SMARCA4 Likely Culprit in a Rare Ovarian Cancer

Four teams have published research implicating mutations in the SMARCA4 gene in a rare type of ovarian cancer that kills mainly young women and girls. The results may offer guidance to researchers in developing a treatment for the lethal cancer, known as small cell carcinoma of the ovary, hypercalcemic type (SCCOHT).

SCCOHT stands out because of its virulence and the youth of its sufferers. The average age of patients is 24, but children as young as 14 months have developed the cancer. The prognosis for someone with SCCOHT is bleak. Because the tumor has often progressed by the time it is diagnosed, about 65% of patients die within 2 years.

Even if the cancer is caught early, SCCOHT “is absolutely refractory to standard treatment,” such as chemotherapy with agents like cisplatin or cyclophosphamide, says David Huntsman, MD, of the University of British Columbia in Canada, coauthor of one of the papers. “This cancer was an enigma, and there were no leads for developing treatment strategies,” he says.

Now, researchers have solved one of the mysteries surrounding the cancer. Three teams used next-generation sequencing to pinpoint tumor mutations and presented their findings online in Nature Genetics in March. A Polish group published similar results last year. All four teams homed in on mutations in the gene SMARCA4. Douglas Levine, MD, of the Memorial Sloan-Kettering Cancer Center in New York, NY, and colleagues, identified SMARCA4 mutations in all 12 of the SCCOHT tumors they examined. Separately, William Foulkes, PhD, of McGill University in Montreal, Canada, and colleagues showed that some mutations can be inherited, leading to familial clustering of SCCOHT.

The mutations deprive cells of BRG1, the protein encoded by SMARCA4. The protein is absent from almost all SCCOHT tumors, the three Nature Genetics papers reported. In the ovary, loss of the protein seems to be specific to SCCOHT, Huntsman and colleagues determined in their study. They found that only 2 of the 485 non-SCCOHT ovarian tumors they evaluated were missing the protein. However, SMARCA4 mutations are not exclusive to SCCOHT. They also appear in cancer cell lines and tumor samples from organs such as the lung, and they might help initiate abnormal growth.

BRG1 is a core member of the SWI/SNF complex that remodels chromatin to control gene expression. Researchers still need to elucidate how loss of SMARCA4 leads to ovarian cancer and pin down the cell of origin for the tumor.

By identifying SMARCA4 mutations in SCCOHT, these studies “provide the first clue to how we could go about developing a treatment,” says Huntsman. However, what strategies will be most effective against the tumor remains to be seen.