Study Implicates SMARCA4 Gene as Key Player in Oncogenesis of Small Cell Carcinoma of the Ovary
According to a new study, mutations in the SMARCA4 remodeling gene may play a key role in the development of small cell carcinoma of the ovary, hypercalcemic type. The findings by Ramos et al were published in Nature Genetics and suggest that loss of SMARCA4 expression may serve as a biomarker for diagnosis and treatment determinations.
Small cell carcinoma of the ovary, hypercalcemic type, is a rare but devastating form of cancer that is usually not diagnosed until the disease is in its advanced stages. Since the cancer does not respond to standard therapy, more than 75% of patients will die from this disease within 2 years of diagnosis. However, a team of researchers from the Translational Genomics Research Institute in Phoenix, Arizona, made a breakthrough discovery suggesting that the presence of mutations in the SMARCA4 remodeling gene, which is most commonly associated with lung, brain, and pancreatic cancer, may be a major factor not only in the oncogenesis of small cell carcinoma of the ovary but in other more common diseases.
Study Details and Results
In order to determine the genetic etiology of small cell carcinoma of the ovary, hypercalcemic type, the investigators analyzed 12 patient tumor samples. Although the mean age of patients with this type of cancer is 24 years old, one tumor sample came from a 9-year-old girl.
Next-generation sequencing was performed on each sample to determine the presence of SMARCA4 mutations. SMARCA4 mutations were discovered in over two-thirds of the samples. In addition, immunohistochemical analyses showed that 82% of tumor samples lacked the SMARCA4 protein. In fact, all tumor samples with SMARCA4 mutations did not present with the SMARCA4 protein.
The investigators also performed immunohistochemical analysis of 485 primary ovarian epithelial, sex cord stromal, and germ cell tumors to determine the presence of the SMARCA4protein. Only two of these tumors were negative for SMARCA4 staining.
Key Factor in Oncogenesis
The results of this study indicate that the reduction in SMARCA4 expression plays a major role in the development of small cell carcinoma of the ovary, hypercalcemic type. The SMARCA4 protein appears to act as a tumor suppressor in this type of cancer and in a variety of other tumor cell lines.
The investigators suggested that their discovery of the origin of small cell carcinoma of the ovary, hypercalcemic type, could have far-reaching implications for more common cancers. These implications would include a more profound genomic approach to earlier diagnosis and improved outcomes.
“By definitively identifying the relationship between SMARCA4 and [small cell carcinoma of the ovary, hypercalcemic type], we have high confidence that we have set the stage for clinical trials that could provide patients with immediate benefit,” said lead author Pilar Ramos, of Translational Genomics Research Institute, in a statement.
David G. Huntsman, MD, of the University of British Columbia, and Jeffrey M. Trent, PhD, of Translational Genomics Research Institute, are the corresponding authors for the Nature Genetics article.
The study authors reported no potential conflicts of interest.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
