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Open AccessArticle

Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) beyond SMARCA4 Mutations: A Comprehensive Genomic Analysis

Medical Oncologist, Gynecology Unit, Lead Translational Research Team, INSERM U981, Gustave Roussy, 94805 Villejuif, France
Gynecological Unit, Department of Medicine, Gustave Roussy, 94805 Villejuif, France
Bioinformatics Core Facility, Gustave Roussy Cancer Center, UMS CNRS 3655/INSERM 23 AMMICA, 94805 Villejuif, France
Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10001, USA
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10001, USA
Genomic Platform Gustave Roussy Cancer Institute, 94805 Villejuif, France
Department of Pathology, Hospital de la Croix Rousse, 69000 Lyon, France
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10001, USA
Department for BioMedical Research, University of Bern, 3001 Bern, Switzerland
Department of Pathology, Gustave Roussy, 94805 Villejuif, France
Department of Pathology, Institut Curie, Universite Paris Sciences et Lettres, 6 rue d’Ulm, 75005 Paris, France
Author to whom correspondence should be addressed.
Cells 2020, 9(6), 1496;
Received: 29 March 2020 / Revised: 1 June 2020 / Accepted: 11 June 2020 / Published: 19 June 2020
(This article belongs to the Special Issue Molecular and Cellular Mechanisms of Cancers: Ovarian Cancer)
Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) is an aggressive malignancy that occurs in young women, is characterized by recurrent loss-of-function mutations in the SMARCA4 gene, and for which effective treatments options are lacking. The aim of this study was to broaden the knowledge on this rare malignancy by reporting a comprehensive molecular analysis of an independent cohort of SCCOHT cases. We conducted Whole Exome Sequencing in six SCCOHT, and RNA-sequencing and array comparative genomic hybridization in eight SCCOHT. Additional immunohistochemical, Sanger sequencing and functional data are also provided. SCCOHTs showed remarkable genomic stability, with diploid profiles and low mutation load (mean, 5.43 mutations/Mb), including in the three chemotherapy-exposed tumors. All but one SCCOHT cases exhibited 19p13.2-3 copy-neutral LOH. SMARCA4 deleterious mutations were recurrent and accompanied by loss of expression of the SMARCA2 paralog. Variants in a few other genes located in 19p13.2-3 (e.g., PLK5) were detected. Putative therapeutic targets, including MAGEA4, AURKB and CLDN6, were found to be overexpressed in SCCOHT by RNA-seq as compared to benign ovarian tissue. Lastly, we provide additional evidence for sensitivity of SCCOHT to HDAC, DNMT and EZH2 inhibitors. Despite their aggressive clinical course, SCCOHT show remarkable inter-tumor homogeneity and display genomic stability, low mutation burden and few somatic copy number alterations. These findings and preliminary functional data support further exploration of epigenetic therapies in this lethal disease. View Full-Text
Keywords: ovary; small cell carcinoma; hypercalcemic; SMARCA4; SWI/SNF ovary; small cell carcinoma; hypercalcemic; SMARCA4; SWI/SNF
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Auguste, A.; Blanc-Durand, F.; Deloger, M.; Le Formal, A.; Bareja, R.; Wilkes, D.C.; Richon, C.; Brunn, B.; Caron, O.; Devouassoux-Shisheboran, M.; Gouy, S.; Morice, P.; Bentivegna, E.; Sboner, A.; Elemento, O.; Rubin, M.A.; Pautier, P.; Genestie, C.; Cyrta, J.; Leary, A. Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) beyond SMARCA4 Mutations: A Comprehensive Genomic Analysis. Cells 2020, 9, 1496.

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