Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) beyond SMARCA4 Mutations: A Comprehensive Genomic Analysis
Open Access
- 19 June 2020
- Vol. 9 (6), 1496
- https://doi.org/10.3390/cells9061496
Abstract
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.This publication has 44 references indexed in Scilit:
- Proteomic and bioinformatic analysis of mammalian SWI/SNF complexes identifies extensive roles in human malignancyNature Genetics, 2013
- dbNSFP: A lightweight database of human nonsynonymous SNPs and their functional predictionsHuman Mutation, 2011
- Two novel BRM insertion promoter sequence variants are associated with loss of BRM expression and lung cancer riskOncogene, 2011
- A framework for variation discovery and genotyping using next-generation DNA sequencing dataNature Genetics, 2011
- Epigenetic Antagonism between Polycomb and SWI/SNF Complexes during Oncogenic TransformationCancer Cell, 2010
- The Genome Analysis Toolkit: A MapReduce framework for analyzing next-generation DNA sequencing dataGenome Research, 2010
- The novel mouse Polo-like kinase 5 responds to DNA damage and localizes in the nucleolusNucleic Acids Research, 2010
- Fast and accurate long-read alignment with Burrows–Wheeler transformBioinformatics, 2010
- Results of a prospective dose-intensive regimen in 27 patients with small cell carcinoma of the ovary of the hypercalcemic typeAnnals of Oncology, 2007
- The UCSC Genome Browser DatabaseNucleic Acids Research, 2003