Rare Ovarian Cancer Linked to SMARCA Mutations

Patients with a rare but aggressive form of ovarian cancer had mutations in the chromatin regulatorSMARCA4, suggesting a causative role of these mutations, according to results of a small clinical study released at the Society of Gynecologic Oncology 45th Annual Meeting on Women’s Cancer in Tampa, Florida.

All 12 patients with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), had variants in the chromatin regulatorSMARCA4. Immunoblotting and immunohistochemistry confirmed loss ofSMARCA4in 7 of 9 patients with mutations and available tissue.

Laboratory studies showed that reintroduction ofSMARCA4resulted in dose-dependent suppression of cell growth, according to a presentation.

“Loss ofSMARCA4protein in the mutated small cell carcinoma of the ovary, hypercalcemia type tumors indicates functional consequence,” said Jennifer Mueller, MD, a fellow at Memorial Sloan Kettering Cancer Center. “In vitro data support an oncogenic role forSMARCA4in SCCOHT. TheSMARCA4tumor suppressor is a likely driver of SCCOHT.”

SCCOHT is a rare, aggressive form of ovarian cancer that occurs at an early age (mean age at diagnosis, 23 years), has few treatment options, and usually recurs within a year, regardless of treatment. The origin of SCCOHT remains unclear, and identification of somatic mutations associated with the cancer might lead to more effective approaches to treatment.

In an effort to identify potentially large table mutations in SCCOHT, Mueller and colleagues performed next-generation sequencing on specimens from 12 patients (median age 26.5 years; range, 18-42 years). The sequencing encompassed 279 cancer-associated genes. RNA sequencing was employed to determine mutation expression and the consequence of splice-site variants.

All 12 patients had inactivating biallelic variants inSMARCA4, including 4 splice site, 7 nonsense, and 3 frameshift mutations, as well as 2 exon deletions. One patient had a germ-line mutation with somatic loss of the wildtype allele.

In characterizingSMARCA4mutations, Mueller explained that the gene is well characterized, contains essential enzymatically active domains, and is a key subunit in the SWI/SNF chromatin remodeling complex. The chromatin remodeling complex behaves like a tumor suppressor in other cancers.

Levine DA, Mueller JJ, Jelinic P, et al.SMARCA4