The Experts below are selected from a list of 28338 Experts worldwide ranked by ideXlab platform
Tatsuhiro Shibata - One of the best experts on this subject based on the ideXlab platform.
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CIC break-apart fluorescence in-situ hybridization misses a subset of CIC-DUX4 sarcomas: a clinicopathological and molecular study.
Histopathology, 2017Co-Authors: Akihiko Yoshida, Yasuhito Arai, Wakako Mukai, Natsuko Hama, Eisuke Kobayashi, Kan Yonemori, Koichi Ogura, Toru Motoi, Akira Kawai, Tatsuhiro ShibataAbstract:Aims Approximately 60–70% of high-grade round-cell sarcomas that lack the EWSR1 rearrangement harbour a rearrangement of the CIC gene, most commonly CIC-DUX4. Recent studies have established that CIC-rearranged sarcomas constitute a distinct group characterised by recognisable histology and immunoprofiles, such as positivity for ETV4 and WT1 and negativity for NKX2.2. Although these sarcomas are increasingly diagnosed in practice by fluorescence in situ hybridisation (FISH) with CIC break-apart probes, the optimal modality to diagnose these sarcomas has not been determined. In this study, we describe 4 round cell sarcomas that showed false-negative results by CIC break-apart FISH assays. Methods and results These sarcomas showed characteristic histology of CIC-rearranged sarcomas, and all were immunohistochemically positive for ETV4 and WT1 and negative for NKX2.2. Although FISH showed non-atypical negative signals for CIC rearrangement, high-throughput RNA sequencing identified CIC-DUX4 and its fusion breakpoint in all cases. Their clinical and histological findings as well as fusion points determined by RNA sequencing did not significantly differ from those of 9 FISH-positive CIC-DUX4 sarcoma cases. We estimated that the FISH false-negative rate for CIC-rearranged sarcomas was 14%. Although neither histology nor immunoprofiles (e.g., ETV4 and WT1) are entirely sensitive or specific for CIC-rearranged sarcomas, the observation that these 4 cases were successfully identified by such phenotypes suggested their practical utility. Conclusions CIC break-apart FISH assays missed a significant minority of CIC-DUX4 sarcomas, and full awareness of typical morphology and judicious immunohistochemical workups, including analyses of ETV4 and WT1, should complement diagnostic assessment. This article is protected by copyright. All rights reserved.
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NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma.
Human pathology, 2017Co-Authors: Shintaro Sugita, Yasuhito Arai, Tomoyuki Aoyama, Hiroko Asanuma, Wakako Mukai, Natsuko Hama, Makoto Emori, Tatsuhiro Shibata, Tadashi HasegawaAbstract:Summary CIC- rearranged sarcoma is a new entity of undifferentiated small round cell sarcoma characterized by chimeric fusions with CIC rearrangement. We report a NUTM2A-CIC fusion sarcoma in a 43-year-old woman who died of rapidly progressive disease. Histologic analysis revealed multinodular proliferation of small round tumor cells with mild nuclear pleomorphism. The sclerotic fibrous septa separated the tumor into multiple nodules. Immunohistochemistry showed that the tumor cells were diffusely positive for vimentin, focally positive for cytokeratin, and negative for CD99 and NKX2.2. Tumor cells were also negative for ETV4, which was recently identified as a specific marker for CIC -rearranged sarcoma. High-throughput RNA sequencing of a formalin-fixed, paraffin-embedded clinical sample unveiled a novel NUTM2A-CIC fusion between NUTM2A exon 7 and CIC exon 12, and fluorescence in situ hybridization identified CIC and NUTM2A split signals. This case shared several clinicopathological findings with previously reported CIC -rearranged cases. We recognized the tumor as a genetically distinct variant of CIC -rearranged sarcomas with a novel NUTM2A-CIC fusion.
Tadashi Hasegawa - One of the best experts on this subject based on the ideXlab platform.
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NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma.
Human pathology, 2017Co-Authors: Shintaro Sugita, Yasuhito Arai, Tomoyuki Aoyama, Hiroko Asanuma, Wakako Mukai, Natsuko Hama, Makoto Emori, Tatsuhiro Shibata, Tadashi HasegawaAbstract:Summary CIC- rearranged sarcoma is a new entity of undifferentiated small round cell sarcoma characterized by chimeric fusions with CIC rearrangement. We report a NUTM2A-CIC fusion sarcoma in a 43-year-old woman who died of rapidly progressive disease. Histologic analysis revealed multinodular proliferation of small round tumor cells with mild nuclear pleomorphism. The sclerotic fibrous septa separated the tumor into multiple nodules. Immunohistochemistry showed that the tumor cells were diffusely positive for vimentin, focally positive for cytokeratin, and negative for CD99 and NKX2.2. Tumor cells were also negative for ETV4, which was recently identified as a specific marker for CIC -rearranged sarcoma. High-throughput RNA sequencing of a formalin-fixed, paraffin-embedded clinical sample unveiled a novel NUTM2A-CIC fusion between NUTM2A exon 7 and CIC exon 12, and fluorescence in situ hybridization identified CIC and NUTM2A split signals. This case shared several clinicopathological findings with previously reported CIC -rearranged cases. We recognized the tumor as a genetically distinct variant of CIC -rearranged sarcomas with a novel NUTM2A-CIC fusion.
Severa Bunda - One of the best experts on this subject based on the ideXlab platform.
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c-Src Phosphorylates and Inhibits the Function of the CIC Tumor Suppressor Protein.
Molecular cancer research : MCR, 2020Co-Authors: Severa Bunda, Pardeep Heir, Yasin Mamatjan, Gelareh Zadeh, Kenneth AldapeAbstract:Capicua (CIC) is a transcriptional repressor that counteracts activation of genes in response to receptor tyrosine kinase (RTK)/Ras/ERK signaling. Following activation of RTK, ERK enters the nucleus and serine-phosphorylates CIC, releasing it from its targets to permit gene expression. We recently showed that ERK triggers ubiquitin-mediated degradation of CIC in glioblastoma (GBM). In this study, we examined whether another important downstream effector of RTK/EGFR, the non-RTK c-Src, affects CIC repressor function in GBM. We found that c-Src binds and tyrosine-phosphorylates CIC on residue 1455 to promote nuclear export of CIC. On the other hand, CIC-mutant allele (CIC-Y1455F), that escapes c-Src-mediated tyrosine phosphorylation, remains localized to the nucleus and retains strong repressor function against CIC targets, the oncogenic transcription factors ETV1 and ETV5. Furthermore, we show that the orally available Src family kinase inhibitor, dasatinib, which prevents EGF-mediated tyrosine phosphorylation of CIC and attenuates elevated ETV1 and ETV5 levels, reduces viability of GBM cells and glioma stem cells (GSC), but not of their control cells with undetectable c-Src activity. In fact, GBM cells and GSC expressing the tyrosine-defective CIC mutant (Y1455F) lose sensitivity to dasatinib, further endorsing the effect of dasatinib on Src-mediated tyrosine phosphorylation of CIC. These findings elucidate important mechanisms of CIC regulation and provide the rationale to target c-Src alongside ERK pathway inhibitors as a way to fully restore CIC tumor suppressor function in neoplasms such as GBM. IMPLICATIONS: c-Src tyrosine-phosphorylates CIC exports to cytoplasm and inactivates its repressor function in GBM.
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CIC protein instability contributes to tumorigenesis in glioblastoma.
Nature communications, 2019Co-Authors: Severa Bunda, Pardeep Heir, Stefan Pusch, Julie Metcalf, Sameer Agnihotri, Mamatjan Yasin, Kelly Burrell, Sheila MansouriAbstract:Capicua (CIC) is a transcriptional repressor that counteracts activation of genes downstream of receptor tyrosine kinase (RTK)/Ras/ERK signaling. It is well-established that tumorigenesis, especially in glioblastoma (GBM), is attributed to hyperactive RTK/Ras/ERK signaling. While CIC is mutated in other tumors, here we show that CIC has a tumor suppressive function in GBM through an alternative mechanism. We find that CIC protein levels are negligible in GBM due to continuous proteasome-mediated degradation, which is mediated by the E3 ligase PJA1 and show that this occurs through binding of CIC to its DNA target and phosphorylation on residue S173. PJA1 knockdown increased CIC stability and extended survival using in-vivo models of GBM. Deletion of the ERK binding site resulted in stabilization of CIC and increased therapeutic efficacy of ERK inhibition in GBM models. Our results provide a rationale to target CIC degradation in Ras/ERK-driven tumors, including GBM, to increase efficacy of ERK inhibitors.
Kristian Helin - One of the best experts on this subject based on the ideXlab platform.
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The Tumor Suppressor CIC Directly Regulates MAPK Pathway Genes via Histone Deacetylation
Cancer research, 2018Co-Authors: Simon Weissmann, Paul A. C. Cloos, Simone Sidoli, Ole Nørregaard Jensen, Steven M. Pollard, Kristian HelinAbstract:Oligodendrogliomas (ODG) are brain tumors accounting for approximately 10% of all central nervous system cancers. CIC is a transcription factor that is mutated in most patients with ODG; these mutations are believed to be a key oncogenic event in such cancers. Analysis of the Drosophila melanogaster orthologue of CIC, Capicua, indicates that CIC loss phenocopies activation of the EGFR/RAS/MAPK pathway, and studies in mammalian cells have demonstrated a role for CIC in repressing the transcription of the PEA3 subfamily of ETS transcription factors. Here we address the mechanism by which CIC represses transcription and assess the functional consequences of CIC inactivation. Genome-wide binding patterns of CIC in several cell types revealed that CIC target genes were enriched for MAPK effector genes involved in cell cycle regulation and proliferation. CIC binding to target genes was abolished by high MAPK activity, which led to their transcriptional activation. CIC interacted with the SIN3 deacetylation complex and, based on our results, we suggest that CIC functions as a transcriptional repressor through the recruitment of histone deacetylases. Independent single amino acid substitutions found in ODG tumors prevented CIC from binding its target genes. Taken together, our results show that CIC is a transcriptional repressor of genes regulated by MAPK signaling, and that ablation of CIC function leads to increased histone acetylation levels and transcription at these genes, ultimately fueling mitogen-independent tumor growth.
Wakako Mukai - One of the best experts on this subject based on the ideXlab platform.
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CIC break-apart fluorescence in-situ hybridization misses a subset of CIC-DUX4 sarcomas: a clinicopathological and molecular study.
Histopathology, 2017Co-Authors: Akihiko Yoshida, Yasuhito Arai, Wakako Mukai, Natsuko Hama, Eisuke Kobayashi, Kan Yonemori, Koichi Ogura, Toru Motoi, Akira Kawai, Tatsuhiro ShibataAbstract:Aims Approximately 60–70% of high-grade round-cell sarcomas that lack the EWSR1 rearrangement harbour a rearrangement of the CIC gene, most commonly CIC-DUX4. Recent studies have established that CIC-rearranged sarcomas constitute a distinct group characterised by recognisable histology and immunoprofiles, such as positivity for ETV4 and WT1 and negativity for NKX2.2. Although these sarcomas are increasingly diagnosed in practice by fluorescence in situ hybridisation (FISH) with CIC break-apart probes, the optimal modality to diagnose these sarcomas has not been determined. In this study, we describe 4 round cell sarcomas that showed false-negative results by CIC break-apart FISH assays. Methods and results These sarcomas showed characteristic histology of CIC-rearranged sarcomas, and all were immunohistochemically positive for ETV4 and WT1 and negative for NKX2.2. Although FISH showed non-atypical negative signals for CIC rearrangement, high-throughput RNA sequencing identified CIC-DUX4 and its fusion breakpoint in all cases. Their clinical and histological findings as well as fusion points determined by RNA sequencing did not significantly differ from those of 9 FISH-positive CIC-DUX4 sarcoma cases. We estimated that the FISH false-negative rate for CIC-rearranged sarcomas was 14%. Although neither histology nor immunoprofiles (e.g., ETV4 and WT1) are entirely sensitive or specific for CIC-rearranged sarcomas, the observation that these 4 cases were successfully identified by such phenotypes suggested their practical utility. Conclusions CIC break-apart FISH assays missed a significant minority of CIC-DUX4 sarcomas, and full awareness of typical morphology and judicious immunohistochemical workups, including analyses of ETV4 and WT1, should complement diagnostic assessment. This article is protected by copyright. All rights reserved.
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NUTM2A-CIC fusion small round cell sarcoma: a genetically distinct variant of CIC-rearranged sarcoma.
Human pathology, 2017Co-Authors: Shintaro Sugita, Yasuhito Arai, Tomoyuki Aoyama, Hiroko Asanuma, Wakako Mukai, Natsuko Hama, Makoto Emori, Tatsuhiro Shibata, Tadashi HasegawaAbstract:Summary CIC- rearranged sarcoma is a new entity of undifferentiated small round cell sarcoma characterized by chimeric fusions with CIC rearrangement. We report a NUTM2A-CIC fusion sarcoma in a 43-year-old woman who died of rapidly progressive disease. Histologic analysis revealed multinodular proliferation of small round tumor cells with mild nuclear pleomorphism. The sclerotic fibrous septa separated the tumor into multiple nodules. Immunohistochemistry showed that the tumor cells were diffusely positive for vimentin, focally positive for cytokeratin, and negative for CD99 and NKX2.2. Tumor cells were also negative for ETV4, which was recently identified as a specific marker for CIC -rearranged sarcoma. High-throughput RNA sequencing of a formalin-fixed, paraffin-embedded clinical sample unveiled a novel NUTM2A-CIC fusion between NUTM2A exon 7 and CIC exon 12, and fluorescence in situ hybridization identified CIC and NUTM2A split signals. This case shared several clinicopathological findings with previously reported CIC -rearranged cases. We recognized the tumor as a genetically distinct variant of CIC -rearranged sarcomas with a novel NUTM2A-CIC fusion.