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

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.

Atypical teratoid/rhabdoid tumors (ATRTs) with SMARCA4 mutation are molecularly distinct from SMARCB1-deficient cases

“…1 d). As EPHA5 is known to be significantly upregulated in SCCOHT as well [ 1 ], Ephrin signaling might be one of the tumor-promoting pathways in tumors driven by SMARCA4 deficiency. Finally, network analysis suggested further processes including neuronal function associated terms such as Neuroactive ligand-receptor interaction and Membrane depolarization to be altered in ATRT-SMARCA4 (Supplementary Fig.…”

Update on SWI/SNF‐related gynecologic mesenchymal neoplasms: SMARCA4‐deficient uterine sarcoma and SMARCB1‐deficient vulvar neoplasms

“…Other SMARCA4‐deficient tumors have shown promising responses to CDK4/6 inhibition 49,50 so it is reasonable to propose that these therapies may also be beneficial in SDUS, though there have been no clinical trials including SDUS to date. Very early studies have proposed inhibiting EZH2 in SCCOHT, with or without combination with histone deacetylase (HDAC) inhibition 19,20,51‐53 . Receptor tyrosine kinase inhibitors such as Ponatinib have also shown promising results in pre‐clinical trials for SCCOHT 54 .…”

“…Generally the clinical setting, tumor morphology, and SMARCA4 loss/WT‐1 positivity is sufficient to confidently establish the diagnosis. Molecularly, these tumors are characterized by SMARCA4 mutation, deletion, and/or copy number loss of heterozygosity with few other genetic alterations 9‐15,19 …”

SMARCA4‐deficient rhabdoid tumours show intermediate molecular features between SMARCB1‐deficient rhabdoid tumours and small cell carcinomas of the ovary, hypercalcaemic type

“…Given the notable genomic stability and low mutational burden previously reported in ECRT SMARCB1 and SCCOHT [38], we sought to verify whether the genomic landscape of ECRT SMARCA4 showed similar characteristics. When compared with the TCGA panel of malignancies, ECRT SMARCA4 ranked among the least mutated tumour types, similar to ECRT SMARCB1 and SCCOHT [7,38] (Figure 1C). No recurrent pathogenic variants in genes other than SMARCA4 were detected across the five tumours (Figure 1D and supplementary material, Tables S3 and S4).…”