TY - JOUR
T1 - Gene duplication, rather than epigenetic changes, drives FGF4 overexpression in KIT/PDGFRA/SDH/RAS-P WT GIST
AU - Urbini, Milena
AU - Astolfi, Annalisa
AU - Indio, Valentina
AU - Nannini, Margherita
AU - Schipani, Angela
AU - Bacalini, Maria Giulia
AU - Angelini, Sabrina
AU - Ravegnini, Gloria
AU - Calice, Giovanni
AU - Del Gaudio, Massimo
AU - Secchiero, Paola
AU - Ulivi, Paola
AU - Gruppioni, Elisa
AU - Pantaleo, Maria Abbondanza
PY - 2020/12
Y1 - 2020/12
N2 - 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.
AB - 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.
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U2 - 10.1038/s41598-020-76519-y
DO - 10.1038/s41598-020-76519-y
M3 - Article
C2 - 33199729
AN - SCOPUS:85096043800
VL - 10
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 19829
ER -