Next Article in Journal
Heterochromatin Morphodynamics in Late Oogenesis and Early Embryogenesis of Mammals
Previous Article in Journal
Update on Circulating Tumor Cells in Genitourinary Tumors with Focus on Prostate Cancer
Previous Article in Special Issue
M2 Macrophages Infiltrating Epithelial Ovarian Cancer Express MDR1: A Feature That May Account for the Poor Prognosis
Open AccessArticle

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

1
Medical Oncologist, Gynecology Unit, Lead Translational Research Team, INSERM U981, Gustave Roussy, 94805 Villejuif, France
2
Gynecological Unit, Department of Medicine, Gustave Roussy, 94805 Villejuif, France
3
Bioinformatics Core Facility, Gustave Roussy Cancer Center, UMS CNRS 3655/INSERM 23 AMMICA, 94805 Villejuif, France
4
Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY 10001, USA
5
Institute for Computational Biomedicine, Weill Cornell Medicine, New York, NY 10001, USA
6
Genomic Platform Gustave Roussy Cancer Institute, 94805 Villejuif, France
7
Department of Pathology, Hospital de la Croix Rousse, 69000 Lyon, France
8
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY 10001, USA
9
Department for BioMedical Research, University of Bern, 3001 Bern, Switzerland
10
Department of Pathology, Gustave Roussy, 94805 Villejuif, France
11
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; https://doi.org/10.3390/cells9061496
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
Show Figures

Figure 1

MDPI and ACS Style

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.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop