression of the FGF4 oncogene[8]. FGFR1 was found to be highly expressed in G ISTs7,8,10,11, and activation of the downstream signalling of FGFR, through AKT or MAPK, was demonstrated both in quadruple WT and SDH-deficient GISTs, supporting the presence of an autocrine loop between FGF4 and FGFR17,8 Together, these data highlight the involvement of FGF4 in the biology of GISTs that do not rely on KIT or PDGFRA. In the present work, we studied the methylation status and the structure of FGF4 duplication in quadruple WT GISTs to assess whether epigenetic changes occurred and whether they could be involved in the regulation of FGF4 expression
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