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

Cells

Marc Deloger¹  Olivier Elemento²  DavidC. Wilkes²  Joanna Cyrta²  Rohan Bareja²  Andrea Sboner²  MarkA. Rubin³  Catherine Genestie⁴  Mojgan Devouassoux-Shisheboran⁵  Olivier Caron⁶  Catherine Richon⁶  Félix Blanc-Durand⁷  Philippe Morice⁷  Sébastien Gouy⁷  Béatrice Brunn⁷  Patricia Pautier⁷  Enrica Bentivegna⁷  Aurélie Auguste⁸  AudreyLe Formal⁸  Alexandra Leary⁸ 

[1] 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;Department for BioMedical Research, University of Bern, 3001 Bern, Switzerland;Department of Pathology, Gustave Roussy, 94805 Villejuif, France;Department of Pathology, Hospital de la Croix Rousse, 69000 Lyon, France;Genomic Platform Gustave Roussy Cancer Institute, 94805 Villejuif, France;Gynecological Unit, Department of Medicine, Gustave Roussy, 94805 Villejuif, France;Medical Oncologist, Gynecology Unit, Lead Translational Research team, INSERM U981, Gustave Roussy, 94805 Villejuif, France;

关键词: ovary;    small cell carcinoma;    hypercalcemic;    SMARCA4;    SWI/SNF;   

DOI  :  10.3390/cells9061496

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown