Gene duplication, rather than epigenetic changes, drives FGF4 overexpression in KIT/PDGFRA/SDH/RAS-P WT GIST

Milena Urbini, Annalisa Astolfi, Valentina Indio, Margherita Nannini, Angela Schipani, Maria Giulia Bacalini, Sabrina Angelini, Gloria Ravegnini, Giovanni Calice, Massimo Del Gaudio, Paola Secchiero, Paola Ulivi, Elisa Gruppioni, Maria Abbondanza Pantaleo

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number19829
JournalScientific Reports
Volume10
Issue number1
DOIs
Publication statusPublished - Dec 2020

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Gene duplication, rather than epigenetic changes, drives FGF4 overexpression in KIT/PDGFRA/SDH/RAS-P WT GIST'. Together they form a unique fingerprint.

Cite this