Jennifer Mueller, MD
Every patient with a rare but aggressive form of ovarian cancer had tumors with the same type of mutations, suggesting a causative role for the mutations, results of a small clinical study suggested.
All 12 patients with small cell carcinoma of the ovary, hypercalcemic type (SCCOHT) had variants in the chromatin regulator SMARCA4. Immunoblotting and immunohistochemistry confirmed loss of SMARCA4 in seven of nine patients with mutations and available tissue.
Laboratory studies showed that reintroduction of SMARCA4 resulted in dose-dependent suppression of cell growth, according to a presentation at the Society of Gynecologic Oncology 45th Annual Meeting on Women’s Cancer in Tampa, Florida.
“Loss of SMARCA4 protein 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 for SMARCA4 in SCCOHT. The SMARCA4 tumor 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 could lead to more effective approaches to treatment.
In an effort to identify potentially targetable 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 bi-allelic variants in SMARCA4, including four splice site, seven nonsense, and three frameshift mutations, as well as two exon deletions. One patient had a germline mutation with somatic loss of the wild-type allele.
In characterizing SMARCA4 mutations, Mueller said 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 mutations in small cell carcinoma of the ovary. Presented at: SGO 45th Annual Meeting on Women’s Cancer; March 22-25, 2014; Tampa, FL. LBA4.