title: No small surprise - small cell carcinoma of the ovary, hypercalcaemic type, is a malignant rhabdoid tumour.
abstract: Whole-exome sequencing (WES) is revolutionizing medical diagnostics and taxonomy. In less than 5 years since its first use, WES has revealed unexpected molecular drivers of numerous cancers. Here, we describe our use of WES to uncover the true nature of an enigmatic pathological entity, small-cell carcinoma of the ovary, hypercalcaemic type (SCCOHT), which has resisted definitive characterisation since it was first described in 1979. We conducted WES using three families with SCCOHT and identified deleterious mutations in the chromatin-remodelling gene SMARCA4 (encoding BRG1) in all cases. Follow-up of these findings, using both Sanger sequencing and WES of formalin-fixed paraffin-embedded tumours, showed that virtually all SCCOHTs we studied lacked functional SMARCA4/BRG1. Notably, this gene, and the related SMARCB1 gene, is mutated in most, if not all, atypical teratoid/rhabdoid tumours and malignant rhabdoid tumours. Other groups have similar findings. We review the relationship between these three neoplasms, discuss how they were distinguished from morphologically similar neoplasms, consider their similarities and show how WES has revealed that SCCOHTs are in fact rhabdoid tumours. We propose that SCCOHT be renamed 'malignant rhabdoid tumour of the ovary' (MRTO) to reflect these observations.
authors.affiliation: Department of Medical Genetics, Lady Davis Institute and Segal Cancer Centre, Jewish General Hospital, McGill University, Montreal, QC, Canada; Department of Human Genetics, McGill University, Montreal, QC, Canada; Department of Medical Genetics, Research Institute, McGill University Health Centre, Montreal, QC, Canada.
authors.forename: William D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: Blaise A
authors.initials: BA
authors.lastname: Clarke
authors.forename: Martin
authors.initials: M
authors.lastname: Hasselblatt
authors.forename: Jacek
authors.initials: J
authors.lastname: Majewski
authors.forename: Steffen
authors.initials: S
authors.lastname: Albrecht
authors.forename: W Glenn
authors.initials: WG
authors.lastname: McCluggage
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D018288:Carcinoma, Small Cell / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D059472:Exome; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006801:Humans; D006934:Hypercalcemia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D007150:Immunohistochemistry; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D018335:Rhabdoid Tumor / Q000737:chemistry / Q000235:genetics* / Q000473:pathology; D000071796:SMARCB1 Protein; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human; D014157:Transcription Factors; C084108:SMARCA4 protein, human; D004265:DNA Helicases
keywords: SMARCB1; hypercalcaemic type; rhabdoid tumour; small cell carcinoma of the ovary