Loss of BRG1 (<i>SMARCA4</i>) Immunoexpression in a Pediatric Non-Central Nervous System Tumor Cohort

Saunders, Jessica; Ingley, Katrina M; Wang, Xiu Qing; Harvey, Melissa; Armstrong, Linlea; Ng, Tony; Dunham, Christopher; Bush, Jonathan W.

doi:10.1177/1093526619869154

Cited by 10 publications

(12 citation statements)

References 27 publications

(25 reference statements)

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“…In the vast majority of MRTs, pathogenic variants (hereafter "mutations") affect the SMARCB1 gene. In rare cases (about 0.5-2% of ATRT [12,22]), SMARCA4 is mutated instead [17,42,43]. Since these mutations result in loss of the respective protein, loss of staining for either SMARCB1 or SMARCA4 by immunohistochemistry is used as a diagnostic tool to ensure the diagnosis of an ATRT [30].…”

Section: Introductionmentioning

confidence: 99%

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases

et al. 2020

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Atypical teratoid/rhabdoid tumors (ATRTs) are very aggressive childhood malignancies of the central nervous system. The underlying genetic cause are inactivating bi-allelic mutations in SMARCB1 or (rarely) in SMARCA4. ATRT-SMARCA4 have been associated with a higher frequency of germline mutations, younger age, and an inferior prognosis in comparison to SMARCB1 mutated cases. Based on their DNA methylation profiles and transcriptomics, SMARCB1 mutated ATRTs have been divided into three distinct molecular subgroups: ATRT-TYR, ATRT-SHH, and ATRT-MYC. These subgroups differ in terms of age at diagnosis, tumor location, type of SMARCB1 alterations, and overall survival. ATRT-SMARCA4 are, however, less well understood, and it remains unknown, whether they belong to one of the described ATRT subgroups. Here, we examined 14 ATRT-SMARCA4 by global DNA methylation analyses. We show that they form a separate group segregating from SMARCB1 mutated ATRTs and from other SMARCA4-deficient tumors like small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) or SMARCA4 mutated extra-cranial malignant rhabdoid tumors. In contrast, medulloblastoma (MB) samples with heterozygous SMARCA4 mutations do not group separately, but with established MB subgroups. RNA sequencing of ATRT-SMARCA4 confirmed the clustering results based on DNA methylation profiling and displayed an absence of typical signature genes upregulated in SMARCB1 deleted ATRT. In summary, our results suggest that, in line with previous clinical observations, ATRT-SMARCA4 should be regarded as a distinct molecular subgroup.

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Section: Introductionmentioning

confidence: 99%

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases

et al. 2020

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“… * References: (a) Holdhof et al , 2021 [22]; (b) Saunders et al , 2020 [23]; (c) Schneppenheim et al , 2010 [15]; (d) Chun et al , 2016 [30]. …”

Section: Resultsunclassified

“…In 2010, Schneppenheim et al reported a germline truncating pathogenic variant in SMARCA4 in two siblings affected by ATRT and ECRT, respectively [15]. Including that initial description, at least 20 SMARCA4‐deficient ATRTs have since been described, but only eight cases of SMARCA4‐deficient ECRT (ECRT SMARCA4 ) have been published, with SMARCA4 mutational status only reported for five of those cases [15–23]. Thus, a systematic description of the clinical and molecular characteristics of ECRT SMARCA4 is lacking.…”

Section: Introductionmentioning

confidence: 99%

SMARCA4‐deficient rhabdoid tumours show intermediate molecular features between SMARCB1‐deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type

Andrianteranagna

Cyrta

Masliah‐Planchon

et al. 2021

The Journal of Pathology

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Extracranial rhabdoid tumours (ECRTs) are an aggressive malignancy of infancy and early childhood. The vast majority of cases demonstrate inactivation of SMARCB1 (ECRTSMARCB1) on a background of a remarkably stable genome, a low mutational burden, and no other recurrent mutations. Rarely, ECRTs can harbour the alternative inactivation of SMARCA4 (ECRTSMARCA4) instead of SMARCB1. However, very few ECRTSMARCA4 cases have been published to date, and a systematic characterization of ECRTSMARCA4 is missing from the literature. In this study, we report the clinical, pathological, and genomic features of additional cases of ECRTSMARCA4 and show that they are comparable to those of ECRTSMARCB1. We also assess whether ECRTSMARCB1, ECRTSMARCA4, and small cell carcinomas of the ovary, hypercalcaemic type (SCCOHT) represent distinct or overlapping entities at a molecular level. Using DNA methylation and transcriptomics‐based tumour classification approaches, we demonstrate that ECRTSMARCA4 display molecular features intermediate between SCCOHT and ECRTSMARCB1; however, ECRTSMARCA4 appear to be more closely related to SCCOHT by DNA methylation. Conversely, both transcriptomics and DNA methylation show a larger gap between SCCOHT and ECRTSMARCB1, potentially supporting their continuous separate classification. Lastly, we show that ECRTSMARCA4 display concomitant lack of SMARCA4 (BRG1) and SMARCA2 (BRM) expression at the protein level, similar to what is seen in SCCOHT. Overall, these results expand our knowledge on this rare tumour type and explore the similarities and differences among entities from the ‘rhabdoid tumour’ spectrum. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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“…SCCOHT is the rarest type in this group, and it is caused by somatic and/or [19]. In this type, cancer cells resemble rhabdomyoblasts, which are small and round with hyperchromatic nuclei and are immunohistochemically characterized by the increased expression of vimentin, epithelial membrane antigen, and cytokeratins, as well as by the loss of BRG1 protein expression [20]. Additionally, 62% of adult patients and a similar percentage of children exhibit hypercalcemia when diagnosed with SCCOHT [6].…”

Section: Discussionmentioning

confidence: 99%

Ovarian carcinoma in children with constitutional mutation of SMARCA4: single-family report and literature review

et al. 2021

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Ovarian carcinoma is an extremely rare malignancy in children, often developing on the underlying inherited background. Female carriers of pathogenic germline mutations of SMARCA4 are at risk of an aggressive type of undifferentiated ovarian cancer called small cell carcinoma of the ovary, hypercalcemic type (SCCOHT). Regardless of age of the patient, stage of the disease, and oncological treatment, the prognosis for SCCOHT is poor. Therefore, early intervention with risk-reducing surgeries is recommended for these patients. In this study, we report genetic testing of a family with two children carrying pathogenic germline mutations of SMARCA4 and summarize the course of SCCOHT in all pediatric patients reported in the literature with constitutional defects identified within the SMARCA4 locus.

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Loss of BRG1 (SMARCA4) Immunoexpression in a Pediatric Non-Central Nervous System Tumor Cohort

Cited by 10 publications

References 27 publications

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases

SMARCA4‐deficient rhabdoid tumours show intermediate molecular features between SMARCB1‐deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type

Ovarian carcinoma in children with constitutional mutation of SMARCA4: single-family report and literature review

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