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Gene fusions evidence in a KIT/PDGFRA wild-type GIST without mutations in SDH units identified by a whole transcriptome study.
Abstracts that were granted an exception in accordance with ASCO's Conflict of Interest Policy are designated with a caret symbol (^).
Background: A subset of KIT/PDGFRA wild-type GIST (WT) harbour mutations in SDH units. In the majority of the remaining cases of WT GIST no other molecular events are identified.We performed a RNA-seq in a WT GIST without mutations in SDH genes using next generation approach to discover molecular events in this GIST population. Methods: In 2003, a 63-year old woman underwent surgery for an ileal GIST (size 6 cm, MI 6/50HPF).After 6 years, she developed a recurrence with a single hepatic lesion. The KIT and PDGFRA analysis of the lesion did not show mutations. Therefore, she did not receive imatinib but she underwent a surgical removal. The analysis of all SDH units did not show mutations. So paired-end RNA-seq (75X2) was performed with Illumina HiScanSQ platform. After mapping the short reads on the human genome(HG19), SNVs and InDels were called by SNVMix2 with an accurate filtering procedures including predictors of mutations effect at protein level. Gene fusions discovery was done considering the agreement between DeFuse, ChimeraScan and FusionMap tools and validated by SangerSequencing using primers spanning the mRNA breakpoints. Results: Four different gene fusions and 206 non-synonymous SNVs were discovered, of which 62 were called deleterious by at least one predictor, and they are undergoing further validation. SPRED2-NELFCD gene fusion originated from an interchromosomal translocation-inversion between chr 20 and 2. The event involved exon1 of SPRED2 and exon11 of NELFCD, probably leading to inactivation of both genes. NELFCD encodes a component of the NELF complex that negatively regulates transcription elongation by RNA pol II, while SPRED2 is a member of the Sprouty /SPRED family that repress growth factor-induced activation of the MAPK/ERK pathway. The other three events were intrachromosomal aberrations: MARK2-PPFIA1 and PLA2G16-ATL3 on chr 11 and ASCC1-C10orf11 on chr 10. Only the first event led to an in-frame fusion (MARK2 ex1- PPFIA1 ex2) probably dysregulating the expression of the downstream gene. Conclusions: This is the first evidence of gene fusions in GIST. The oncogenetic role and the tumor frequency of these events deserve to be studied.