Small cell carcinoma of the ovary hypercalcaemic type (SCCOHT) is a rare and lethal cancer that affects young women at a mean age of 24 (range 14 months to 43 years). Patients are typically diagnosed with advanced stage disease and do not respond to standard of care chemotherapy. Outcomes are dismal, with a 65% recurrence rate and 2-year survival less than 35%. The scarcity of prospective clinical trials for this poorly characterized tumour has hindered progress to identify effective treatment approaches.

Leveraging high throughput genomic technologies, we and others have recently identified inactivating mutations in the SWI/SNF chromatin remodelling gene SMARCA4 with concomitant loss of SMARCA4 protein in the majority of SCCOHT tumours. The loss of SMARCA4 protein is highly specific for SCCOHT with only 2/485 (0.4%) of primary ovarian epithelial, sex cord-stromal, and germ cell tumours showing negative immunostaining for SMARCA4. We also report the identification of a homozygous inactivating mutation in the gene SMARCB1 in one SCCOHT tumour with wild-type SMARCA4, suggesting SMARCB1 inactivation may also play a role in the pathogenesis of SCCOHT. Across all published studies to date, SMARCA4 mutations and protein loss have been reported in 64 of 69 SCCOHT cases (including 2 cell lines). This breakthrough discovery is the first significant insight into the pathogenesis of the disease and firmly establishes SMARCA4 as a tumour suppressor. This research defines a new opportunity for genetic testing of family members at risk, and sets the stage for rapid advancement in the biological understanding, differential diagnosis, and treatment of this rare recalcitrant tumour type.