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

• Main Authors: Aurélie Auguste, Félix Blanc-Durand, Marc Deloger, Audrey Le Formal, Rohan Bareja, David C. Wilkes, Catherine Richon, Béatrice Brunn, Olivier Caron, Mojgan Devouassoux-Shisheboran, Sébastien Gouy, Philippe Morice, Enrica Bentivegna, Andrea Sboner, Olivier Elemento, Mark A. Rubin, Patricia Pautier, Catherine Genestie, Joanna Cyrta, Alexandra Leary
• Format: Article
• Language: English
• Published: MDPI AG 2020-06-01
• Series: Cells
• Subjects: ovary; small cell carcinoma; hypercalcemic; SMARCA4; SWI/SNF
• Online Access: https://www.mdpi.com/2073-4409/9/6/1496

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 <i>SMARCA4</i> 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. <i>SMARCA4</i> deleterious mutations were recurrent and accompanied by loss of expression of the <i>SMARCA2 </i>paralog. Variants in a few other genes located in 19p13.2-3 (e.g., <i>PLK5</i>) were detected. Putative therapeutic targets, including <i>MAGEA4,</i> <i>AURKB</i> and <i>CLDN6</i>, 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.