Infrequent SMARCB1/INI1 gene alteration in epithelioid sarcoma: a useful tool in distinguishing epithelioid sarcoma from malignant rhabdoid tumor

Kohashi, Kenichi; Izumi, Toshihiro; Oda, Yoshinao; Tamiya, Sadafumi; Taguchi, Tomoaki; Iwamoto, Yukihide; Hasegawa, Tadashi; Tsuneyoshi, Masazumi

doi:10.1016/j.humpath.2008.08.007

Cited by 118 publications

(111 citation statements)

References 18 publications

(57 reference statements)

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“…We found 31 (86%) SMARCB1-negative epithelioid sarcoma and from these cases, 6 (19%) contained biallelic alterations, thus 25 cases for methylation analysis remained. Our results are in good harmony with others, except the ratio of biallelic mutant cases, which is slightly higher than Kohashi et al 10 This can be explained by the fact that our analysis is the third one in this regard and therefore there are not much data to compare.…”

Section: Discussionsupporting

confidence: 85%

“…6 Many studies reported the absence of nuclear staining of SMARCB1 in approximately 90% of tumors. [7][8][9][10] Recent studies of molecular analysis of the SMARCB1 gene revealed only 10% of epithelioid sarcoma cases had both absent SMARCB1 expression and mutation of SMARCB1 that suppress expression. In cases without DNA alterations, either epigenetic changes or post-transcriptional modification could prevent expression of SMARCB1.…”

mentioning

confidence: 99%

“…In cases without DNA alterations, either epigenetic changes or post-transcriptional modification could prevent expression of SMARCB1. 10 In addition to point mutations and deletions, transcriptional repression by hypermethylation of promoter sequences is an alternative mechanism of inactivation of tumorsuppressor genes in cancer. 11,12 Further mechanisms of epigenetic silencing of gene expression include post-translational modification of histones.…”

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confidence: 99%

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SMARCB1 protein and mRNA loss is not caused by promoter and histone hypermethylation in epithelioid sarcoma

et al. 2013

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About 10% of epithelioid sarcomas have biallelic mutation of the SMARCB1 (SWI/SNF-related, matrixassociated, actin-dependent regulator of chromatin, subfamily b, member 1) gene resulting in a lack of this nuclear protein. It has been suggested that SMARCB1 may be silenced by epigenetic changes in the remaining 90% of tumors. Thus, we hypothesized that the promoter of SMARCB1 is hypermethylated. We also examined SMARCB1 mRNA level to determine if a post-translational change was possible. Thirty-six cases of epithelioid sarcomas were studied. Immunohistochemistry and mutation analysis of the SMARCB1 gene were performed to select appropriate cases. Methylation status was assessed by methylation-specific PCR. Laser capture microdissection of tumor cells followed by real-time PCR was applied to examine the expression of SMARCB1 mRNA. Of 36 epithelioid sarcomas, 31 (86%) displayed a lack of SMARCB1 nuclear protein. In all, 4 (13%) of 31 SMARCB1-negative cases harbored biallelic deletion while 9 (33%) cases showed single-allelic deletion. One (4%) frameshift deletion of exon 3 and one point mutation of exon 7 were also found. In 16 (59%) cases, both alleles were intact. Altogether, 25/31 (81%) SMARCB1-negative cases had at least one intact allele. None of these cases demonstrated promoter hypermethylation. Low levels of SMARCB1 mRNA were found in all cases with tumor tissue extracted RNA (because of the minimal normal cell contamination) but no mRNA could be detected in laser dissected cases (containing only tumor cells). Enhancer of zeste homolog 2 (EZH2) overexpression was not characteristic of epithelioid sarcoma. Thus, loss of SMARCB1 expression in epithelioid sarcoma is caused neither by DNA hypermethylation nor by post-translational modifications. Most likely it is the microRNA destruction of SMARCB1 mRNA but further investigations are needed to elucidate this issue. Keywords: epithelioid sarcoma; histone methylation; laser capture microdissection; methylation-specific PCR; promoter hypermethylation; SMARCB1The SMARCB1 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily b, member 1; also known as INI1, BAF47 and hSNF5) gene, located on chromosomal position 22q11.23, encodes a core subunit of the SWI/SNF ATP-dependent chromatin remodeling complex. 1 Such observations show these complexes regulate gene expression, at least in part, by inducing a nucleosome conformation that is more approachable to the transcriptional machinery. 2 Recently, inactivation of both alleles of the SMARCB1 gene was identified in the majority of malignant rhabdoid tumors, suggesting that loss-of-function mutations of the gene contributed to the oncogenesis of this type of tumor.

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Section: Discussionsupporting

confidence: 85%

mentioning

confidence: 99%

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confidence: 99%

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SMARCB1 protein and mRNA loss is not caused by promoter and histone hypermethylation in epithelioid sarcoma

et al. 2013

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“…19 Although there is an immunohistochemical overlap with positivity for keratin and EMA, INI1 protein, absent in the majority of cases of epitheloid sarcoma, is a reliable marker for supporting the diagnosis. [20][21][22] In contrast, cutaneous myoepithelial tumors have a retained INI1 protein in all of our cases (data not shown). In this context, it should be noted that in a subset of myoepithelial carcinomas of soft tissue the INI1 protein is absent.…”

Section: Ewsr1 In Cutaneous Myoepitheliomamentioning

confidence: 59%

“…20,23,24 Although genetic aberrations in INI1, located on 22q11, are reported in epithelioid sarcoma, EWSR1 rearrangements are never described. 19,22,25,26 On histomorphological grounds, extraskeletal myxoid chondrosarcomas and ossifying fibromyxoid tumors may also enter the differential diagnosis. Although extraskeletal myxoid chondrosarcomas are classically located in the deep soft tissues, ossifying fibromyxoid tumors are commonest located in the subcutis, and involvement of the skin has rarely been reported.…”

Section: Ewsr1 In Cutaneous Myoepitheliomamentioning

confidence: 99%

EWSR1 gene rearrangement occurs in a subset of cutaneous myoepithelial tumors: a study of 18 cases

et al. 2011

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Cutaneous myoepithelial tumors form a clinicopathological spectrum ranging from mixed tumor to myoepithelioma and myoepithelial carcinoma. Recently, EWSR1 rearrangement has been described in a subset of soft tissue myoepithelial tumors, whereas the cutaneous counterparts showed this aberration in a minority of cases. This raises the question whether cutaneous myoepithelial tumors have comparable genetic alterations. We examined 18 cases of cutaneous myoepithelial tumors arising in 7 female and 11 male patients (age range, 34-86 years; mean, 58 years). Eight mixed tumors occurred at the head, and one at the scrotum. Six myoepitheliomas arose at the extremities, and one case each at the back and head. One myoepithelial carcinoma occurred at the cheek. The tumor size ranged from 0.3 to 1.7 cm (mean, 1.0 cm). All mixed tumors and three myoepitheliomas were limited to the dermis. Four myoepitheliomas and the myoepithelial carcinoma involved the subcutis. Mixed tumors and myoepitheliomas were composed of myoepithelial cells with a variable cytomorphology, architecture and stromal background. Ductal structures were seen by definition in mixed tumors. The myoepithelial carcinoma represented an infiltrative dermal neoplasm consisting of atypical spindle cells. Immunohistochemically, all cases tested were positive for EMA and calponin, whereas S100, CK, ASMA and GFAP were expressed in 90%, 80%, 78% and 50% of the cases tested, respectively. By fluorescent in situ hybridization analysis, 7 out of 16 cases (44%) exhibited EWSR1 rearrangement. Four of them were mixed tumors, two were myoepitheliomas and one was a myoepithelial carcinoma, confirming that these lesions represent a spectrum of dermal myoepithelial tumors. Follow-up information, available for five patients (including the patient with a myoepithelial carcinoma), revealed no evidence of disease in all cases (range, 6-72 months). Our study provides a genetic relationship of myoepithelial tumors of the skin with their counterparts in soft tissue, bone and visceral localization by sharing EWSR1 rearrangement.

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Fine‐needle aspiration of renal and extrarenal rhabdoid tumors

Thomson

Klijanienko

Couturier

et al. 2010

Cancer Cytopathology

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BACKGROUND:Rhabdoid tumors (RT) are rare, renal or extrarenal, high‐grade malignancies. The cytologic diagnosis may be confirmed if combined with genomic results. In the current study, the authors present the cytologic and ancillary techniques used to diagnose RT in their series of 20 tumors in 13 patients.METHODS:Clinical charts as well as cytologic, histologic, karyotypic, and molecular biology results were reviewed.RESULTS:Twelve fine‐needle aspirations (FNAs) were performed for primary diagnosis, 7 were to confirm a metastasis, and 1 was to confirm local recurrence. Primary tumors were in the kidney in 7 cases and 13 were extrarenal. Patient age ranged from 5 months to 26 years. There were 7 females and 6 males. FNAs were cell‐rich in 16 cases and cell‐poor in 4 cases and revealed a mix of atypical spindle‐shaped, round, rhabdoid, or epithelioid cells, singly or in clusters. Mitosis and necrosis occasionally were present. The original cytologic diagnosis was malignant in all cases. There were no unsatisfactory or false‐negative samples. In the 12 primary tumors, the preliminary FNA diagnosis was RT in 7 cases (58%), rhabdomyosarcoma in 4 cases (33%), and malignant peripheral nerve sheath tumor in 1 case (8%). Karyotypes were available in 6 cases, 3 of which demonstrated chromosome 22 changes. Fluorescence in situ hybridization revealed loss of probe signals for the SMARCB1 gene locus in 5 cases; DNA sequence analysis performed in 9 cases revealed deletions in codons of the SMARCB1 gene in 7 cases and a mutation in 2 cases.CONCLUSIONS:The primary diagnosis of RT is possible on FNA. In the current study, 12 of 13 cases were diagnosed by FNA with a combination of clinical information, immunocytochemistry, and molecular analysis. Cancer (Cancer Cytopathol) 2010;. © 2010 American Cancer Society

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Infrequent SMARCB1/INI1 gene alteration in epithelioid sarcoma: a useful tool in distinguishing epithelioid sarcoma from malignant rhabdoid tumor

Cited by 118 publications

References 18 publications

SMARCB1 protein and mRNA loss is not caused by promoter and histone hypermethylation in epithelioid sarcoma

SMARCB1 protein and mRNA loss is not caused by promoter and histone hypermethylation in epithelioid sarcoma

EWSR1 gene rearrangement occurs in a subset of cutaneous myoepithelial tumors: a study of 18 cases

Fine‐needle aspiration of renal and extrarenal rhabdoid tumors

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