Methylation profiling of sarcoma and TFCP2-rearranged rhadomyosarcoma samples
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ABSTRACT:
PROVIDER: EGAD00010002451 | EGA |
REPOSITORIES: EGA
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Project description:Linking clinical multi-omics analyses with mechanistic studies may improve the understanding of rare cancers. We leverage two precision oncology programs to investigate rhabdomyosarcoma with FUS/EWSR1-TFCP2 fusions, an orphan malignancy without effective therapies. All tumors exhibit outlier ALK expression, partly accompanied by intragenic deletions and aberrant splicing resulting in truncated ALK variants that are oncogenic and sensitive to ALK inhibitors. Additionally, recurrent CKDN2A/MTAP co-deletions provide a rationale for CDK4/6- and PRMT5-targeted therapies. Functional studies show that FUS-TFCP2 blocks myogenic differentiation, induces transcription of ALK and truncated TERT, and inhibits DNA repair. Unlike other fusion-driven sarcomas, TFCP2-rearranged tumors exhibit genomic instability and signs of defective homologous recombination. DNA methylation profiling indicate a close relationship with undifferentiated sarcomas. Finally, in two patients, sarcoma was preceded by benign lesions carrying FUS-TFCP2, providing insight into stepwise sarcomagenesis. This study illustrates the potential of linking precision oncology with preclinical research to gain insight into the classification, pathogenesis, and therapeutic vulnerabilities of rare cancers.
2023-11-06 | GSE224183 | GEO
Project description:Expression profiling of Ewing sarcoma samples in the frame of the CIT program from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). Ewing sarcoma a rare pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. A genome-wide association study of at least 401 French ES patients compared to either 684 French or 3668 US self-described Caucasian controls consistently revealed candidate loci at chromosomes 1 and 10 (p<10-6). These loci were further replicated in two independent sets of cases and controls. Joint analysis identified rs9430161 (p=1.4x10-20; OR=2.2, CI99=1.8-2.7) 25kb upstream to TARDBP (1p36.22) and rs224278 (p=4.0x10-17 OR=1.7, CI99=1.4-1.9) 5kb upstream to EGR2 (10q21). The frequency of the major risk haplotypes in the European population were observed to be less prevalent in the African population, suggesting that variants at these loci could contribute to the differences in ES incidence observed between continents. TARDBP shares structural similarities with EWSR1 and FUS (TLS) EGR2 is an EWSR1-ETS target gene. Variants at both loci were associated with expression levels of TARDBP, ADO and EGR2. 117 Ewing sarcoma samples were profiled using affymetrix hgu133Plus2 arrays.
2012-02-11 | E-GEOD-34620 | biostudies-arrayexpress
Project description:The FET family of fusion oncogenes carry one of the three genes, FUS, EWSR1 or TAF15, as 5’‑partners juxtaposed to one of many different DNA binding transcription factor genes as 3’‑partners. FET fusion oncogenes are pathognomonic for many types of sarcoma and leukemia, such as FUS-DDIT3 in myxoid liposarcoma (MLS) and EWSR1-FLI1 in Ewing sarcoma (EWS). We used recombinant FET N-terminal domains in a pulldown screen to find interaction partners to the FET proteins and identified components of the SWI/SNF complex. The ~2 MDa SWI/SNF chromatin remodeling complex utilizes energy from ATP hydrolysis to remodel nucleosomes and expose DNA. We used immunoprecipitation followed by mass spectrometry or western blot analysis to extensively characterize the interaction between FET fusion oncoproteins and the SWI/SNF complex.
2019-03-13 | PXD012680 | Pride
Project description:Expression profiling of Ewing sarcoma samples in the frame of the CIT program from the french Ligue Nationale Contre le Cancer (http://cit.ligue-cancer.net). Ewing sarcoma a rare pediatric tumor characterized by EWSR1-ETS fusions, is predominantly observed in populations of European ancestry. A genome-wide association study of at least 401 French ES patients compared to either 684 French or 3668 US self-described Caucasian controls consistently revealed candidate loci at chromosomes 1 and 10 (p<10-6). These loci were further replicated in two independent sets of cases and controls. Joint analysis identified rs9430161 (p=1.4x10-20; OR=2.2, CI99=1.8-2.7) 25kb upstream to TARDBP (1p36.22) and rs224278 (p=4.0x10-17 OR=1.7, CI99=1.4-1.9) 5kb upstream to EGR2 (10q21). The frequency of the major risk haplotypes in the European population were observed to be less prevalent in the African population, suggesting that variants at these loci could contribute to the differences in ES incidence observed between continents. TARDBP shares structural similarities with EWSR1 and FUS (TLS) EGR2 is an EWSR1-ETS target gene. Variants at both loci were associated with expression levels of TARDBP, ADO and EGR2.
2012-02-11 | GSE34620 | GEO
Project description:Some specific sarcomas and leukemias are defined by characteristic FET (FUS, EWSR1, TAF15) fusion oncogenes. Myxoid liposarcoma and Ewing sarcoma are the most common entities characterized by FUS-DDIT3 and EWSR1-FLI1, respectively. Here, we performed whole transcriptome analysis of HT1080 cells with either ectopic FUS-DDIT3 or ectopic EWSR1-FLI1 expression.
2019-03-12 | GSE125941 | GEO
Project description:Many rare cancers are not well understood, and pathogenesis-directed therapies are often lacking, resulting in poor patient outcomes. Leveraging two (inter)national precision oncology trials that enroll large numbers of rare cancers, we investigated the clinical, histopathologic, molecular, and functional characteristics of rhabdomyosarcoma (RMS) with fusions of FUS or EWSR1 to the TFCP2 transcription factor, a recently discovered ultra-rare entity whose classification, pathogenesis, and optimal treatment are unclear. Unusually for fusion-driven sarcomas, most cases had highly rearranged genomes, including chromothripsis, and signs of defective homologous recombination DNA repair. All tumors showed extreme expression of a truncated TERT variant and the ALK receptor tyrosine kinase, which was additionally affected by intragenic deletions and aberrant splicing, resulting in the expression of shortened variants in 58% of cases. Three ALK variants were oncogenic in immortalized cells, and patient-derived tumor cells expressing two variants responded to certain ALK inhibitors. Other recurrent alterations included CDKN2A/MTAP co-deletions and mutations in PAPPA2, encoding an IGFBP5-specific proteinase, in 67% and 25% of cases, respectively. DNA methylation analysis, along with 19 other soft-tissue sarcoma classes, revealed a close relationship with undifferentiated sarcoma but not other RMS subtypes, suggesting that TFCP2-rearranged RMS is a separate entity, possibly arising from a distinct cell of origin. Expression of TFCP2 fusions in immortalized human cells blocked late myogenic differentiation and significantly induced genes that were also highly expressed in patient tumors, including ALK, TERT, and two known regulators of skeletal muscle cells, IGFBP5 and PTH1R. Genome-wide chromatin profiling demonstrated direct binding of FUS-TFCP2 to the ALK and TERT loci outside their regular promoters, which correlated with the expression of alternative transcript variants. Finally, FUS-TFCP2 inhibited the repair of DNA double-strand breaks in immortalized cells, rendering them sensitive to treatment with cisplatin. This study provides insight into the pathogenesis and therapeutic vulnerabilities of a new RMS subtype and illustrates the value of linking comprehensive molecular diagnostics and functional annotation within multicenter consortia to improve the understanding and clinical management of rare cancers.
2023-11-06 | GSE224182 | GEO
Project description:Many rare cancers are not well understood, and pathogenesis-directed therapies are often lacking, resulting in poor patient outcomes. Leveraging two (inter)national precision oncology trials that enroll large numbers of rare cancers, we investigated the clinical, histopathologic, molecular, and functional characteristics of rhabdomyosarcoma (RMS) with fusions of FUS or EWSR1 to the TFCP2 transcription factor, a recently discovered ultra-rare entity whose classification, pathogenesis, and optimal treatment are unclear. Unusually for fusion-driven sarcomas, most cases had highly rearranged genomes, including chromothripsis, and signs of defective homologous recombination DNA repair. All tumors showed extreme expression of a truncated TERT variant and the ALK receptor tyrosine kinase, which was additionally affected by intragenic deletions and aberrant splicing, resulting in the expression of shortened variants in 58% of cases. Three ALK variants were oncogenic in immortalized cells, and patient-derived tumor cells expressing two variants responded to certain ALK inhibitors. Other recurrent alterations included CDKN2A/MTAP co-deletions and mutations in PAPPA2, encoding an IGFBP5-specific proteinase, in 67% and 25% of cases, respectively. DNA methylation analysis, along with 19 other soft-tissue sarcoma classes, revealed a close relationship with undifferentiated sarcoma but not other RMS subtypes, suggesting that TFCP2-rearranged RMS is a separate entity, possibly arising from a distinct cell of origin. Expression of TFCP2 fusions in immortalized human cells blocked late myogenic differentiation and significantly induced genes that were also highly expressed in patient tumors, including ALK, TERT, and two known regulators of skeletal muscle cells, IGFBP5 and PTH1R. Genome-wide chromatin profiling demonstrated direct binding of FUS-TFCP2 to the ALK and TERT loci outside their regular promoters, which correlated with the expression of alternative transcript variants. Finally, FUS-TFCP2 inhibited the repair of DNA double-strand breaks in immortalized cells, rendering them sensitive to treatment with cisplatin. This study provides insight into the pathogenesis and therapeutic vulnerabilities of a new RMS subtype and illustrates the value of linking comprehensive molecular diagnostics and functional annotation within multicenter consortia to improve the understanding and clinical management of rare cancers.
2023-11-06 | GSE224181 | GEO
Project description:Affymetrx U95Av2 GeneChip hybridizations, RNA extracted from primary human pediatric alveolar (aRMS) and embryonal (eRMS) rhabdomyosarcoma, plus primary pediatric Ewing's sarcoma (EWS) Keywords = pediatric sarcoma Keywords = Ewing's sarcoma Keywords = rhabdomyosarcoma Keywords: other
2004-03-13 | GSE967 | GEO
Project description:Fused in sarcoma (FUS) encodes a low complexity RNA-binding protein with diverse roles in transcriptional activation and RNA processing. While oncogenic fusions of FUS and transcription factor DNA-binding domains are associated with soft tissue sarcomas, dominant mutations in FUS cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). FUS has also been implicated in DNA double-strand break repair (DSBR) and genome maintenance. However, the underlying mechanisms are unknown. Here we employed quantitative proteomics, transcriptomics, and DNA copy number analysis (Sort-Seq), in conjunction with FUS-/- cells to ascertain roles of FUS in genome protection. FUS-/- cells exhibited alterations in the recruitment and retention of DSBR factors BRCA1 and 53BP1 but were not overtly sensitive to genotoxins. By contrast, FUS-deficient cells had reduced proliferative potential that correlated with reduced replication fork speed, diminished loading of pre-replication complexes, and attenuated expression of S-phase associated genes. FUS interacted with lagging strand DNA synthesis factors and other replisome components, but did not translocate with active replication forks. Using a Sort-Seq workflow, we show that FUS contributes to genome-wide control of DNA replication timing and is essential for the early replication of transcriptionally active DNA. These findings illuminate new roles for FUS in DNA replication initiation and timing that may contribute to genome instability and functional defects in cells harboring disease-associated FUS fusions.
2020-05-13 | GSE147784 | GEO
Project description:Expression data from Sarcoma Tumors expressing the EWSR1-CREB fusions
| PRJNA708292 | ENA