Unknown,Transcriptomics,Genomics,Proteomics

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Expression data from 34 Synovial Sarcomas

ABSTRACT: Background: Synovial sarcoma (SS) occur in children as well as in adults, although metastatic events are much more common in the latter. Whereas the importance of the t(X;18) translocation in SS oncogenesis is well established, the genetic basis of SS metastasis is still poorly understood. We recently reported expression (CINSARC) and genomic (GI) prognostic signatures related to chromosome integrity in sarcomas and gastrointestinal stromal tumors (GISTs). Here we investigate whether these signatures can also predict outcomes in SS. Methods: One hundred primary untreated SS were selected for expression and genomic profiling in a training/validation approach. Results: CINSARC and GI have strong, independent and validated prognostic values (p<0.0001). Comparing expression profiles of tumors with or without metastasis, 14 genes common with the CINSARC signature were identified and the two top-ranked genes, KIF14 and CDCA2, were validated as prognostic markers in an independent cohort. Comparing genomic profiles of adult vs. pediatric SS, we show that metastasis is associated with genome complexity in both situations and that the adult genome is more frequently rearranged. Accordingly, pediatric patients with an even genomic profile do not develop metastasis. Conclusions: Metastasis development in SS is strongly associated with chromosome complexity, and CINSARC and GI are validated independent prognostic factors. The differences in metastasis frequency between adults and children are associated with genome instability, which is much more frequent in adults. GI is potentially the best overall biomarker, and clearly the most clinically relevant, considering that genome profiling from formalin fixed samples is already used in pathology. 34 Synovial Sarcomas hybridized to Agilent-026652 Whole Human Genome Microarray 4x44K

ORGANISM(S): Homo sapiens

SUBMITTER: cM-CM-)line brulard

PROVIDER: E-GEOD-40018 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:Translocation-related sarcomas (TRSs) harbor an oncogenic fusion gene generated by chromosome translocation and account for approximately one-third of all sarcomas; however, effective targeted therapies have not yet been established. We previously reported that a pan-PI3K inhibitor, ZSTK474, was suggested to be effective for sarcomas in a phase I clinical trial, and demonstrated its efficacy in preclinical model, particularly in cell lines from synovial sarcomas (SS), Ewing’s sarcomas (ES) and alveolar rhabdomyosarcomas (ARMS), all of which harbor chromosomal translocation. Actually, ZSTK474 selectively induced apoptosis in these types of sarcoma cell lines, but the precise mechanism of apoptosis induction remained unclear. Here, we performed transcriptional analyses in SS cell lines including Aska-SS, SYO-1, Yamato-SS and Fuji treated with or without ZSTK474. Gene set enrichment analyses (GSEA) and Gene ontology (GO) analysis revealed that SS cell lines treated with ZSTK474 significantly reduced signatures of PI3K signaling. In addition, upon treatment with ZSTK474, the expression of apoptosis and cell cycle related genes was significantly changed. Importantly, PI3K inhibitors triggered induction of PUMA and BIM, resulting in loss of mitochondrial membrane potential, and the expression knockdown of these genes by RNA interference efficiently suppressed the apoptosis, suggesting their functional involvement in the apoptosis progression. In contrast, TRS-derived cell lines/patient-derived cells from alveolar soft part sarcoma (ASPS), CIC-DUX4 sarcoma and dermatofibrosarcoma protuberans failed to undergo apoptosis nor induce PUMA and BIM expression, as well as cell lines derived from non-TRSs and carcinomas. These results indicate that PI3K inhibitors selectively induce apoptosis in selective TRSs such as ES and SS via the induction of PUMA and BIM and subsequent loss of mitochondrial membrane potential, which would be a proof of concept for PI3K-targeted therapy especially for such TRS patients.

Project description:Synovial sarcoma (SynSa) is an aggressive mesenchymal tumor, comprising approximately 10% of all soft tissue sarcomas. Over half of SynSa patients develop metastasis or local recurrence, but the underlying molecular mechanisms of the aggressive clinical behavior remain poorly characterized. Sixty four frozen tumor specimens from 54 SynSa patients were subjected to array comparative genomic hybridization (aCGH) and gene expression profiling. The examined set of tumor specimens included 16 primary tumors from untreated patients who did not develop metastasis/local recurrence (SynSa1 group), 26 primary tumors from untreated patients who developed metastases or local recurrence during follow-up (SynSa2 group), and 22 metachronous metastatic/recurrent SynSa tumors (SynSa3 group). AURKA and KIF18A, which play important roles in various mitotic events, were the two most up-regulated genes in SynSa2 and SynSa3 groups compared to the SynSa1 group. Expression profiles of SynSa2 and SynSa3 tumors did not show any significant differences. Analysis of genomic index (GI) based on aCGH profiles demonstrated that the SynSa1 group consisted of tumors with significantly less complex genomes compared to SynSa2 and SynSa3 groups. There was no significant difference in genome complexity between SynSa2 and SynSa3 tumors. Primary SynSa tumors from patients who develop metastases or local recurrence share common molecular features with metastatic/recurrent tumors. Presented data suggest that the aggressive clinical SynSa behavior is determined early in tumorigenesis and might be related to impaired regulation of mitotic mechanisms. Introduction: Synovial sarcoma (SynSa) is an aggressive mesenchymal tumor, comprising approximately 10% of all soft tissue sarcomas. Over half of SynSa patients develop metastasis or local recurrence, but the underlying molecular mechanisms of the aggressive clinical behavior remain poorly characterized. Materials and methods: Sixty four frozen tumor specimens from 54 SynSa patients were subjected to array comparative genomic hybridization (aCGH) and gene expression profiling. The examined set of tumor specimens included 16 primary tumors from untreated patients who did not develop metastasis/local recurrence (SynSa1 group), 26 primary tumors from untreated patients who developed metastases or local recurrence during follow-up (SynSa2 group), and 22 metachronous metastatic/recurrent SynSa tumors (SynSa3 group). Results: AURKA and KIF18A, which play important roles in various mitotic events, were the two most up-regulated genes in SynSa2 and SynSa3 groups compared to the SynSa1 group. Expression profiles of SynSa2 and SynSa3 tumors did not show any significant differences. Analysis of genomic index (GI) based on aCGH profiles demonstrated that the SynSa1 group consisted of tumors with significantly less complex genomes compared to SynSa2 and SynSa3 groups. There was no significant difference in genome complexity between SynSa2 and SynSa3 tumors. Conclusions: Primary SynSa tumors from patients who develop metastases or local recurrence share common molecular features with metastatic/recurrent tumors. Presented data suggest that the aggressive clinical SynSa behavior is determined early in tumorigenesis and might be related to impaired regulation of mitotic mechanisms. Gene expression profiling of 15 primary tumors from untreated patients who did not develop metastasis/local recurrence (SynSa1 group), 21 primary tumors from untreated patients who developed metastases or local recurrence during follow-up (SynSa2 group), and 21 metachronous metastatic/recurrent SynSa tumors (SynSa3 group); Agilent One-Color technology.

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Expression data from 34 Synovial Sarcomas

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