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RNAseq of 76 samples from Uveal Melanoma tumors

ABSTRACT: Hotspot mutations in the spliceosome gene SF3B1 are reported in 20% of uveal melanomas. SF3B1 is involved in 3'-splice site (3'ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1 R625/K666 mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3'ss

PROVIDER: EGAS00001002932 | EGA |

REPOSITORIES: EGA

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b4290dba-60d5-4af4-a857-5c0419dff5de - samples

Project description:Hotspot mutations in the spliceosome gene SF3B1 are reported in 20% of uveal melanomas. SF3B1 is involved in 3'-splice site (3'ss) recognition during RNA splicing; however, the molecular mechanisms of its mutation have remained unclear. Here we show, using RNA-Seq analyses of uveal melanoma, that the SF3B1 R625/K666 mutation results in deregulated splicing at a subset of junctions, mostly by the use of alternative 3'ss.

| EGAD00001004398 | EGA

Cancer associated SF3B1 hotspot mutations induce cryptic 3' splice site selection through use of a different branch point

Project description:Recurrent mutations in the spliceosome are observed in several human cancers but their functional and therapeutic significance remain elusive. SF3B1, the most frequently mutated component of the spliceosome in cancer, is involved in the recognition of the branch point sequence (BPS) during selection of the 3’ splice site (ss) in RNA splicing. Here, we report that common and tumor-specific splicing aberrations are induced by SF3B1 mutations and establish aberrant 3’ ss selection as the most frequent splicing defect. Strikingly, mutant SF3B1 utilizes a BPS that differs from that used by wild-type SF3B1 and requires the canonical 3’ ss to enable aberrant splicing during the second step. Approximately 50% of the aberrantly spliced mRNAs are subjected to nonsense-mediated decay resulting in downregulation of gene and protein expression. These findings ascribe functional significance to the consequences of SF3B1 mutations in cancer. 72 samples, including two sets of patient data and cell lines with two additional technical replicates each

2015-09-08 | E-GEOD-72790 | biostudies-arrayexpress

Transcriptomic analyses of primary uveal melanomas

Project description:SF3B1 is coding an essential splicing factor. This gene was found recurrently mutated in uveal melanoma. To understand the consequences of these hotspot SF3B1 mutations, we performed high coverage RNA-seq on 74 primary uveal melanomas, which were treated by primary enucleation. We analyzed data for aberrant splicing in relation with SF3B1 status.

2016-07-03 | E-MTAB-4097 | biostudies-arrayexpress

Cancer associated SF3B1 hotspot mutations induce cryptic 3' splice site selection through use of a different branch point

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Novel SF3B1 Deletion Mutations Result in Aberrant RNA Splicing in CLL Patients

Project description:Recurrent mutations in RNA splicing factors SF3B1, U2AF1, and SRSF2 have been reported in hematologic cancers including myelodysplastic syndromes (MDS) and chronic lymphocytic leukemia (CLL). However, SF3B1 is the only splicing associated gene to be found mutated in CLL and has been shown to induce aberrant splicing. To investigate if any other genomic aberration caused similar transcriptome changes, we clustered RNASeq samples based on an alternative 3’ splice site (ss) pattern previously identified in SF3B1-mutant CLL patients. Out of 215 samples, we identified 37 (17%) with alternative 3’ ss usage, the majority of which harbored known SF3B1 hotspot mutations. Interestingly, 3 patient samples carried previously unreported in-frame deletions in SF3B1 around K700, the most frequent mutation hotspot. To study the functional effects of these deletions, we used various minigenes demonstrating that recognition of canonical 3’ ss and alternative branchsite are required for aberrant splicing, as observed for SF3B1 p.K700E. The common mechanism of action of these deletions and substitutions result in similar sensitivity of primary cells towards splicing inhibitor E7107. Altogether, these data demonstrate that novel SF3B1 in-frame deletion events identified in CLL result in aberrant splicing, a common biomarker in spliceosome-mutant cancers.

2017-06-27 | GSE95352 | GEO

Splicing patterns in SF3B1 mutated uveal melanoma generate shared immunogenic tumor-specific neo-epitopes [scRNA-seq]

Project description:Purpose: In this study, we show that mutations of the splicing factor SF3B1 in uveal melanoma (UM) generate immunogenic neo-antigens.

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Splicing patterns in SF3B1 mutated uveal melanoma generate shared immunogenic tumor-specific neo-epitopes [scADT-seq]

Project description:Purpose: In this study, we show that mutations of the splicing factor SF3B1 in uveal melanoma (UM) generate immunogenic neo-antigens.

2021-03-26 | GSE169605 | GEO

Splicing patterns in SF3B1 mutated uveal melanoma generate shared immunogenic tumor-specific neo-epitopes [scTCR-seq]

Project description:Purpose: In this study, we show that mutations of the splicing factor SF3B1 in uveal melanoma (UM) generate immunogenic neo-antigens.

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Splicing patterns in SF3B1 mutated uveal melanoma generate shared immunogenic tumor-specific neo-epitopes [bulk TCR-seq]

Project description:Purpose: In this study, we show that mutations of the splicing factor SF3B1 in uveal melanoma (UM) generate immunogenic neo-antigens.

2021-03-31 | GSE171166 | GEO

Cancer-Causing Mutations in SF3B1 Alter Splicing by Disrupting Interaction with SUGP1

Project description:SF3B1, which encodes an essential spliceosomal protein, is frequently mutated in myelodysplastic syndromes (MDS) and many cancers. However, the defect of mutant SF3B1 is unknown. Here, we analyzed RNA-sequencing data from MDS patients and confirmed that SF3B1 mutants use aberrant 3' splice sites. To elucidate the underlying mechanism, we purified complexes containing either wild-type or the hotspot K700E mutant SF3B1, and found that levels of a poorly studied spliceosomal protein, SUGP1, were reduced in mutant spliceosomes. Strikingly, SUGP1 knockdown completely recapitulated the splicing errors, whereas SUGP1 overexpression drove the protein, which our data suggests plays an important role in branchsite recognition, into the mutant spliceosome and partially rescued splicing. Other hotspot SF3B1 mutants showed similar altered splicing and diminished interaction with SUGP1. Our study demonstrates that SUGP1 loss is the sole defect of mutant SF3B1 spliceosomes and, since this defect can be rescued, suggests possibilities for therapeutic intervention.

2019-07-24 | GSE128805 | GEO

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