Consistent SMARCB1 homozygous deletions in epithelioid sarcoma and in a subset of myoepithelial carcinomas can be reliably detected by FISH in archival material. Issue 6 (3rd March 2014)

• Record Type: Journal Article
• Authors: Le, Francois; Zhang, Lei; Fletcher, Christopher D.; Ribeiro, Agnes; Singer, Samuel; Italiano, Antoine; Neuville, Agnes; Houlier, Aurélie; Chibon, Frederic; Coindre, Jean‐Michel; Antonescu, Cristina R.
• Is Part Of: Genes, chromosomes & cancer. Volume 53:Issue 6(2014:Jun.)
• Page Start: 475
• Page End: 486
• Publication Date: 2014-03-03
• Subjects: Cancer -- Genetic aspects -- Periodicals; 616.994042
• DOI: 10.1002/gcc.22159
• Languages: English
• ISSNs: 1045-2257

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>Epithelioid sarcomas (ES) are mesenchymal neoplasms subclassified into distal and proximal subtypes based on their distinct clinical presentations and histologic features. Consistent loss of SMARCB1 nuclear expression has been considered as the hallmark abnormality for both subtypes, a feature shared with atypical teratoid/rhabdoid tumor of infancy (ATRT). While virtually all ATRTs harbor underlying <italic>SMARCB1</italic> somatic or germline alterations, mechanisms of SMARCB1 inactivation in ES are less well defined. To further define mechanisms of SMARCB1 inactivation a detailed molecular analysis was performed on 40 ES (25 proximal and 15 distal ES, with classic morphology and negative SMARCB1 expression) for their genomic status of <italic>SMARCB1</italic> and related genes encoding the SWI/SNF subunits (<italic>PBRM1, BRG1, BRM, SMARCC1/2</italic> and <italic>ARID1A)</italic> by FISH using custom BAC probes. An additional control group was included spanning a variety of 41 soft tissue neoplasms with either rhabdoid/epithelioid features or selected histotypes previously shown to lack SMARCB1 by IHC. Furthermore, 12 ES were studied by array CGH (aCGH) and an independent TMA containing 50 additional ES cases was screened for Aurora Kinase A (AURKA) and cyclin D1 immunoexpression. Homozygous <italic>SMARCB1</italic> deletions were found by FISH in 36/40 ES (21/25 proximal‐type). One of the distal‐type ES displayed homozygous <italic>SMARCB1</italic> deletion in the tumor cells, along with a heterozygous deletion within normal tissue, finding confirmed by array CGH. None of the proximal ES lacking homozygous <italic>SMARCB1</italic> deletions displayed alterations in other SWI/SNF subunits gene members. Among controls, only the SMARCB1‐immunonegative myoepithelial carcinomas displayed <italic>SMARCB1</italic> homozygous deletions in 3/5 cases, while no gene specific abnormalities were seen among all other histologic subtypes of sarcomas tested regardless of the SMARCB1 protein status. There was no consistent pattern of AURKA and Cyclin D1 expression. The array CGH was successful in 9/12 ES, confirming the <italic>SMARCB1</italic> and other SWI/SNF genes copy numbers detected by FISH. Our study confirms the shared pathogenesis of proximal and distal ES, showing consistent <italic>SMARCB1</italic> homozygous deletions. Additionally we report the first ES case associated with a <italic>SMARCB1</italic> constitutional deletion, establishing a previously undocumented link with ATRT. Alternative mechanisms of SMARCB1 inactivation in <italic>SMARCB1</italic>‐disomic ES remain to be identified, but appear unrelated to large genomic abnormalities in other SWI/SNF subunits. © 2014 Wiley Periodicals, Inc.</p> </abstract>