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Jaclyn A Biegel - One of the best experts on this subject based on the ideXlab platform.

  • case based review atypical teratoid Rhabdoid Tumor
    Neuro-Oncology Practice, 2019
    Co-Authors: Cody L Nesvick, Jaclyn A Biegel, Amulya Nageswara A Rao, Aditya Raghunathan, David J Daniels
    Abstract:

    Atypical teratoid/Rhabdoid Tumor (AT/RT) is a rare CNS cancer that typically occurs in children younger than 3 years of age. Histologically, AT/RTs are embryonal Tumors that contain a Rhabdoid component as well as areas with primitive neuroectodermal, mesenchymal, and epithelial features. Compared to other CNS Tumors of childhood, AT/RTs are characterized by their rapid growth, short symptomatic prodrome, and large size upon presentation, often leading to brain compression and intracranial hypertension requiring urgent intervention. For decades, the mainstay of care has been a combination of maximal safe surgical resection followed by adjuvant chemotherapy and radiotherapy. Despite advances in each of these modalities, the relative paucity of data on these Tumors, their inherently aggressive course, and a lack of molecular data have limited advances in treatment over the past 3 decades. Recent large-scale, multicenter interdisciplinary studies, however, have significantly advanced our understanding of the molecular pathogenesis of these Tumors. Multiple clinical trials testing molecularly targeted therapies are underway, offering hope for patients with AT/RT and their families.

  • concurrent myeloid sarcoma atypical teratoid Rhabdoid Tumor and hypereosinophilia in an infant with a germline smarcb1 mutation
    Pediatric Blood & Cancer, 2017
    Co-Authors: Jonathan L Metts, Sunita I Park, Bruno P Soares, Cindy Y Fong, Jaclyn A Biegel, Kelly C Goldsmith
    Abstract:

    We report a 1-year-old female child presenting with hypereosinophilia who was found to have concurrent myeloid sarcoma and a central nervous system (CNS) atypical teratoid/Rhabdoid Tumor (AT/RT). She was later found to have a germline mutation in SMARCB1. Concurrent hematologic malignancy and CNS AT/RT have not previously been described in the context of a SMARCB1 loss-of-function germline mutation.

  • biology and treatment of Rhabdoid Tumor
    Critical Reviews in Oncogenesis, 2015
    Co-Authors: James I Geller, Jacquelyn J Roth, Jaclyn A Biegel
    Abstract:

    Rhabdoid Tumor is a rare, highly aggressive malignancy that primarily affects infants and young children. These Tumors typically arise in the brain and kidney, although extrarenal, non-central nervous system Tumors in almost all soft-tissue sites have been described. SMARCB1 is a member of the SWI/SNF chromatin-remodeling complex and functions as a Tumor suppressor in the vast majority of Rhabdoid Tumors. Patients with germline mutations or deletions affecting SMARCB1 are predisposed to the development of Rhabdoid Tumors, as well as the genetic disorder schwannomatosis. The current hypothesis is that Rhabdoid Tumors are driven by epigenetic dysregulation, as opposed to the alteration of a specific biologic pathway. The strategies for novel therapeutic approaches based on what is currently known about Rhabdoid Tumor biology are presented.

  • the role of smarcb1 ini1 in development of Rhabdoid Tumor
    Cancer Biology & Therapy, 2009
    Co-Authors: Charles W M Roberts, Jaclyn A Biegel
    Abstract:

    Rhabdoid Tumors are especially lethal cancers that predominantly strike young children. The vast majority of Rhabdoid Tumors contain bi-allelic inactivating mutations in the SMARCB1 gene. Here we review clinicopathologic features of Rhabdoid Tumors and present recent insights into the mechanisms that drive oncogenesis in the absence of SMARCB1 function. Rhabdoid Tumors are highly malignant neoplasms that typically arise in infancy and early childhood. The Tumors develop in the brain and spinal cord [referred to as atypical teratoid/Rhabdoid Tumor (AT/RT)], kidney and/or soft tissues (termed malignant Rhabdoid Tumor or extra-renal Rhabdoid Tumor). The histologic appearance of these malignancies can be quite variable. Most Tumors contain at least some fields with classic Rhabdoid cells, with large nuclei containing a single prominent nucleolus, and cytoplasm with distinct pale eosinophilic inclusions. Tumors demonstrating only classic Rhabdoid cells are rare, instead, they often have areas composed of spindled or pleomorphic undifferentiated cells without a Rhabdoid phenotype. A classic Rhabdoid component may be entirely absent. Central nervous system AT/RTs typically demonstrate a variety of primitive neuroectodermal, epithelial or mesenchymal cells, which underlies the difficulty in distinguishing these Tumors from other primitive neuroectodermal Tumors or choroid plexus carcinomas.1 Immunohistochemistry is often used in the differential diagnosis, based on the typical expression of smooth muscle actin, epithelial membrane antigen and vimentin. Lack of expression of the SMARCB1 protein, as described below, is also employed as a specific means of distinguishing Rhabdoid Tumors from other malignancies with similar histologic features, especially for diagnosis of AT/RT versus primitive neuroectodermal Tumor.2 The development of Rhabdoid Tumors was initially associated with monosomy 22 and subsequently, deletions and translocations involving chromosome band 22q11.2.3,4 Positional cloning studies ultimately identified SMARCB1 (INI1/SNF5/BAF47) as the gene responsible for the initiation of malignant Rhabdoid Tumors and central nervous system AT/RT.5 In the appropriate clinical setting, germline and somatic mutations and deletions of SMARCB1 may be diagnostic for renal and extra-renal Rhabdoid Tumors as well as AT/RT, however the role of SMARCB1 inactivation in other CNS Tumors, such as choroid plexus carcinoma,6,7 remains controversial. Recently, SMARCB1 has also been implicated in the development of familial schwannomatosis,8–12 although it is not clear if there is a similar spectrum of mutations and deletions to those seen in classic Rhabdoid Tumors. In Rhabdoid Tumors, SMARCB1 appears to function as a classic Tumor suppressor gene, such that germline mutations and deletions predispose to the development of these malignancies, and somatic loss or mutation of the other allele constitutes the second hit. Inactivation of both copies of the gene leads to loss of protein expression in the nucleus, which can be detected by immunohistochemistry. The immunohistochemistry assay for the SMARCB1 protein (BAF47) is currently used as an adjunct to histology in the differential diagnosis of Rhabdoid Tumors in both children and adults.2 Loss of expression of SMARCB1 has also been observed in the majority of epithelioid sarcomas [ES],13 fifty percent of epithelioid malignant peripheral nerve sheath Tumors 13 and renal medullary carcinomas [RMC].14 However, molecular genetic studies to determine the mechanism for loss of expression of the protein in ES have been conflicting and have yet to be reported in RMC.15,16 Thus the frequency with which the typical bi-allelic mutations or deletions in the SMARCB1 locus that are seen in Rhabdoid Tumors are also responsible for the loss of protein expression observed in ES is somewhat unclear. Individuals with germline alterations of SMARCB1 are predisposed to Rhabdoid Tumors of the brain, kidney and soft tissues and may present with more than one primary Tumor.5,17,18 These children are most often diagnosed within the first year of life and tend to have a worse prognosis.19 It is not known whether the poor prognosis is related to the presence of a germline mutation in all of their cells, or the fact that they develop multiple and progressive primary Tumors that are resistant to therapy. In most patients, the germline mutations or deletions are de novo and parents are reported to be unaffected. Reports of multiple affected siblings with CNS Tumors with the same germline mutation, in which neither parent was a carrier, implicated gonadal mosaicism as a mechanism that can result in a familial associated genetic predisposition to cancer.20 To date, there have been only three reports of Rhabdoid Tumors associated with inherited SMARCB1 mutations in multi-generation families.21–23 In two cases, the affected children had a germline SMARCB1 mutation inherited from their unaffected carrier mother. In a recently described family multiple members had either schwannomas or AT/RT associated with inheritance of an exon 6 duplication in the SMARCB1 gene.23 Therefore, reduced penetrance for SMARCB1, i.e., variable risk of development of Rhabdoid Tumor or schwannoma associated with a germline mutation, gonadal mosaicism and risk of multiple primary Tumors all need to be considered in developing recurrence risks for affected families. Finally, Rhabdoid Tumors have been seen in the context of a germline chromosome band 22q11.2 deletion that encompasses the SMARCB1 locus.18 Depending on the size of the deletion, these patients may also be at risk for heart defects, development delay and other congenital abnormalities associated with the loss of additional genes in the 22q11.2 region. As high-density array comparative genomic hybridization or single nucleotide polymorphism based oligonucleotide arrays are increasingly being used to screen for genetic disorders in patients with congenital abnormalities and developmental delay, additional individuals will likely be found with germline deletions of SMARCB1. Clinical monitoring protocols for these individuals will need to be developed because of their increased risk of malignancy. A germline mutation or deletion may be present in 15–30% of patients with Rhabdoid Tumor, although active studies are ongoing to refine these numbers. Genetic counseling and clinical molecular genetic testing for a germline SMARCB1 mutation or deletion in patients who present with schwannomatosis or Rhabdoid Tumor, even if it appears to be sporadic, is highly recommended. Consistent with its role as a Tumor suppressor, deletion and mutation analyses of CNS, renal and extrarenal Rhabdoid Tumors have demonstrated bi-allelic alterations of the SMARCB1 gene.5,17,24 The majority of coding sequence mutations are point or frameshift mutations that introduce a novel stop codon and predict premature truncation of the protein. There are several hot spots for SMARCB1 mutations, and two mutations appear to be specific for CNS Tumors. A cytosine or guanine deletion in codon 382 in exon 9 has been documented in the majority of CNS AT/RTs. Both the delC and delG cause a frameshift; but eliminate the final stop codon, and are predicted to result in the addition of 96 amino acids to the C terminal end of the protein. Interestingly, this mutation has not yet been observed in the germline. A c.601C > T mutation in exon 5 has also been documented in a large number of AT/RTs, but may also be present as a germline mutation. In primary Tumors, the messenger RNA or protein is likely to be unstable, however, since the altered proteins are not detected by western blot analysis or immunohistochemistry. In a recent report, 51 Rhabdoid Tumors from a variety of anatomic locations were studied using a combination of direct sequence analysis of the nine coding exons, multiplex ligation dependent probe amplification (MLPA) and oligonucleotide based single nucleotide polymorphism [SNP] arrays.25 Bi-allelic inactivating events in SMARCB1 were identified in all but one Tumor. Notably, despite the differences in anatomic location, half of the Tumors (24/51) were characterized by homozygous deletions of SMARCB1. This included over one third (13 of 36) of the CNS AT/RTs as well as the majority of both renal (6/8) and extra renal (5/7) Tumors. The advantage of the SNP based genotyping array platform was evidenced by the large number of cases (11 Tumors) with copy number neutral loss of heterozygosity for most of the long arm of chromosome 22. The renal Rhabdoid Tumors were more likely to have complex patterns of deletion and duplication as evidenced by the array studies, whereas the extra-renal Rhabdoid Tumors were more likely to have smaller deletions in 22q11.22 to 22q11.23. In most cases, this is due to unbalanced translocations at the SMARCB1 locus. These data strongly support SMARCB1 as being the primary gene responsible for the development of Rhabdoid Tumors. However, a small number of Rhabdoid Tumors retain expression of the protein, even with Rhabdoid histology and familial Rhabdoid Tumors have been reported that are not associated with a SMARCB1 mutation. 26,27 These reports raise the possibility of a second Rhabdoid Tumor locus, distinct from SMARCB1.

  • imprinted cdkn1c is a Tumor suppressor in Rhabdoid Tumor and activated by restoration of smarcb1 and histone deacetylase inhibitors
    PLOS ONE, 2009
    Co-Authors: Elizabeth M Algar, Jaclyn A Biegel, Andrea Muscat, Vinod Dagar, Christian H Rickert, C W Chow, Paul G Ekert, Richard Saffery, Jeffrey M Craig, Ricky W Johnstone
    Abstract:

    SMARCB1 is deleted in Rhabdoid Tumor, an aggressive paediatric malignancy affecting the kidney and CNS. We hypothesized that the oncogenic pathway in Rhabdoid Tumors involved epigenetic silencing of key cell cycle regulators as a consequence of altered chromatin-remodelling, attributable to loss of SMARCB1, and that this hypothesis if proven could provide a biological rationale for testing epigenetic therapies in this disease. We used an inducible expression system to show that the imprinted cell cycle inhibitor CDKN1C is a downstream target for SMARCB1 and is transcriptionally activated by increased histone H3 and H4 acetylation at the promoter. We also show that CDKN1C expression induces cell cycle arrest, CDKN1C knockdown with siRNA is associated with increased proliferation, and is able to compete against the anti-proliferative effect of restored SMARCB1 expression. The histone deacetylase inhibitor (HDACi), Romidepsin, specifically restored CDKN1C expression in Rhabdoid Tumor cells through promoter histone H3 and H4 acetylation, recapitulating the effect of SMARCB1 on CDKNIC allelic expression, and induced cell cycle arrest in G401 and STM91-01 Rhabdoid Tumor cell lines. CDKN1C expression was also shown to be generally absent in clinical specimens of Rhabdoid Tumor, however CDKN1A and CDKN1B expression persisted. Our observations suggest that maintenance of CDKN1C expression plays a critical role in preventing Rhabdoid Tumor growth. Significantly, we report for the first time, parallels between the molecular pathways of SMARCB1 restoration and Romidepsin treatment, and demonstrate a biological basis for the further exploration of histone deacetylase inhibitors as relevant therapeutic reagents in the treatment of Rhabdoid Tumor.

Yoshinao Oda - One of the best experts on this subject based on the ideXlab platform.

  • reclassification of Rhabdoid Tumor and pediatric undifferentiated unclassified sarcoma with complete loss of smarcb1 ini1 protein expression three subtypes of Rhabdoid Tumor according to their histological features
    Modern Pathology, 2016
    Co-Authors: Kenichi Kohashi, Hidetaka Yamamoto, Yukihide Iwamoto, Tomoaki Taguchi, Yuichi Yamada, Yukichi Tanaka, Hiroshi Kishimoto, Yoshinao Oda
    Abstract:

    Rhabdoid Tumor is characterized by Rhabdoid cells and shows complete loss of SMARCB1/INI1 protein expression. In existing classifications, the diagnostic synonyms vary depending on the anatomic site: Rhabdoid Tumors in the central nervous system or extra-central nervous system are, respectively, classified as atypical teratoid/Rhabdoid Tumor or malignant Rhabdoid Tumor. In this study, we analyzed the histological, immunohistochemical, microRNA, and clinicopathological statuses of Tumors initially diagnosed as malignant Rhabdoid Tumor (n=33), atypical teratoid/Rhabdoid Tumor (n=11), and pediatric undifferentiated/unclassified sarcoma (n=8) with complete loss of SMARCB1/INI1 expression, and considered the possibility of their histological reclassification. Our analysis indicated that the Tumors could be histologically reclassified into three groups: conventional-type Tumors resembling malignant Rhabdoid Tumor, atypical teratoid/Rhabdoid-type Tumors resembling atypical teratoid/Rhabdoid Tumor, and small cell-type Tumors resembling malignant lymphoma. The reclassified conventional type was composed of 27 malignant Rhabdoid Tumors and 9 atypical teratoid/Rhabdoid Tumors (36 cases). The atypical teratoid/Rhabdoid type consisted of six malignant Rhabdoid Tumors, two atypical teratoid/Rhabdoid Tumors, and two undifferentiated/unclassified sarcomas (10 cases). The six cases of small cell type were made up of six undifferentiated/unclassified sarcomas. All of the available Tumor specimens were positive for vimentin and epithelial marker (EMA, CAM5.2, or AE1/AE3). MicroRNA profiles were not significantly different between the conventional- and small cell-type Tumors (Pearson's correlation coefficient: 0.888300 or 0.891388). There was no significant difference in overall survival between atypical teratoid/Rhabdoid Tumor and malignant Rhabdoid Tumor (P=0.16). In addition, there were no significant differences in survival between any of the reclassified combinations. In conclusion, we could classify eight Tumors initially diagnosed as undifferentiated/unclassified sarcomas into two cases of atypical teratoid/Rhabdoid type and six cases of small cell type. We suggest that reclassification of malignant Rhabdoid Tumors into three groups according to their histologic features rather than the traditional classification by sites of origin would be favorable for their histopathological diagnosis.

  • erg and sall4 expressions in smarcb1 ini1 deficient Tumors a useful tool for distinguishing epithelioid sarcoma from malignant Rhabdoid Tumor
    Human Pathology, 2015
    Co-Authors: Kenichi Kohashi, Hidetaka Yamamoto, Yukihide Iwamoto, Tomoaki Taguchi, Yuichi Yamada, Yuka Hotokebuchi, Yoshinao Oda
    Abstract:

    ERG is immunoexpressed in vascular endothelial Tumors, blastic extramedullary myeloid Tumors, and Tumors with ERG-involved translocation, such as prostate carcinoma or Ewing sarcoma. Recently, ERG immunoexpression was reported in an epithelioid sarcoma, which is a SMARCB1/INI1-deficient Tumor, although epithelioid sarcoma is not associated with chromosomal translocations involving ERG and is categorized as a Tumor with uncertain differentiation. SALL4 is essential for a proliferation and stabilization of embryonic stem cells. It was reported that SALL4 expression may aid in distinguishing epithelioid sarcoma from malignant Rhabdoid Tumor. We analyzed the frequency of ERG and SALL4 expressions in 80 SMARCB1/INI1-deficient Tumors, including 45 epithelioid sarcomas (conventional-type, 24; proximal-type, 20), 17 malignant Rhabdoid Tumors, 5 atypical teratoid/Rhabdoid Tumors, 6 undifferentiated/unclassified sarcomas, 5 myoepithelial Tumors, and 4 extraskeletal myxoid chondrosarcomas. We found that ERG expression was present in 18 of the epithelioid sarcomas (41%), including 13 conventional-type (54%) and 5 proximal-type (25%), whereas all 17 of the malignant Rhabdoid Tumors exhibited negative immunoreactivity. One atypical teratoid/Rhabdoid Tumor (20%), 1 myoepithelial carcinoma (20%), 1 undifferentiated/unclassified sarcoma (17%), and no extraskeletal myxoid chondrosarcomas (0%) also showed ERG expression. SALL4 expression was recognized in 5 epithelioid sarcomas (11%), 12 malignant Rhabdoid Tumors (71%), 2 atypical teradoid/Rhabdoid Tumors (40%), 4 undifferentiated/unclassified sarcomas (67%), 1 myoepithelial Tumor (20%), and none of the extraskeletal myxoid chondrosarcomas (0%). Therefore, the evaluation of ERG and SALL4 immunoexpressions may be a useful diagnostic tool to distinguish epithelioid sarcoma, especially proximal type, from malignant Rhabdoid Tumor.

  • differential microrna expression profiles between malignant Rhabdoid Tumor and epithelioid sarcoma mir193a 5p is suggested to downregulate smarcb1 mrna expression
    Modern Pathology, 2014
    Co-Authors: Kenichi Kohashi, Hidetaka Yamamoto, Yukihide Iwamoto, Tomoaki Taguchi, Yuichi Yamada, Yuka Hotokebuchi, Reiko Kumagai, Yoshinao Oda
    Abstract:

    Malignant Rhabdoid Tumor and epithelioid sarcoma are classified as Tumors of uncertain differentiation. However, it is controversial whether these Tumors are distinct entities because they share similar histological and immunohistochemical features such as the existence of Rhabdoid cells or complete loss of SMARCB1 protein expression. MicroRNAs are small non-coding RNAs, and it is suggested that knowledge of microRNA expression profiles in cancer may have substantial value for diagnostics. We first analyzed microRNA expression profiles in 13 frozen materials (five malignant Rhabdoid Tumors, two proximal type epithelioid sarcomas, and six conventional type epithelioid sarcomas) and subsequently examined the specific microRNA expressions in 29 paraffin-embedded materials (8 malignant Rhabdoid Tumors, 13 proximal type epithelioid sarcomas, and 8 conventional type epithelioid sarcomas) and 13 previously described frozen materials by quantitative RT–PCR. According to the unsupervised hierarchical clustering of microRNA, proximal type epithelioid sarcoma and conventional type epithelioid sarcoma were classified into the same category, whereas malignant Rhabdoid Tumor was a distinct category from both types of epithelioid sarcoma. In addition, when malignant Rhabdoid Tumor with SMARCB1 gene alterations and proximal type and conventional type epithelioid sarcoma with no SMARCB1 gene alterations were compared, 56 microRNAs were isolated as being significantly different (ANOVA, P<0.05). Among them, quantitative RT–PCR using frozen and paraffin-embedded materials demonstrated that expression levels of miR193a-5p (P=0.002), which has been suggested to downregulate SMARCB1 mRNA expression, showed statistically different expression levels between malignant Rhabdoid Tumor and epithelioid sarcoma with no SMARCB1 gene alterations. These results suggest that epithelioid sarcoma, especially proximal type epithelioid sarcoma, and malignant Rhabdoid Tumor are distinct Tumors with respect to the microRNA expression profiles and that miR193a-5p may have an important role in the inhibition of SMARCB1 mRNA expression.

  • infrequent smarcb1 ini1 gene alteration in epithelioid sarcoma a useful tool in distinguishing epithelioid sarcoma from malignant Rhabdoid Tumor
    Human Pathology, 2009
    Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Tomoaki Taguchi, Teiyu Izumi, Tadashi Hasegawa, Masazumi Tsuneyoshi
    Abstract:

    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.

Kenichi Kohashi - One of the best experts on this subject based on the ideXlab platform.

  • reclassification of Rhabdoid Tumor and pediatric undifferentiated unclassified sarcoma with complete loss of smarcb1 ini1 protein expression three subtypes of Rhabdoid Tumor according to their histological features
    Modern Pathology, 2016
    Co-Authors: Kenichi Kohashi, Hidetaka Yamamoto, Yukihide Iwamoto, Tomoaki Taguchi, Yuichi Yamada, Yukichi Tanaka, Hiroshi Kishimoto, Yoshinao Oda
    Abstract:

    Rhabdoid Tumor is characterized by Rhabdoid cells and shows complete loss of SMARCB1/INI1 protein expression. In existing classifications, the diagnostic synonyms vary depending on the anatomic site: Rhabdoid Tumors in the central nervous system or extra-central nervous system are, respectively, classified as atypical teratoid/Rhabdoid Tumor or malignant Rhabdoid Tumor. In this study, we analyzed the histological, immunohistochemical, microRNA, and clinicopathological statuses of Tumors initially diagnosed as malignant Rhabdoid Tumor (n=33), atypical teratoid/Rhabdoid Tumor (n=11), and pediatric undifferentiated/unclassified sarcoma (n=8) with complete loss of SMARCB1/INI1 expression, and considered the possibility of their histological reclassification. Our analysis indicated that the Tumors could be histologically reclassified into three groups: conventional-type Tumors resembling malignant Rhabdoid Tumor, atypical teratoid/Rhabdoid-type Tumors resembling atypical teratoid/Rhabdoid Tumor, and small cell-type Tumors resembling malignant lymphoma. The reclassified conventional type was composed of 27 malignant Rhabdoid Tumors and 9 atypical teratoid/Rhabdoid Tumors (36 cases). The atypical teratoid/Rhabdoid type consisted of six malignant Rhabdoid Tumors, two atypical teratoid/Rhabdoid Tumors, and two undifferentiated/unclassified sarcomas (10 cases). The six cases of small cell type were made up of six undifferentiated/unclassified sarcomas. All of the available Tumor specimens were positive for vimentin and epithelial marker (EMA, CAM5.2, or AE1/AE3). MicroRNA profiles were not significantly different between the conventional- and small cell-type Tumors (Pearson's correlation coefficient: 0.888300 or 0.891388). There was no significant difference in overall survival between atypical teratoid/Rhabdoid Tumor and malignant Rhabdoid Tumor (P=0.16). In addition, there were no significant differences in survival between any of the reclassified combinations. In conclusion, we could classify eight Tumors initially diagnosed as undifferentiated/unclassified sarcomas into two cases of atypical teratoid/Rhabdoid type and six cases of small cell type. We suggest that reclassification of malignant Rhabdoid Tumors into three groups according to their histologic features rather than the traditional classification by sites of origin would be favorable for their histopathological diagnosis.

  • erg and sall4 expressions in smarcb1 ini1 deficient Tumors a useful tool for distinguishing epithelioid sarcoma from malignant Rhabdoid Tumor
    Human Pathology, 2015
    Co-Authors: Kenichi Kohashi, Hidetaka Yamamoto, Yukihide Iwamoto, Tomoaki Taguchi, Yuichi Yamada, Yuka Hotokebuchi, Yoshinao Oda
    Abstract:

    ERG is immunoexpressed in vascular endothelial Tumors, blastic extramedullary myeloid Tumors, and Tumors with ERG-involved translocation, such as prostate carcinoma or Ewing sarcoma. Recently, ERG immunoexpression was reported in an epithelioid sarcoma, which is a SMARCB1/INI1-deficient Tumor, although epithelioid sarcoma is not associated with chromosomal translocations involving ERG and is categorized as a Tumor with uncertain differentiation. SALL4 is essential for a proliferation and stabilization of embryonic stem cells. It was reported that SALL4 expression may aid in distinguishing epithelioid sarcoma from malignant Rhabdoid Tumor. We analyzed the frequency of ERG and SALL4 expressions in 80 SMARCB1/INI1-deficient Tumors, including 45 epithelioid sarcomas (conventional-type, 24; proximal-type, 20), 17 malignant Rhabdoid Tumors, 5 atypical teratoid/Rhabdoid Tumors, 6 undifferentiated/unclassified sarcomas, 5 myoepithelial Tumors, and 4 extraskeletal myxoid chondrosarcomas. We found that ERG expression was present in 18 of the epithelioid sarcomas (41%), including 13 conventional-type (54%) and 5 proximal-type (25%), whereas all 17 of the malignant Rhabdoid Tumors exhibited negative immunoreactivity. One atypical teratoid/Rhabdoid Tumor (20%), 1 myoepithelial carcinoma (20%), 1 undifferentiated/unclassified sarcoma (17%), and no extraskeletal myxoid chondrosarcomas (0%) also showed ERG expression. SALL4 expression was recognized in 5 epithelioid sarcomas (11%), 12 malignant Rhabdoid Tumors (71%), 2 atypical teradoid/Rhabdoid Tumors (40%), 4 undifferentiated/unclassified sarcomas (67%), 1 myoepithelial Tumor (20%), and none of the extraskeletal myxoid chondrosarcomas (0%). Therefore, the evaluation of ERG and SALL4 immunoexpressions may be a useful diagnostic tool to distinguish epithelioid sarcoma, especially proximal type, from malignant Rhabdoid Tumor.

  • differential microrna expression profiles between malignant Rhabdoid Tumor and epithelioid sarcoma mir193a 5p is suggested to downregulate smarcb1 mrna expression
    Modern Pathology, 2014
    Co-Authors: Kenichi Kohashi, Hidetaka Yamamoto, Yukihide Iwamoto, Tomoaki Taguchi, Yuichi Yamada, Yuka Hotokebuchi, Reiko Kumagai, Yoshinao Oda
    Abstract:

    Malignant Rhabdoid Tumor and epithelioid sarcoma are classified as Tumors of uncertain differentiation. However, it is controversial whether these Tumors are distinct entities because they share similar histological and immunohistochemical features such as the existence of Rhabdoid cells or complete loss of SMARCB1 protein expression. MicroRNAs are small non-coding RNAs, and it is suggested that knowledge of microRNA expression profiles in cancer may have substantial value for diagnostics. We first analyzed microRNA expression profiles in 13 frozen materials (five malignant Rhabdoid Tumors, two proximal type epithelioid sarcomas, and six conventional type epithelioid sarcomas) and subsequently examined the specific microRNA expressions in 29 paraffin-embedded materials (8 malignant Rhabdoid Tumors, 13 proximal type epithelioid sarcomas, and 8 conventional type epithelioid sarcomas) and 13 previously described frozen materials by quantitative RT–PCR. According to the unsupervised hierarchical clustering of microRNA, proximal type epithelioid sarcoma and conventional type epithelioid sarcoma were classified into the same category, whereas malignant Rhabdoid Tumor was a distinct category from both types of epithelioid sarcoma. In addition, when malignant Rhabdoid Tumor with SMARCB1 gene alterations and proximal type and conventional type epithelioid sarcoma with no SMARCB1 gene alterations were compared, 56 microRNAs were isolated as being significantly different (ANOVA, P<0.05). Among them, quantitative RT–PCR using frozen and paraffin-embedded materials demonstrated that expression levels of miR193a-5p (P=0.002), which has been suggested to downregulate SMARCB1 mRNA expression, showed statistically different expression levels between malignant Rhabdoid Tumor and epithelioid sarcoma with no SMARCB1 gene alterations. These results suggest that epithelioid sarcoma, especially proximal type epithelioid sarcoma, and malignant Rhabdoid Tumor are distinct Tumors with respect to the microRNA expression profiles and that miR193a-5p may have an important role in the inhibition of SMARCB1 mRNA expression.

  • infrequent smarcb1 ini1 gene alteration in epithelioid sarcoma a useful tool in distinguishing epithelioid sarcoma from malignant Rhabdoid Tumor
    Human Pathology, 2009
    Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Tomoaki Taguchi, Teiyu Izumi, Tadashi Hasegawa, Masazumi Tsuneyoshi
    Abstract:

    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.

Michael C Fruhwald - One of the best experts on this subject based on the ideXlab platform.

  • transposable element insertion as a mechanism of smarcb1 inactivation in atypical teratoid Rhabdoid Tumor
    Genes Chromosomes and Cancer, 2021
    Co-Authors: Christian Thomas, Susanne Bens, Karolina Nemes, Kathrin Oehlhuber, Patrick Soschinski, Arend Koch, Florian Oyen, Uwe Kordes, Marcel Kool, Michael C Fruhwald
    Abstract:

    Atypical teratoid/Rhabdoid Tumor (AT/RT) is a malignant brain Tumor predominantly occurring in infants. Biallelic SMARCB1 mutations causing loss of nuclear SMARCB1/INI1 protein expression represent the characteristic genetic lesion. Pathogenic SMARCB1 mutations comprise single nucleotide variants, small insertions/deletions, large deletions, which may be also present in the germline (Rhabdoid Tumor predisposition syndrome 1), as well as somatic copy-number neutral loss of heterozygosity (LOH). In some SMARCB1-deficient AT/RT underlying biallelic mutations cannot be identified. Here we report the case of a 24-months-old girl diagnosed with a large brain Tumor. The malignant Rhabdoid Tumor showed loss of nuclear SMARCB1/INI1 protein expression and the diagnosis of AT/RT was confirmed by DNA methylation profiling. While FISH, MLPA, Sanger sequencing and DNA methylation data-based imbalance analysis did not disclose alterations affecting SMARCB1, OncoScan array analysis revealed a 28.29 Mb sized region of copy-number neutral LOH on chromosome 22q involving the SMARCB1 locus. Targeted next-generation sequencing did also not detect a single nucleotide variant but instead revealed insertion of an AluY element into exon 2 of SMARCB1. Specific PCR-based Sanger sequencing verified the Alu insertion (SMARCB1 c.199_200 Alu ins) resulting in a frame-shift truncation not present in the patient's germline. In conclusion, transposable element insertion represents a hitherto not widely recognized mechanism of SMARCB1 disruption in AT/RT, which might not be detected by several widely applied conventional diagnostics assays. This finding has particular clinical implications, if Rhabdoid predisposition syndrome 1 is suspected, but germline SMARCB1 alterations cannot be identified. This article is protected by copyright. All rights reserved.

  • Rhabdoid Tumor predisposition syndrome
    2017
    Co-Authors: Karolina Nemes, Susanne Bens, Uwe Kordes, Marcel Kool, Reinhard Schneppenheim, Martin Hasselblatt, Reiner Siebert, Franck Bourdeaut, Pascal Johann, Michael C Fruhwald
    Abstract:

    Clinical characteristics Rhabdoid Tumor predisposition syndrome (RTPS) is characterized by a markedly increased risk of developing Rhabdoid Tumors – rare and highly aggressive malignant Tumors occurring predominantly in infants and children younger than age three years. Rhabdoid Tumors can occur in almost any anatomic location, commonly in the central nervous system (i.e., atypical teratoid/Rhabdoid Tumor [AT/RT]); more than 50% occur in the cerebellum. Other common locations include extracranial extrarenal malignant Rhabdoid Tumors (e.g., Rhabdoid Tumors of the head and neck, paravertebral muscles, liver, bladder, mediastinum, retroperitoneum, pelvis, and heart) (eMRT), Rhabdoid Tumor of the kidney (RTK), and possibly small-cell carcinoma of the ovary (hypercalcemic type). Individuals with RTPS typically present before age 12 months with synchronous Tumors that exhibit aggressive clinical behavior. Diagnosis/testing The diagnosis of RTPS is established in a proband with a Rhabdoid Tumor and/or a family history of Rhabdoid Tumor and/or multiple SMARCA4- or SMARCB1-deficient Tumors (synchronous or metachronous) and identification of a germline heterozygous pathogenic variant in SMARCA4 or SMARCB1 by molecular genetic testing. Management Treatment of manifestations: Due to the rarity of RTPS, standards for management are evolving. Most individuals are treated by intensive multimodal therapeutic strategies, according to institutional preference combining surgery, radiotherapy, and chemotherapy. Prevention of primary manifestations: Prophylactic bilateral oophorectomy may be discussed after childbearing. Prevention of secondary manifestations: Consider risk-reducing treatment strategies (e.g., postpone or replace radiotherapy with high-dose chemotherapy or proton beam therapy; targeted therapy used concomitantly with, or before, standard chemotherapy). Surveillance: From birth to age one year: Monthly physical and neurologic examination, head ultrasound, and abdominal and pelvic ultrasound recommended. If not feasible for patients with AT/RT, monthly head ultrasound plus abdominal and pelvic ultrasound every two to three months is a minimum requirement. If fontanelle closes prematurely consider head MRI every two to three months. For patients with eMRT, RTK: monthly head, abdominal, and pelvic ultrasound examination. If ultrasound is not sufficient consider MRI at least every two to three months for affected site and ultrasound for all other sites. Whole-body MRI is desirable but not universally available. From age one year to age four to five years: For patients with AT/RT: brain and total spine MRI every three months If available, consider whole-body MRI. (Note: Whole-body MRI resolution may not be sufficent for brain MRI, which would then need to be performed separately). For patients with eMRT, RTK: abdominal and pelvic ultrasound or MRI (or whole-body MRI) every three months. After age four years: Twice-yearly physical examination in a Tumor predisposition clinic with targeted imaging for symptomatic areas. For patients with SMARCA4-related SCCOHT: abdominal and pelvic ultrasound every six months. Evaluation of relatives at risk: It is appropriate to evaluate apparently asymptomatic older and younger at-risk relatives of an affected individual in order to identify as early as possible those who would benefit from prompt initiation of screening, treatment, and preventive measures. Genetic counseling RTPS is inherited in an autosomal dominant manner. The vast majority of individuals diagnosed with RTPS have the disorder as the result of a de novo germline SMARCB1 pathogenic variant. Most reported individuals diagnosed with SMARCA4-related RTPS inherited a pathogenic variant from an unaffected parent. Each child of an individual with a germline SMARCA4 or SMARCB1 pathogenic variant has a 50% chance of inheriting the pathogenic variant. However, penetrance appears to be incomplete and the types of RTPS-related Tumors can vary among different members of the same family. Prenatal testing and preimplantation genetic testing are possible if the pathogenic variant in the family is known.

  • synchronous congenital malignant Rhabdoid Tumor of the orbit and atypical teratoid Rhabdoid Tumor feasibility and efficacy of multimodal therapy in a long term survivor
    Cancer Genetics and Cytogenetics, 2014
    Co-Authors: Angela Seeringer, Reinhard Schneppenheim, Martin Hasselblatt, Reiner Siebert, Harald Reinhard, Kerstin Bartelheim, Ivo Leuschner, Michael C Fruhwald
    Abstract:

    Among infant malignancies, congenital Tumors, especially those of the central nervous system (CNS), constitute a rather unique subgroup. Poor survival rates (28% in CNS Tumors) may be attributed to the aggressive biology as well as specific therapeutic limitations innate to the young age of affected patients. Our patient developed synchronous congenital Tumors: an atypical teratoid/Rhabdoid Tumor (AT/RT) localized in the right lateral ventricle of the brain and a malignant Rhabdoid Tumor (MRT) in the soft tissue of the right orbit. A de novo germline chromosomal deletion in 22q encompassing the SMARCB1 gene was detected, prompting the diagnosis of a de novo Rhabdoid Tumor predisposition syndrome 1 (RTPS1). The patient was reported to the European Rhabdoid Registry (EU-RHAB) and treated according to the Rhabdoid 2007 recommendation. Despite the very young age of the patient, the initially desperate situation of RTPS1, and the synchronous localization of congenital Rhabdoid Tumors, intensive chemotherapy was well tolerated; the child is still in complete remission 5 years following diagnosis. In conclusion, RTPS1 with congenital synchronous MRTs is not necessarily associated with a detrimental outcome. Intensive multidrug chemotherapy, including high dose chemotherapy, may be feasible and justified.

  • Rhabdoid Tumors integrating biological insights with clinical success a report from the smarcb1 and Rhabdoid Tumor symposium paris december 12 14 2013
    Cancer Genetics and Cytogenetics, 2014
    Co-Authors: Franck Bourdeaut, Susan N Chi, Michael C Fruhwald
    Abstract:

    Malignant Rhabdoid Tumors (MRTs) of the central nervous system (atypical teratoid, Rhabdoid Tumor (AT/RT)), kidney (Rhabdoid Tumor of the kidney (RTK)), and soft tissues all share an aggressive clinical behavior and dismal prognosis. The burden of the intensive treatment required to cure patients is a matter of great concern given the young median age at diagnosis, regardless of Tumor location. Thus, a greater understanding of the oncogenic properties of SMARCB1 and the SWI/SNF complex, as well as the clinical aspects of malignant Rhabdoid Tumors is necessary. Towards this aim, the first international SMARCB1 and Rhabdoid Tumor symposium was held in Paris, France in December 2013, organized by the collaborative efforts of the Dana-Farber Cancer Institute (Susan Chi), Swabian Children's Cancer Center/EU-RHAB Center (Michael Fruhwald) and Curie Institute (Franck Bourdeaut). This workshop of physicians and other scientists fostered the integration of biologic insights towards clinical application in Rhabdoid Tumors, and other SWI/SNF-related cancers. The following report is a synopsis of the highlights of this meeting.

  • favorable outcome of patients affected by Rhabdoid Tumors due to Rhabdoid Tumor predisposition syndrome rtps
    Pediatric Blood & Cancer, 2014
    Co-Authors: Uwe Kordes, Reinhard Schneppenheim, Martin Hasselblatt, Harald Reinhard, Kerstin Bartelheim, Piergiorgio Modena, Maura Massimino, Veronica Biassoni, Michael C Fruhwald
    Abstract:

    Rhabdoid Tumor predisposition syndrome is usually associated with shorter survival in patients with malignant Rhabdoid Tumors regardless of anatomical origin. Here we present four children harboring truncating heterozygous SMARCB1/INI1 germline mutations with favorable outcome. All four patients received multi-modality treatment, three according to therapeutic recommendations by the EU-RHAB registry, two without radiotherapy, and mean event-free survival accounts for 7 years. In conclusion, intensive treatment with curative intent is justified for children with Rhabdoid Tumors even if an underlying Rhabdoid predisposition syndrome is demonstrated. Pediatr Blood Cancer 2014;61:919–921. © 2013 Wiley Periodicals, Inc.

Hidetaka Yamamoto - One of the best experts on this subject based on the ideXlab platform.

  • reclassification of Rhabdoid Tumor and pediatric undifferentiated unclassified sarcoma with complete loss of smarcb1 ini1 protein expression three subtypes of Rhabdoid Tumor according to their histological features
    Modern Pathology, 2016
    Co-Authors: Kenichi Kohashi, Hidetaka Yamamoto, Yukihide Iwamoto, Tomoaki Taguchi, Yuichi Yamada, Yukichi Tanaka, Hiroshi Kishimoto, Yoshinao Oda
    Abstract:

    Rhabdoid Tumor is characterized by Rhabdoid cells and shows complete loss of SMARCB1/INI1 protein expression. In existing classifications, the diagnostic synonyms vary depending on the anatomic site: Rhabdoid Tumors in the central nervous system or extra-central nervous system are, respectively, classified as atypical teratoid/Rhabdoid Tumor or malignant Rhabdoid Tumor. In this study, we analyzed the histological, immunohistochemical, microRNA, and clinicopathological statuses of Tumors initially diagnosed as malignant Rhabdoid Tumor (n=33), atypical teratoid/Rhabdoid Tumor (n=11), and pediatric undifferentiated/unclassified sarcoma (n=8) with complete loss of SMARCB1/INI1 expression, and considered the possibility of their histological reclassification. Our analysis indicated that the Tumors could be histologically reclassified into three groups: conventional-type Tumors resembling malignant Rhabdoid Tumor, atypical teratoid/Rhabdoid-type Tumors resembling atypical teratoid/Rhabdoid Tumor, and small cell-type Tumors resembling malignant lymphoma. The reclassified conventional type was composed of 27 malignant Rhabdoid Tumors and 9 atypical teratoid/Rhabdoid Tumors (36 cases). The atypical teratoid/Rhabdoid type consisted of six malignant Rhabdoid Tumors, two atypical teratoid/Rhabdoid Tumors, and two undifferentiated/unclassified sarcomas (10 cases). The six cases of small cell type were made up of six undifferentiated/unclassified sarcomas. All of the available Tumor specimens were positive for vimentin and epithelial marker (EMA, CAM5.2, or AE1/AE3). MicroRNA profiles were not significantly different between the conventional- and small cell-type Tumors (Pearson's correlation coefficient: 0.888300 or 0.891388). There was no significant difference in overall survival between atypical teratoid/Rhabdoid Tumor and malignant Rhabdoid Tumor (P=0.16). In addition, there were no significant differences in survival between any of the reclassified combinations. In conclusion, we could classify eight Tumors initially diagnosed as undifferentiated/unclassified sarcomas into two cases of atypical teratoid/Rhabdoid type and six cases of small cell type. We suggest that reclassification of malignant Rhabdoid Tumors into three groups according to their histologic features rather than the traditional classification by sites of origin would be favorable for their histopathological diagnosis.

  • erg and sall4 expressions in smarcb1 ini1 deficient Tumors a useful tool for distinguishing epithelioid sarcoma from malignant Rhabdoid Tumor
    Human Pathology, 2015
    Co-Authors: Kenichi Kohashi, Hidetaka Yamamoto, Yukihide Iwamoto, Tomoaki Taguchi, Yuichi Yamada, Yuka Hotokebuchi, Yoshinao Oda
    Abstract:

    ERG is immunoexpressed in vascular endothelial Tumors, blastic extramedullary myeloid Tumors, and Tumors with ERG-involved translocation, such as prostate carcinoma or Ewing sarcoma. Recently, ERG immunoexpression was reported in an epithelioid sarcoma, which is a SMARCB1/INI1-deficient Tumor, although epithelioid sarcoma is not associated with chromosomal translocations involving ERG and is categorized as a Tumor with uncertain differentiation. SALL4 is essential for a proliferation and stabilization of embryonic stem cells. It was reported that SALL4 expression may aid in distinguishing epithelioid sarcoma from malignant Rhabdoid Tumor. We analyzed the frequency of ERG and SALL4 expressions in 80 SMARCB1/INI1-deficient Tumors, including 45 epithelioid sarcomas (conventional-type, 24; proximal-type, 20), 17 malignant Rhabdoid Tumors, 5 atypical teratoid/Rhabdoid Tumors, 6 undifferentiated/unclassified sarcomas, 5 myoepithelial Tumors, and 4 extraskeletal myxoid chondrosarcomas. We found that ERG expression was present in 18 of the epithelioid sarcomas (41%), including 13 conventional-type (54%) and 5 proximal-type (25%), whereas all 17 of the malignant Rhabdoid Tumors exhibited negative immunoreactivity. One atypical teratoid/Rhabdoid Tumor (20%), 1 myoepithelial carcinoma (20%), 1 undifferentiated/unclassified sarcoma (17%), and no extraskeletal myxoid chondrosarcomas (0%) also showed ERG expression. SALL4 expression was recognized in 5 epithelioid sarcomas (11%), 12 malignant Rhabdoid Tumors (71%), 2 atypical teradoid/Rhabdoid Tumors (40%), 4 undifferentiated/unclassified sarcomas (67%), 1 myoepithelial Tumor (20%), and none of the extraskeletal myxoid chondrosarcomas (0%). Therefore, the evaluation of ERG and SALL4 immunoexpressions may be a useful diagnostic tool to distinguish epithelioid sarcoma, especially proximal type, from malignant Rhabdoid Tumor.

  • differential microrna expression profiles between malignant Rhabdoid Tumor and epithelioid sarcoma mir193a 5p is suggested to downregulate smarcb1 mrna expression
    Modern Pathology, 2014
    Co-Authors: Kenichi Kohashi, Hidetaka Yamamoto, Yukihide Iwamoto, Tomoaki Taguchi, Yuichi Yamada, Yuka Hotokebuchi, Reiko Kumagai, Yoshinao Oda
    Abstract:

    Malignant Rhabdoid Tumor and epithelioid sarcoma are classified as Tumors of uncertain differentiation. However, it is controversial whether these Tumors are distinct entities because they share similar histological and immunohistochemical features such as the existence of Rhabdoid cells or complete loss of SMARCB1 protein expression. MicroRNAs are small non-coding RNAs, and it is suggested that knowledge of microRNA expression profiles in cancer may have substantial value for diagnostics. We first analyzed microRNA expression profiles in 13 frozen materials (five malignant Rhabdoid Tumors, two proximal type epithelioid sarcomas, and six conventional type epithelioid sarcomas) and subsequently examined the specific microRNA expressions in 29 paraffin-embedded materials (8 malignant Rhabdoid Tumors, 13 proximal type epithelioid sarcomas, and 8 conventional type epithelioid sarcomas) and 13 previously described frozen materials by quantitative RT–PCR. According to the unsupervised hierarchical clustering of microRNA, proximal type epithelioid sarcoma and conventional type epithelioid sarcoma were classified into the same category, whereas malignant Rhabdoid Tumor was a distinct category from both types of epithelioid sarcoma. In addition, when malignant Rhabdoid Tumor with SMARCB1 gene alterations and proximal type and conventional type epithelioid sarcoma with no SMARCB1 gene alterations were compared, 56 microRNAs were isolated as being significantly different (ANOVA, P<0.05). Among them, quantitative RT–PCR using frozen and paraffin-embedded materials demonstrated that expression levels of miR193a-5p (P=0.002), which has been suggested to downregulate SMARCB1 mRNA expression, showed statistically different expression levels between malignant Rhabdoid Tumor and epithelioid sarcoma with no SMARCB1 gene alterations. These results suggest that epithelioid sarcoma, especially proximal type epithelioid sarcoma, and malignant Rhabdoid Tumor are distinct Tumors with respect to the microRNA expression profiles and that miR193a-5p may have an important role in the inhibition of SMARCB1 mRNA expression.

  • infrequent smarcb1 ini1 gene alteration in epithelioid sarcoma a useful tool in distinguishing epithelioid sarcoma from malignant Rhabdoid Tumor
    Human Pathology, 2009
    Co-Authors: Kenichi Kohashi, Yoshinao Oda, Hidetaka Yamamoto, Sadafumi Tamiya, Yukihide Iwamoto, Tomoaki Taguchi, Teiyu Izumi, Tadashi Hasegawa, Masazumi Tsuneyoshi
    Abstract:

    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.