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Masazumi Tsuneyoshi - One of the best experts on this subject based on the ideXlab platform.
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reduced expression of SMARCB1 ini1 protein in synovial sarcoma
Modern Pathology, 2010Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Hiroshi Matono, Yukihide Iwamoto, Tomoaki Taguchi, Masazumi TsuneyoshiAbstract:Synovial sarcoma is classified as a tumor of uncertain differentiation, and some synovial sarcomas have rhabdoid cells. In previous studies, all malignant rhabdoid tumors and renal medullary carcinomas, some extraskeletal myxoid chondrosarcomas, almost all epithelioid sarcomas and half of epithelioid malignant peripheral nerve sheath tumors showed a loss of SMARCB1/INI1 protein expression in tumor cells and all of these tumors are also known to have rhabdoid cells. We analyzed the immunohistochemical and mRNA expression of SMARCB1/INI1 in 95 synovial sarcomas (73 monophasic fibrous type, 18 biphasic type and 4 poorly differentiated type) and 30 spindle cell sarcomas (3 adult fibrosarcomas, 7 fibrosarcomas arising in dermatofibrosarcoma protuberans, 10 leiomyosarcomas and 10 malignant peripheral nerve sheath tumors) resembling monophasic fibrous synovial sarcoma. The results have shown that 66 of the 95 synovial sarcoma cases (69%) had reduced SMARCB1/INI1 protein expression, whereas the remaining 29 cases (31%) and all 30 spindle cell sarcomas showed preserved this protein expression. No case with a complete loss of SMARCB1/INI1 protein expression was recognized. The median values of SMARCB1/INI1 mRNA expression in non-tumor skeletal muscle and synovial sarcoma with reduced protein expression were 12.86 and 134.01, respectively, and a statistically significant difference was detected between these two groups (P=0.0000004). However, there was no statistically significant difference of prognosis between the synovial sarcoma group with reduced and that with preserved SMARCB1/INI1 protein expression (P=0.46). Therefore, it was suggested that there is a post-transcriptional SMARCB1/INI1 regulatory mechanism in the tumor cells of synovial sarcoma.
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infrequent SMARCB1 ini1 gene alteration in epithelioid sarcoma a useful tool in distinguishing epithelioid sarcoma from malignant rhabdoid tumor
Human Pathology, 2009Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Tomoaki Taguchi, Teiyu Izumi, Tadashi Hasegawa, Masazumi TsuneyoshiAbstract:Loss of SMARCB1/INI1 protein expression is considered useful for confirming a histologic diagnosis of malignant rhabdoid tumor. However, loss of SMARCB1/INI1 protein expression has recently been reported in other tumors as well, including a few cases of epithelioid sarcoma. In addition, the histopathologic differences between proximal-type epithelioid sarcoma and malignant rhabdoid tumor have not been conclusively defined. We analyzed SMARCB1/INI1 protein expression in 54 epithelioid sarcoma (proximal-type, 25; distal-type, 29) and examined alterations of the SMARCB1/INI1 gene in the cases lacking protein expression. We found that 19 (76.0%) proximal-type epithelioid sarcoma and 27 (93.1%) distal-type epithelioid sarcoma showed loss of SMARCB1/INI1 protein expression. Analysis of 39 cases with loss of protein expression revealed 4 cases (10.3%) with SMARCB1/INI1 gene alterations at the DNA level (homozygous deletion, 2; 1- or 2-bp deletion, 2) that could have induced the loss of gene products, and all 4 of these were proximal-type epithelioid sarcoma. Epithelioid sarcoma was thus associated with a high frequency of loss of SMARCB1/INI1 protein expression similar to that in malignant rhabdoid tumor. However, the frequency of SMARCB1/INI1 gene alteration at the DNA level in proximal-type epithelioid sarcoma was significantly lower than that in malignant rhabdoid tumor. In addition, the prognosis of patients with malignant rhabdoid tumor is significantly worse than that of patients with proximal-type epithelioid sarcoma (P = .001). Therefore, proximal-type epithelioid sarcoma and malignant rhabdoid tumor are suggested to be distinctive tumors with respect to the mechanism of the loss of SMARCB1/INI1 protein expression. Analysis of alterations in the SMARCB1/INI1 gene may thus be a useful diagnostic tool to distinguish proximal-type epithelioid sarcoma from malignant rhabdoid tumor.
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SMARCB1 ini1 protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving ews a special reference to SMARCB1 ini1 negative variant extraskeletal myxoid chondrosarcoma
The American Journal of Surgical Pathology, 2008Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Tomoaki Taguchi, Teiyu Izumi, Yumi Oshiro, Masazumi TsuneyoshiAbstract:Several previous studies have demonstrated the lack of SMARCB1/INI1 protein expression in only the malignant rhabdoid tumor (MRT). Several sarcoma groups are associated with a tumor-specific translocation involving EWS. Moreover, the EWS and SMARCB1/INI1 genes are located on the same 22q chromosome. We analyzed the status of SMARCB1/INI1 protein expression in 93 cases of sarcomas associated with chromosomal translocation involving EWS, comprising 52 Ewing's sarcoma/primitive neuroectodermal tumors, 24 extraskeletal myxoid chondrosarcomas (EMCS), 14 clear cell sarcomas of soft tissue, 2 desmoplastic small round cell tumors, and 1 myxoid/round cell liposarcoma. In addition, we analyzed the detailed SMARCB1/INI1 gene alteration in cases, which lacked its protein expression. Consequently, 4 EMCS showed no SMARCB1/INI1 expression, and 2 of these 4 cases revealed homozygous deletion and frameshift mutation of the SMARCB1/INI1 gene, respectively. These cases showed histologic findings compatible with EMCS, according to the most recent WHO classification, but no major fusion gene transcripts were detected. Moreover, 3 out of 4 SMARCB1/INI1 negative variant EMCS disclosed rhabdoid features. Therefore, the lack of SMARCB1/INI1 protein expression may be associated with rhabdoid features. The immunohistochemical result of the SMARCB1/INI expression is not an absolute diagnostic criteria for MRT and careful histologic evaluation is required to make a precise diagnosis of MRT.
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highly aggressive behavior of malignant rhabdoid tumor a special reference to SMARCB1 ini1 gene alterations using molecular genetic analysis including quantitative real time pcr
Journal of Cancer Research and Clinical Oncology, 2007Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Tomoaki Taguchi, Teiyu Izumi, Shigeru Ohta, Sachiyo Suita, Masazumi TsuneyoshiAbstract:SMARCB1/INI1, which negatively regulates cell cycle progression from G0/G1 into the S-phase via the p16INK4a-RB-E2F pathway, has been reported to be inactivated homozygously by deletion and/or mutations in malignant rhabdoid tumor (MRT). In the current study, we investigated the alteration of the SMARCB1/INI1 gene using simple methods, and its gene product at the protein level. Moreover, we investigated the status of hyperphosphorylation in RB protein, known as a key cell cycle molecule. Three cell lines and 11 formalin-fixed, paraffin-embedded specimens of MRT were investigated. SMARCB1/INI1 gene alteration was analyzed with simple methods as a quantitative real-time PCR and direct sequencing method. Furthermore, SMARCB1/INI1 and RB protein were immunohistochemically evaluated. In 12 of 14 cases, we detected genetic alterations comprised of nine (including three cell lines) homozygous deletions and three mutations, which can induce abnormal expression of gene products. At the protein level, SMARCB1/INI1 immunohistochemical expressions were not detected in any cases. Twelve out of 14 cases showed high-level (+5) expression of tRB (both hyperphosphorylated and underphosphorylated RB), combined with low-level (+1) expression of uRB (underphosphorylated RB), indicating a high rate of hyperphosphorylation. We could analyze the SMARCB1/INI1 gene alteration with simple methods, and SMARCB1/INI1 gene alteration was found in 12 of 14 cases. Especially, quantitative real-time PCR was a convenient and accurate method. In addition, a high rate of hyperphosphorylation of RB gene was recognized. These results suggest that the clinically aggressive character of MRT is caused by the inactivation of the SMARCB1/INI1 gene.
Kenichi Kohashi - One of the best experts on this subject based on the ideXlab platform.
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oncogenic roles of SMARCB1 ini1 and its deficient tumors
Cancer Science, 2017Co-Authors: Kenichi Kohashi, Yoshinao OdaAbstract:SMARCB1/INI1 is one of the core subunit proteins of the ATP-dependent SWI/SNF chromatin remodeling complex, and is identified as a potent and bona fide tumor suppressor. Interactions have been demonstrated between SMARCB1/INI1 and key proteins in various pathways related to tumor proliferation and progression: the p16-RB pathway, WNT signaling pathway, sonic hedgehog signaling pathway and Polycomb pathway. Initially, no detectable SMARCB1/INI1 protein expression was found in malignant rhabdoid tumor cells, whereas all other kinds of tumor cells and non-tumorous tissue showed SMARCB1/INI1 protein expression. Therefore, immunohistochemical testing for the SMARCB1/INI1 antibody has been considered useful in confirming the histologic diagnosis of malignant rhabdoid tumors. However, recently, aberrant expression of SMARCB1/INI1 has been found in various tumors such as epithelioid sarcomas, schwannomatosis, synovial sarcomas, and so on. In addition, it has been reported that aberrant expression can be classified into three patterns: complete loss, mosaic expression and reduced expression. Although the various pathways related to mechanisms of tumorigenesis and tumor proliferation are complexly intertwined, the clarification of these mechanisms may contribute to therapeutic strategies in SMARCB1/INI1-deficient tumors. In terms of pathological classifications, SMARCB1/INI1-deficient tumors may be re-classified by genetic backgrounds.
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reduced expression of SMARCB1 ini1 protein in synovial sarcoma
Modern Pathology, 2010Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Hiroshi Matono, Yukihide Iwamoto, Tomoaki Taguchi, Masazumi TsuneyoshiAbstract:Synovial sarcoma is classified as a tumor of uncertain differentiation, and some synovial sarcomas have rhabdoid cells. In previous studies, all malignant rhabdoid tumors and renal medullary carcinomas, some extraskeletal myxoid chondrosarcomas, almost all epithelioid sarcomas and half of epithelioid malignant peripheral nerve sheath tumors showed a loss of SMARCB1/INI1 protein expression in tumor cells and all of these tumors are also known to have rhabdoid cells. We analyzed the immunohistochemical and mRNA expression of SMARCB1/INI1 in 95 synovial sarcomas (73 monophasic fibrous type, 18 biphasic type and 4 poorly differentiated type) and 30 spindle cell sarcomas (3 adult fibrosarcomas, 7 fibrosarcomas arising in dermatofibrosarcoma protuberans, 10 leiomyosarcomas and 10 malignant peripheral nerve sheath tumors) resembling monophasic fibrous synovial sarcoma. The results have shown that 66 of the 95 synovial sarcoma cases (69%) had reduced SMARCB1/INI1 protein expression, whereas the remaining 29 cases (31%) and all 30 spindle cell sarcomas showed preserved this protein expression. No case with a complete loss of SMARCB1/INI1 protein expression was recognized. The median values of SMARCB1/INI1 mRNA expression in non-tumor skeletal muscle and synovial sarcoma with reduced protein expression were 12.86 and 134.01, respectively, and a statistically significant difference was detected between these two groups (P=0.0000004). However, there was no statistically significant difference of prognosis between the synovial sarcoma group with reduced and that with preserved SMARCB1/INI1 protein expression (P=0.46). Therefore, it was suggested that there is a post-transcriptional SMARCB1/INI1 regulatory mechanism in the tumor cells of synovial sarcoma.
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infrequent SMARCB1 ini1 gene alteration in epithelioid sarcoma a useful tool in distinguishing epithelioid sarcoma from malignant rhabdoid tumor
Human Pathology, 2009Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Tomoaki Taguchi, Teiyu Izumi, Tadashi Hasegawa, Masazumi TsuneyoshiAbstract:Loss of SMARCB1/INI1 protein expression is considered useful for confirming a histologic diagnosis of malignant rhabdoid tumor. However, loss of SMARCB1/INI1 protein expression has recently been reported in other tumors as well, including a few cases of epithelioid sarcoma. In addition, the histopathologic differences between proximal-type epithelioid sarcoma and malignant rhabdoid tumor have not been conclusively defined. We analyzed SMARCB1/INI1 protein expression in 54 epithelioid sarcoma (proximal-type, 25; distal-type, 29) and examined alterations of the SMARCB1/INI1 gene in the cases lacking protein expression. We found that 19 (76.0%) proximal-type epithelioid sarcoma and 27 (93.1%) distal-type epithelioid sarcoma showed loss of SMARCB1/INI1 protein expression. Analysis of 39 cases with loss of protein expression revealed 4 cases (10.3%) with SMARCB1/INI1 gene alterations at the DNA level (homozygous deletion, 2; 1- or 2-bp deletion, 2) that could have induced the loss of gene products, and all 4 of these were proximal-type epithelioid sarcoma. Epithelioid sarcoma was thus associated with a high frequency of loss of SMARCB1/INI1 protein expression similar to that in malignant rhabdoid tumor. However, the frequency of SMARCB1/INI1 gene alteration at the DNA level in proximal-type epithelioid sarcoma was significantly lower than that in malignant rhabdoid tumor. In addition, the prognosis of patients with malignant rhabdoid tumor is significantly worse than that of patients with proximal-type epithelioid sarcoma (P = .001). Therefore, proximal-type epithelioid sarcoma and malignant rhabdoid tumor are suggested to be distinctive tumors with respect to the mechanism of the loss of SMARCB1/INI1 protein expression. Analysis of alterations in the SMARCB1/INI1 gene may thus be a useful diagnostic tool to distinguish proximal-type epithelioid sarcoma from malignant rhabdoid tumor.
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SMARCB1 ini1 protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving ews a special reference to SMARCB1 ini1 negative variant extraskeletal myxoid chondrosarcoma
The American Journal of Surgical Pathology, 2008Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Tomoaki Taguchi, Teiyu Izumi, Yumi Oshiro, Masazumi TsuneyoshiAbstract:Several previous studies have demonstrated the lack of SMARCB1/INI1 protein expression in only the malignant rhabdoid tumor (MRT). Several sarcoma groups are associated with a tumor-specific translocation involving EWS. Moreover, the EWS and SMARCB1/INI1 genes are located on the same 22q chromosome. We analyzed the status of SMARCB1/INI1 protein expression in 93 cases of sarcomas associated with chromosomal translocation involving EWS, comprising 52 Ewing's sarcoma/primitive neuroectodermal tumors, 24 extraskeletal myxoid chondrosarcomas (EMCS), 14 clear cell sarcomas of soft tissue, 2 desmoplastic small round cell tumors, and 1 myxoid/round cell liposarcoma. In addition, we analyzed the detailed SMARCB1/INI1 gene alteration in cases, which lacked its protein expression. Consequently, 4 EMCS showed no SMARCB1/INI1 expression, and 2 of these 4 cases revealed homozygous deletion and frameshift mutation of the SMARCB1/INI1 gene, respectively. These cases showed histologic findings compatible with EMCS, according to the most recent WHO classification, but no major fusion gene transcripts were detected. Moreover, 3 out of 4 SMARCB1/INI1 negative variant EMCS disclosed rhabdoid features. Therefore, the lack of SMARCB1/INI1 protein expression may be associated with rhabdoid features. The immunohistochemical result of the SMARCB1/INI expression is not an absolute diagnostic criteria for MRT and careful histologic evaluation is required to make a precise diagnosis of MRT.
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highly aggressive behavior of malignant rhabdoid tumor a special reference to SMARCB1 ini1 gene alterations using molecular genetic analysis including quantitative real time pcr
Journal of Cancer Research and Clinical Oncology, 2007Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Tomoaki Taguchi, Teiyu Izumi, Shigeru Ohta, Sachiyo Suita, Masazumi TsuneyoshiAbstract:SMARCB1/INI1, which negatively regulates cell cycle progression from G0/G1 into the S-phase via the p16INK4a-RB-E2F pathway, has been reported to be inactivated homozygously by deletion and/or mutations in malignant rhabdoid tumor (MRT). In the current study, we investigated the alteration of the SMARCB1/INI1 gene using simple methods, and its gene product at the protein level. Moreover, we investigated the status of hyperphosphorylation in RB protein, known as a key cell cycle molecule. Three cell lines and 11 formalin-fixed, paraffin-embedded specimens of MRT were investigated. SMARCB1/INI1 gene alteration was analyzed with simple methods as a quantitative real-time PCR and direct sequencing method. Furthermore, SMARCB1/INI1 and RB protein were immunohistochemically evaluated. In 12 of 14 cases, we detected genetic alterations comprised of nine (including three cell lines) homozygous deletions and three mutations, which can induce abnormal expression of gene products. At the protein level, SMARCB1/INI1 immunohistochemical expressions were not detected in any cases. Twelve out of 14 cases showed high-level (+5) expression of tRB (both hyperphosphorylated and underphosphorylated RB), combined with low-level (+1) expression of uRB (underphosphorylated RB), indicating a high rate of hyperphosphorylation. We could analyze the SMARCB1/INI1 gene alteration with simple methods, and SMARCB1/INI1 gene alteration was found in 12 of 14 cases. Especially, quantitative real-time PCR was a convenient and accurate method. In addition, a high rate of hyperphosphorylation of RB gene was recognized. These results suggest that the clinically aggressive character of MRT is caused by the inactivation of the SMARCB1/INI1 gene.
Yoshinao Oda - One of the best experts on this subject based on the ideXlab platform.
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oncogenic roles of SMARCB1 ini1 and its deficient tumors
Cancer Science, 2017Co-Authors: Kenichi Kohashi, Yoshinao OdaAbstract:SMARCB1/INI1 is one of the core subunit proteins of the ATP-dependent SWI/SNF chromatin remodeling complex, and is identified as a potent and bona fide tumor suppressor. Interactions have been demonstrated between SMARCB1/INI1 and key proteins in various pathways related to tumor proliferation and progression: the p16-RB pathway, WNT signaling pathway, sonic hedgehog signaling pathway and Polycomb pathway. Initially, no detectable SMARCB1/INI1 protein expression was found in malignant rhabdoid tumor cells, whereas all other kinds of tumor cells and non-tumorous tissue showed SMARCB1/INI1 protein expression. Therefore, immunohistochemical testing for the SMARCB1/INI1 antibody has been considered useful in confirming the histologic diagnosis of malignant rhabdoid tumors. However, recently, aberrant expression of SMARCB1/INI1 has been found in various tumors such as epithelioid sarcomas, schwannomatosis, synovial sarcomas, and so on. In addition, it has been reported that aberrant expression can be classified into three patterns: complete loss, mosaic expression and reduced expression. Although the various pathways related to mechanisms of tumorigenesis and tumor proliferation are complexly intertwined, the clarification of these mechanisms may contribute to therapeutic strategies in SMARCB1/INI1-deficient tumors. In terms of pathological classifications, SMARCB1/INI1-deficient tumors may be re-classified by genetic backgrounds.
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reduced expression of SMARCB1 ini1 protein in synovial sarcoma
Modern Pathology, 2010Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Hiroshi Matono, Yukihide Iwamoto, Tomoaki Taguchi, Masazumi TsuneyoshiAbstract:Synovial sarcoma is classified as a tumor of uncertain differentiation, and some synovial sarcomas have rhabdoid cells. In previous studies, all malignant rhabdoid tumors and renal medullary carcinomas, some extraskeletal myxoid chondrosarcomas, almost all epithelioid sarcomas and half of epithelioid malignant peripheral nerve sheath tumors showed a loss of SMARCB1/INI1 protein expression in tumor cells and all of these tumors are also known to have rhabdoid cells. We analyzed the immunohistochemical and mRNA expression of SMARCB1/INI1 in 95 synovial sarcomas (73 monophasic fibrous type, 18 biphasic type and 4 poorly differentiated type) and 30 spindle cell sarcomas (3 adult fibrosarcomas, 7 fibrosarcomas arising in dermatofibrosarcoma protuberans, 10 leiomyosarcomas and 10 malignant peripheral nerve sheath tumors) resembling monophasic fibrous synovial sarcoma. The results have shown that 66 of the 95 synovial sarcoma cases (69%) had reduced SMARCB1/INI1 protein expression, whereas the remaining 29 cases (31%) and all 30 spindle cell sarcomas showed preserved this protein expression. No case with a complete loss of SMARCB1/INI1 protein expression was recognized. The median values of SMARCB1/INI1 mRNA expression in non-tumor skeletal muscle and synovial sarcoma with reduced protein expression were 12.86 and 134.01, respectively, and a statistically significant difference was detected between these two groups (P=0.0000004). However, there was no statistically significant difference of prognosis between the synovial sarcoma group with reduced and that with preserved SMARCB1/INI1 protein expression (P=0.46). Therefore, it was suggested that there is a post-transcriptional SMARCB1/INI1 regulatory mechanism in the tumor cells of synovial sarcoma.
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infrequent SMARCB1 ini1 gene alteration in epithelioid sarcoma a useful tool in distinguishing epithelioid sarcoma from malignant rhabdoid tumor
Human Pathology, 2009Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Tomoaki Taguchi, Teiyu Izumi, Tadashi Hasegawa, Masazumi TsuneyoshiAbstract:Loss of SMARCB1/INI1 protein expression is considered useful for confirming a histologic diagnosis of malignant rhabdoid tumor. However, loss of SMARCB1/INI1 protein expression has recently been reported in other tumors as well, including a few cases of epithelioid sarcoma. In addition, the histopathologic differences between proximal-type epithelioid sarcoma and malignant rhabdoid tumor have not been conclusively defined. We analyzed SMARCB1/INI1 protein expression in 54 epithelioid sarcoma (proximal-type, 25; distal-type, 29) and examined alterations of the SMARCB1/INI1 gene in the cases lacking protein expression. We found that 19 (76.0%) proximal-type epithelioid sarcoma and 27 (93.1%) distal-type epithelioid sarcoma showed loss of SMARCB1/INI1 protein expression. Analysis of 39 cases with loss of protein expression revealed 4 cases (10.3%) with SMARCB1/INI1 gene alterations at the DNA level (homozygous deletion, 2; 1- or 2-bp deletion, 2) that could have induced the loss of gene products, and all 4 of these were proximal-type epithelioid sarcoma. Epithelioid sarcoma was thus associated with a high frequency of loss of SMARCB1/INI1 protein expression similar to that in malignant rhabdoid tumor. However, the frequency of SMARCB1/INI1 gene alteration at the DNA level in proximal-type epithelioid sarcoma was significantly lower than that in malignant rhabdoid tumor. In addition, the prognosis of patients with malignant rhabdoid tumor is significantly worse than that of patients with proximal-type epithelioid sarcoma (P = .001). Therefore, proximal-type epithelioid sarcoma and malignant rhabdoid tumor are suggested to be distinctive tumors with respect to the mechanism of the loss of SMARCB1/INI1 protein expression. Analysis of alterations in the SMARCB1/INI1 gene may thus be a useful diagnostic tool to distinguish proximal-type epithelioid sarcoma from malignant rhabdoid tumor.
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SMARCB1 ini1 protein expression in round cell soft tissue sarcomas associated with chromosomal translocations involving ews a special reference to SMARCB1 ini1 negative variant extraskeletal myxoid chondrosarcoma
The American Journal of Surgical Pathology, 2008Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Tomoaki Taguchi, Teiyu Izumi, Yumi Oshiro, Masazumi TsuneyoshiAbstract:Several previous studies have demonstrated the lack of SMARCB1/INI1 protein expression in only the malignant rhabdoid tumor (MRT). Several sarcoma groups are associated with a tumor-specific translocation involving EWS. Moreover, the EWS and SMARCB1/INI1 genes are located on the same 22q chromosome. We analyzed the status of SMARCB1/INI1 protein expression in 93 cases of sarcomas associated with chromosomal translocation involving EWS, comprising 52 Ewing's sarcoma/primitive neuroectodermal tumors, 24 extraskeletal myxoid chondrosarcomas (EMCS), 14 clear cell sarcomas of soft tissue, 2 desmoplastic small round cell tumors, and 1 myxoid/round cell liposarcoma. In addition, we analyzed the detailed SMARCB1/INI1 gene alteration in cases, which lacked its protein expression. Consequently, 4 EMCS showed no SMARCB1/INI1 expression, and 2 of these 4 cases revealed homozygous deletion and frameshift mutation of the SMARCB1/INI1 gene, respectively. These cases showed histologic findings compatible with EMCS, according to the most recent WHO classification, but no major fusion gene transcripts were detected. Moreover, 3 out of 4 SMARCB1/INI1 negative variant EMCS disclosed rhabdoid features. Therefore, the lack of SMARCB1/INI1 protein expression may be associated with rhabdoid features. The immunohistochemical result of the SMARCB1/INI expression is not an absolute diagnostic criteria for MRT and careful histologic evaluation is required to make a precise diagnosis of MRT.
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highly aggressive behavior of malignant rhabdoid tumor a special reference to SMARCB1 ini1 gene alterations using molecular genetic analysis including quantitative real time pcr
Journal of Cancer Research and Clinical Oncology, 2007Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Tomoaki Taguchi, Teiyu Izumi, Shigeru Ohta, Sachiyo Suita, Masazumi TsuneyoshiAbstract:SMARCB1/INI1, which negatively regulates cell cycle progression from G0/G1 into the S-phase via the p16INK4a-RB-E2F pathway, has been reported to be inactivated homozygously by deletion and/or mutations in malignant rhabdoid tumor (MRT). In the current study, we investigated the alteration of the SMARCB1/INI1 gene using simple methods, and its gene product at the protein level. Moreover, we investigated the status of hyperphosphorylation in RB protein, known as a key cell cycle molecule. Three cell lines and 11 formalin-fixed, paraffin-embedded specimens of MRT were investigated. SMARCB1/INI1 gene alteration was analyzed with simple methods as a quantitative real-time PCR and direct sequencing method. Furthermore, SMARCB1/INI1 and RB protein were immunohistochemically evaluated. In 12 of 14 cases, we detected genetic alterations comprised of nine (including three cell lines) homozygous deletions and three mutations, which can induce abnormal expression of gene products. At the protein level, SMARCB1/INI1 immunohistochemical expressions were not detected in any cases. Twelve out of 14 cases showed high-level (+5) expression of tRB (both hyperphosphorylated and underphosphorylated RB), combined with low-level (+1) expression of uRB (underphosphorylated RB), indicating a high rate of hyperphosphorylation. We could analyze the SMARCB1/INI1 gene alteration with simple methods, and SMARCB1/INI1 gene alteration was found in 12 of 14 cases. Especially, quantitative real-time PCR was a convenient and accurate method. In addition, a high rate of hyperphosphorylation of RB gene was recognized. These results suggest that the clinically aggressive character of MRT is caused by the inactivation of the SMARCB1/INI1 gene.
Abbas Agaimy - One of the best experts on this subject based on the ideXlab platform.
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swi snf protein expression status in fumarate hydratase deficient renal cell carcinoma immunohistochemical analysis of 32 tumors from 28 patients
Human Pathology, 2018Co-Authors: Abbas Agaimy, Mahul B Amin, Anthony J Gill, Bernt Popp, Andre Reis, Daniel M Berney, Cristina Magigalluzzi, Mathilde Sibony, Steven C Smith, Saul SusterAbstract:Fumarate hydratase-deficient renal cell carcinoma (FH-RCC) is a rare, aggressive RCC type, originally described in the setting of hereditary leiomyomatosis and RCC syndrome, which is defined by germline FH gene inactivation. Inactivation of components of the switch/sucrose nonfermentable (SWI/SNF) chromatin remodeling complex is involved in renal medullary carcinoma (SMARCB1/INI1 loss), clear cell RCC (PBRM1 loss), and subsets of dedifferentiated RCC of clear cell, chromophobe, and papillary types (loss of different SWI/SNF components). FH-RCC and SWI/SNF-deficient RCC share anaplastic nuclear features and highly aggressive course. We analyzed 32 FH-RCCs from 28 patients using 7 commercially available SWI/SNF antibodies (SMARCB1/INI1, SMARCA2, SMARCA4, SMARCC1, SMARCC2, PBRM1, and ARID1A). Variable loss of SMARCB1, ARID1A, and SMARCC1 was observed in 1 of 31, 2 of 31, and 1 of 29 evaluable cases, respectively; 3 of these 4 SWI/SNF-deficient tumors had confirmed FH mutations. No correlation of SWI/SNF loss with solid or sarcomatoid features was observed. Two tumors with SMARCB1 and ARID1A deficiency had available SWI/SNF molecular data; both lacked SMARCB1 and ARID1A mutations. The remaining 5 SWI/SNF components were intact in all cases. Especially PBRM1 seems not to be involved in the pathogenesis or progression of FH-RCC. Our data showed that a subset of FH-RCC (12%) have a variable loss of SWI/SNF complex subunits, likely as secondary genetic events. This should not be confused with SWI/SNF-deficient RCC of other types. Evaluation of FH and SWI/SNF together with comprehensive molecular genetic profiling is needed to explore possible prognostic implications of FH/SWI-SNF double deficiency and to better understand the somatic mutation landscape in high-grade RCC.
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EWSR1-fusion-negative, SMARCB1-deficient primary pulmonary myxoid sarcoma
Termedia Publishing House, 2017Co-Authors: Abbas Agaimy, Thomas Duell, Alicia T. Morresi-haufAbstract:Primary pulmonary myxoid sarcoma (PPMS) is a recently defined rare neoplasm with histological and molecular similarity to extraskeletal myxoid chondrosarcoma. To date, 20 cases have been reported. A 48-year-old man presented with a huge mass filling the right hemithorax and extending into the tracheobronchial system. Histological findings were consistent with PPMS. Immunohistochemistry was positive for vimentin, CD10, and EMA, but other lineage-specific markers were negative. SMARCB1 (INI1) expression was lost in the tumour cells. FISH analysis ( EWSR1 , FUS , NR4A3 , and SMARCB1 ) revealed no abnormalities. This case suggests SMARCB1 loss as a possible alternative molecular event driving EWSR1-negative PPMS
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swi snf complex deficient undifferentiated rhabdoid carcinomas of the gastrointestinal tract a series of 13 cases highlighting mutually exclusive loss of smarca4 and smarca2 and frequent co inactivation of SMARCB1 and smarca2
The American Journal of Surgical Pathology, 2016Co-Authors: Abbas Agaimy, Ondrej Daum, Bruno Markl, Ines Lichtmannegger, Michal Michal, Arndt HartmannAbstract:Undifferentiated gastrointestinal tract carcinomas are rare highly aggressive neoplasms with frequent but not obligatory rhabdoid features. Recent studies showed loss of SMARCB1 (INI1), a core subunit of the SWI/SNF chromatin remodeling complex, in 50% of tested cases. However, the molecular pathways underlying histologically similar but SMARCB1-intact cases are unknown. We herein analyzed 13 cases for expression of 4 SWI/SNF complex subunits SMARCB1, SMARCA2, SMARCA4, and ARID1A and the mismatch-repair proteins MLH1, MSH2, MSH6, and PMS2 by immunohistochemistry. Patients included 12 men and 1 woman aged 32 to 81 years (median, 57 y). Site of origin was colon (5), small bowel (2), stomach (3), small+large intestine (1), small intestine+ampulla of Vater (1), and esophagogastric junction (1). All tumors showed anaplastic large to medium-sized cells with variable rhabdoid features, pleomorphic giant cells, and, rarely, spindle cell foci. Abortive gland formation was seen in 3 cases and bona fide glandular component in 1 case. Most cases strongly expressed vimentin and variably pancytokeratin. In total, 12/13 cases (92%) showed loss of at least 1 SWI/SNF component. Loss of SMARCB1 (5/13), SMARCA2 (10/13), SMARCA4 (2/13), and ARID1A (2/13) was observed either in combination or isolated. SMARCA2 loss was isolated in 5 cases and coexisted with lost SMARCB1 in 5 cases (all 5 SMARCB1-deficient tumors showed loss of SMARCA2 as well). Co-inactivation of SMARCB1 and SMARCA4 or of SMARCA2 and SMARCA4 was not observed. Two mismatch-repair-deficient cases (MLH1/PMS2) showed concurrent loss of SMARCB1, SMARCA2, and (one of them) ARID1A. This study illustrates for the first time loss of different components of the SWI/SNF complex other than SMARCB1 in undifferentiated gastrointestinal carcinomas including novel SMARCA4-deficient and SMARCA2-deficient cases. Our results underline the close link between SWI/SNF deficiency and the aggressive rhabdoid phenotype. Frequent loss of SMARCA2 possibly points to fragility/vulnerability of the SWI/SNF complex as a consequence of lost core subunit SMARCB1. The exact molecular mechanisms underlying co-inactivation of different SWI/SNF subunits merit further investigations.
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Reappraisal of sinonasal undifferentiated carcinoma: SMARCB1 (INI1)-deficient sinonasal carcinoma: a single-institution experience
Virchows Archiv, 2015Co-Authors: Diana Bell, Abbas Agaimy, Ehab Y. Hanna, Annikka WeissferdtAbstract:Sinonasal carcinomas are rare and of diverse histology, often involve critical anatomic structures, and are associated with an aggressive clinical course and poor prognosis. Differentiating these tumor types may have clinical impact as advances in entity-specific therapeutic intervention could increase survival and quality of life and occasionally result in a cure. Recently, a unique subset of sinonasal carcinomas characterized by basaloid/rhabdoid tumor morphology and loss of expression of SMARCB1 (INI1) was identified. We tested a total of 256 tumors including head and neck ( n = 241) and thoracic ( n = 15) tumors with basaloid/rhabdoid morphology for loss of expression of SMARCB1 (INI1) using full tissue sections and tissue microarrays. Among these, four tumors of the sinonasal tract were found to be SMARCB1 (INI1) deficient and were reclassified as SMARCB1 (INI1)-deficient sinonasal carcinomas. These tumors appear to be restricted to the sinonasal tract, and their unique clinical, morphological, and immunohistochemical features seem to warrant inclusion as a separate new entity among the existing high-grade sinonasal neoplasms. Separation from the other types of sinonasal malignancies is important as the identification of SMARCB1 (INI1) deficiency may provide a new target for novel treatment approaches and may ultimately lead to improved patient survival.
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the expanding family of SMARCB1 ini1 deficient neoplasia implications of phenotypic biological and molecular heterogeneity
Advances in Anatomic Pathology, 2014Co-Authors: Abbas AgaimyAbstract:Since the description of atypical teratoid/rhabdoid tumors of the central nervous system and renal/extrarenal malignant rhabdoid tumors in children, the clinicopathologic spectrum of neoplasms having in common a highly variable rhabdoid cell component (0% to 100%) and consistent loss of nuclear SMARCB1 (INI1) expression has been steadily expanding to include cribriform neuroepithelial tumor of the ventricle, renal medullary carcinoma and a subset of collecting duct carcinoma, epithelioid sarcoma, subsets of miscellaneous benign and malignant soft tissue tumors, and rare rhabdoid carcinoma variants of gastroenteropancreatic, sinonasal, and genitourinary tract origin. Although a majority of SMARCB1-deficient neoplasms arise de novo, the origin of SMARCB1-deficient neoplasia in the background of a phenotypically or genetically definable differentiated SMARCB1-intact "parent neoplasm" has been convincingly demonstrated, highlighting the rare occurrence of rhabdoid tumors as "double-hit neoplasia." As a group, SMARCB1-deficient neoplasms occur over a wide age range (0 to 80 y), may be devoid of rhabdoid cells or display uniform rhabdoid morphology, and follow a clinical course that varies from benign to highly aggressive causing death within a few months irrespective of aggressive multimodality therapy. Generally applicable criteria that would permit easy recognition of these uncommon neoplasms do not exist. Diagnosis is based on site-specific and entity-specific sets of clinicopathologic, immunophenotypic, and/or molecular criteria. SMARCB1 immunohistochemistry has emerged as a valuable tool in confirming or screening for SMARCB1-deficient neoplasms. This review summarizes the different phenotypic and topographic subgroups of SMARCB1-deficient neoplasms including sporadic and familial, benign and malignant, and rhabdoid and nonrhabdoid variants, highlighting their phenotypic heterogeneity and molecular complexity.
Xiaofeng Wang - One of the best experts on this subject based on the ideXlab platform.
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BRD9 defines a SWI/SNF sub-complex and constitutes a specific vulnerability in malignant rhabdoid tumors
Nature Publishing Group, 2019Co-Authors: Xiaofeng Wang, Jeffrey R Haswell, Su Wang, Emma C Troisi, Thomas P. Howard, Bennett K. Wolf, William H. Hawk, Pilar Ramos, Elaine M. Oberlick, Evgeni P. TzvetkovAbstract:Mutations of the SWI/SNF chromatin-remodeling complex member SMARCB1 can cause malignant rhaboid tumors. Here the authors report a BRD9-containing SWI/SNF subcomplex that lacks SMARCB1 and its requirement for the survival of rhaboid tumors
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abstract lb 096 SMARCB1 mediated swi snf complex function is essential for enhancer regulation
Cancer Research, 2017Co-Authors: Xiaofeng Wang, Ryan S Lee, Burak H Alver, Jeffrey R Haswell, Su Wang, Emma C Troisi, Bradley E Bernstein, Peter J Park, Charles W M RobertsAbstract:The gene encoding SMARCB1 (SNF5/INI1/BAF47), a core subunit of the SWI/SNF (BAF) chromatin remodeling complex, is biallelically inactivated in nearly all rhabdoid tumors (RTs), highly aggressive and lethal cancers of early childhood. RTs are among the most genomically stable cancers, suggesting an epigenetic mechanism by which SMARCB1 loss drives cancer. Here, we show that despite having indistinguishable mutational landscapes, human RTs show distinct H3K27ac signatures at enhancers that reveal remnants of differentiation programs. In elucidating the mechanism underlying RTs, we find that SMARCB1 is not only essential for the integrity and abundance of SWI/SNF complexes, but also facilitates their targeting to appropriate enhancers. Loss of SMARCB1 alters enhancer targeting—markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers (SEs). We show that these retained SEs are essential for RT survival, including some that are shared across all RT types, such as SPRY1, and other lineage-specific SEs like SOX2 in brain-derived RTs. Taken together, our findings reveal a novel chromatin-based epigenetic mechanism underlying the tumor suppressive activity of SMARCB1. Citation Format: Xiaofeng Wang, Ryan Lee, Burak Alver, Jeffrey Haswell, Su Wang, Emma Troisi, Bradley Bernstein, Peter Park, Charles Roberts. SMARCB1-mediated SWI/SNF complex function is essential for enhancer regulation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-096. doi:10.1158/1538-7445.AM2017-LB-096
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SMARCB1 mediated swi snf complex function is essential for enhancer regulation
Nature Genetics, 2017Co-Authors: Xiaofeng Wang, Ryan S Lee, Burak H Alver, Jeffrey R Haswell, Su Wang, Jakub Mieczkowski, Yotam DrierAbstract:SMARCB1 (also known as SNF5, INI1, and BAF47), a core subunit of the SWI/SNF (BAF) chromatin-remodeling complex, is inactivated in nearly all pediatric rhabdoid tumors. These aggressive cancers are among the most genomically stable, suggesting an epigenetic mechanism by which SMARCB1 loss drives transformation. Here we show that, despite having indistinguishable mutational landscapes, human rhabdoid tumors exhibit distinct enhancer H3K27ac signatures, which identify remnants of differentiation programs. We show that SMARCB1 is required for the integrity of SWI/SNF complexes and that its loss alters enhancer targeting-markedly impairing SWI/SNF binding to typical enhancers, particularly those required for differentiation, while maintaining SWI/SNF binding at super-enhancers. We show that these retained super-enhancers are essential for rhabdoid tumor survival, including some that are shared by all subtypes, such as SPRY1, and other lineage-specific super-enhancers, such as SOX2 in brain-derived rhabdoid tumors. Taken together, our findings identify a new chromatin-based epigenetic mechanism underlying the tumor-suppressive activity of SMARCB1.