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

Abstract

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.

Cellular context determines DNA methylation profiles in SWI/SNF‐deficient cancers of the gynecologic tract

“…In our study, SDUS was epigenetically more closely related to SMARCB1-deficient MRT as compared to SCCOHT, despite the shared SMARCA4 inactivation. Interestingly, a recent study suggested greater similarities between SMARCA4-deficient MRT and SCCOHT, as compared to SMARCB1-deficient MRT, based on unsupervised clustering analyses of DNA methylation data [18]. Clearly, more comprehensive studies are needed to clarify the relationships between various SWI/SNF-deficient neoplasms, including tumors outside of the gynecologic tract.…”

Case Report of Small Cell Carcinoma of the Ovary, Hypercalcemic Type (Ovarian Rhabdoid Tumor) with SMARCB1 Mutation: A Literature Review of a Rare and Aggressive Condition

“…The morphological and molecular similarities between SCCOHT and RTs led some authors to suggest that SCCOHT should be considered malignant rhabdoid tumors of the ovary [ 22 ]. However, other authors provided molecular arguments based on DNA methylation and transcriptomic profiling that the SMARCA4 -deficient RTs present molecular features distinct from the SMARCB1 -deficient RTs and the SMARCA4 -deficient SCCOHT [ 23 , 24 ], supporting their separate classification. Regarding the SMARCB1 -deficient SCCOHTs, there are only three cases reported in medical literature [ 17 ] and unfortunately, no details regarding morphological or molecular features were described.…”

Current and Emerging Therapeutic Approaches for Extracranial Malignant Rhabdoid Tumors

“…A recent study shed light on the specific transcriptomic and methylation characteristics of these entities. 28 While SMARCB1-deleted extracranial MRT clustered together with ATRT-MYC, the SMARCA4-deficient counterparts tended to form a separate cluster. Along a similar line, the transcriptomic characteristics of SMARCA4-deficient extracranial MRT differed from SMARCB1-deficient extracranial MRT.…”

“… 23 Another feature – distinguishing Group 2 – “ATRT-TYR-like and Group 5 – “ATRT-SHH-like” from most other pediatric brain tumors is genome wide hypermethylation ( Figure 2 ).

Figure 2 Overview of molecular features of the different extracranial MRT subgroups (based on Chun et al 23 and Andrianteranagna et al 28 ).

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“… Overview of molecular features of the different extracranial MRT subgroups (based on Chun et al 23 and Andrianteranagna et al 28 ). …”