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

Auguste, Aurélie; Blanc-Durand, Félix; Deloger, Marc; Le Formal, Audrey; Bareja, Rohan; Wilkes, David C; Richon, Catherine; Brunn, Béatrice; Caron, Olivier; Devouassoux-Shisheboran, Mojgan; Gouy, Sébastien; Morice, Philippe; Bentivegna, Enrica; Sboner, Andrea; Elemento, Olivier; Rubin, Mark A; Pautier, Patricia; Genestie, Catherine; Cyrta, Joanna and Leary, Alexandra (2020). Small Cell Carcinoma of the Ovary, Hypercalcemic Type (SCCOHT) beyond SMARCA4 Mutations: A Comprehensive Genomic Analysis. Cells, 9(6) MDPI 10.3390/cells9061496

[img]
Preview
Text
cells-09-01496.pdf - Published Version
Available under License Creative Commons: Attribution (CC-BY).

Download (5MB) | Preview

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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR)

UniBE Contributor:

Rubin, Mark Andrew, Cyrta, Joanna

Subjects:

600 Technology > 610 Medicine & health

ISSN:

2073-4409

Publisher:

MDPI

Language:

English

Submitter:

Marla Rittiner

Date Deposited:

29 Dec 2020 10:28

Last Modified:

05 Dec 2022 15:43

Publisher DOI:

10.3390/cells9061496

PubMed ID:

32575483

Uncontrolled Keywords:

SMARCA4 SWI/SNF hypercalcemic ovary small cell carcinoma

BORIS DOI:

10.48350/150196

URI:

https://boris.unibe.ch/id/eprint/150196

Actions (login required)

Edit item Edit item
Provide Feedback