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High sensitivity of FISH analysis in detecting homozygous SMARCB1 deletions in poorly differentiated chordoma: a clinicopathologic and molecular study of nine cases.

ABSTRACT: Poorly differentiated chordomas (PDCs) represent a rare subset of notochordal neoplasms, affecting primarily children and associated with an aggressive outcome. In contrast to conventional chordomas, PDC show solid growth and increased cellularity, cytologic atypia, and mitotic activity. Recent studies have shown that PDCs are characterized by recurrent deletions encompassing the SMARCB1 locus, resulting in consistent loss of nuclear SMARCB1 expression. Thus PDC joined the expanding family of SMARCB1-deficient tumors characterized by various SMARCB1 structural abnormalities, ranging from large homozygous deletions to small intragenic mutations. In the present study, we investigate the SMARCB1 abnormalities in a group of nine well-characterized PDCs and to establish the sensitivity of the FISH method in detecting these changes in the clinical setting. We further assessed the pathologic features and clinical behavior of this cohort managed at our referral center over a 20-year period. The mean age at diagnosis was 10 years-of-age. All except one case occurred in the cranial region. All demonstrated strong nuclear expression of brachyury and loss of SMARCB1 expression. FISH identified homozygous SMARCB1 deletions in all except one case; additionally two cases revealed a heterozygous EWSR1 locus co-deletion. Clinical follow-up information was available in five patients. Two patients presented with distant metastases at initial diagnosis. Two of the three remaining patients with primary disease failed both locally and distantly after multimodality therapy. We conclude that PDCs are highly aggressive tumors and the dominant mechanism of loss of SMARCB1 expression is through large, homozygous SMARCB1 deletions that can be readily detected by FISH.

SUBMITTER: Owosho AA

PROVIDER: S-EPMC5732052 | biostudies-literature | 2018 Feb

REPOSITORIES: biostudies-literature

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High sensitivity of FISH analysis in detecting homozygous SMARCB1 deletions in poorly differentiated chordoma: a clinicopathologic and molecular study of nine cases.

Owosho Adepitan A AA Zhang Lei L Rosenblum Marc K MK Antonescu Cristina R CR

Genes, chromosomes & cancer 20171123 2

Poorly differentiated chordomas (PDCs) represent a rare subset of notochordal neoplasms, affecting primarily children and associated with an aggressive outcome. In contrast to conventional chordomas, PDC show solid growth and increased cellularity, cytologic atypia, and mitotic activity. Recent studies have shown that PDCs are characterized by recurrent deletions encompassing the SMARCB1 locus, resulting in consistent loss of nuclear SMARCB1 expression. Thus PDC joined the expanding family of SM ...[more]

PMID: 29119645

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Project description: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 SMARCB1 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 SMARCB1 and related genes encoding the SWI/SNF subunits (PBRM1, BRG1, BRM, SMARCC1/2 and ARID1A) 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 SMARCB1 deletions were found by FISH in 36/40 ES (21/25 proximal-type). One of the distal-type ES displayed homozygous SMARCB1 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 SMARCB1 deletions displayed alterations in other SWI/SNF subunits gene members. Among controls, only the SMARCB1-immunonegative myoepithelial carcinomas displayed SMARCB1 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 SMARCB1 and other SWI/SNF genes copy numbers detected by FISH. Our study confirms the shared pathogenesis of proximal and distal ES, showing consistent SMARCB1 homozygous deletions. Additionally we report the first ES case associated with a SMARCB1 constitutional deletion, establishing a previously undocumented link with ATRT. Alternative mechanisms of SMARCB1 inactivation in SMARCB1-disomic ES remain to be identified, but appear unrelated to large genomic abnormalities in other SWI/SNF subunits.

Project description:BACKGROUND:Extrapulmonary neuroendocrine carcinomas (NECs) are poorly studied and are managed similar to lung NECs, which may not account for differences between the 2 groups of tumors as well as the heterogeneity within extrapulmonary NEC. METHODS:Data from the Surveillance, Epidemiology, and End Results program between 1973 and 2012 were used to estimate the relative percentages of lung NECs and subgroups of extrapulmonary NECs, epidemiological patterns at these sites, and the median and 5-year overall survival rates. RESULTS:Of 162,983 NEC cases, 14,732 were extrapulmonary; of these, 5509 were gastrointestinal (37.44%), 4151 were of unknown primary (28.2%), and 5072 were of other sites (34.4%). Lung NEC had the highest percentage of small cell morphology (95.2%) and gastrointestinal NEC had the least (38.7%), with the rest being other morphologies. Significant differences were noted with regard to median age (range, 48-74 years), percentage of cases of distant stage disease (24%-77%), and incidence according to sex and race. The median survival of patients with lung NEC was 7.6 months, that for patients with gastrointestinal NEC was 7.5 months (range, 25.1 months for NEC at the small intestine to 5.7 months for NEC at the pancreas), and that for patients with unknown NEC was 2.5 months. The 5-year survival rate for patients with local stage disease ranged from 58% to 60% for NECs of the female genital tract and small intestine to 25% for esophageal NECs. The primary tumor site remained statistically significant for survival even after adjusting for known prognostic variables (P<.0001). CONCLUSIONS:To the authors' knowledge, the current study is the largest study of NECs performed to date and also the first with comprehensive epidemiological data. Significant differences in incidence patterns and large variations in survival depending on anatomical site and morphological subtype were noted. A curative approach is possible for patients with nonmetastatic NECs. Cancer 2018;124:807-15. © 2017 American Cancer Society.

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High sensitivity of FISH analysis in detecting homozygous SMARCB1 deletions in poorly differentiated chordoma: a clinicopathologic and molecular study of nine cases.

Publications

High sensitivity of FISH analysis in detecting homozygous SMARCB1 deletions in poorly differentiated chordoma: a clinicopathologic and molecular study of nine cases.

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