Multiple FGFR1 mutations modulate tumorigenic mechanisms in glioneuronal tumors.
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ABSTRACT:
PROVIDER: PRJNA1208468 | ENA |
REPOSITORIES: ENA
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Project description:FGFR1 genetic alterations are associated with human diseases, including brain tumors. We reported multiple FGFR1 mutations in familial and sporadic cases of low-grade glioneuronal tumors, suggesting intrinsic mechanisms of selective pressure toward FGFR1 multiple events arising in the context of a quiet genome. To decipher the molecular mechanisms triggered by multiple FGFR1 mutations, we have mapped the proximal interactome of wild-type, single- and double-mutant FGFR1 proteins through a BioID-MS approach. Our data reveals novel oncogenic functionality for the two hotspots N546K and K656E, linked to evasion of lysosomal degradation. We identified a modulatory role played by the susceptibility variant R661P, which hampers the oncogenic potential of both hotspot mutations by rescuing receptor degradation and reducing N546K affinity for the downstream effector PLCγ. The R661P variant alone abolished the self-renewal capacity of oligodendroglioma cells and showed downregulation of genes involved in neurodevelopment and neuro-glial cell fate decisions, both aspects overcome in the double mutants. This study sheds light on the oncogenic effects associated with FGFR1 alterations and their recurrence in low-mutation burden and therapy naïve tumors.
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Project description:Glioneuronal tumor (GN) is one type of biphasic central nervous system (CNS) tumor that exhibits both glial and neuronal immunohistological characteristics. We report a case of glioneuronal tumor (GN) with a discovery of novel gene fusion of CLIP2-MET resulting from aberrant chromosome 7 abnormalities. The tumor exhibited typical characteristics on histological examinations. We executed an elaborate genomic study on this case including whole-exome sequencing and RNA sequencing. Genomic analysis of the tumor revealed aberrations in chromosomes 1 and 7 and a CLIP2-MET fusion. Further analysis of the upregulated genes revealed substantial connections with MAPK pathway activation. We concluded that the chromosome 7 abnormalities prompted CLIP2-MET gene fusion which successively leads to MAPK pathway activation. We deliberated that MAPK pathway activation is responsible for the oncogenesis of GN based on our case and other previously reported ones.
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Project description:Using ChIP-Seq analysis of ER+/FGFR1-amplified breast cancer cells and PDXs, we found FGFR1 occupancy at transcription start sites with high overlap with histone modifications associated with active gene transcription. Mass spectrometry analysis of the nuclear and chromatin-bound FGFR1 interactome identified RNA-Polymerase II (Pol II) and FOXA1, with FOXA1 silencing impairing FGFR1 recruitment to chromatin. Transduction of FGFR1(SP-)(NLS) into MCF7 cells resulted in overexpression of nuclear FGFR1 and resistance to antiestrogens. Finally, an expression signature associated with nuclear FGFR1 correlated with endocrine resistance in patients treated with antiestrogens
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