Scientists at the Johns Hopkins Kimmel Cancer Center have identified two genes whose mutations appear to be linked to ovarian clear-cell carcinoma. The nature and pattern of the mutations suggest that PPP2R1A functions as an oncogene and ARID1A as a tumor suppressor gene. The researchers say that their results suggest that aberrant chromatin remodeling contributes to the pathogenesis of ovarian clear-cell carcinoma.
The study was published online in the September 8 issue of Science Express. The paper is titled “Frequent Mutations of Chromatin Remodeling Gene ARID1A in Ovarian Clear Cell Carcinoma.”
The team reports that they found an average of 20 mutated genes per ovarian clear-cell cancer studied. ARID1A and PPP2R1A were more commonly mutated among the samples, with ARID1A mutations identified in more than half of the tumors studied.
The investigators evaluated mutations in 18,000 protein-encoding genes in ovarian clear-cell tumors from eight patients at Johns Hopkins and from institutions in Taiwan and Japan. They purified the cancer cells and analyzed genes from those cells and from normal cells obtained from the blood or uninvolved tissues of the same patients. The research group identified 268 mutations in 253 genes among the eight tumors, with an average of 20 mutations per tumor.
Next, they determined the amino acid makeup of four genes with the most prevalent mutations in the tumor and normal tissues of an additional 34 ovarian clear-cell cancer patients. Altogether, ARID1A mutations were identified in 57% of the 42 tumors. PPP2R1A mutations were found in 7.1% of the tumors. The other two genes evaluated were both previously linked to ovarian clear-cell cancer: PIK3CA, which encodes a subunit of phosphatidylinositol-3 kinase, and KRAS, which encodes a well-known oncoprotein.
The protein encoded by ARID1A is a component of the chromatin remodeling complex. When the ARID1A gene is mutated, the chromatin remodeling complex is altered, allowing genes to be incorrectly switched on or off.
The Johns Hopkins scientists say mutated ARID1A can now be linked to epigenetic changes. "The mutations in ARID1A provide an important new link between genetic and epigenetic mechanisms in human cancer and may help identify epigenetic changes that can be targeted with therapies," says Victor Velculescu, M.D., Ph.D., associate professor of oncology at the Johns Hopkins Kimmel Cancer Center.
The researchers next plan to search for genes whose chromatin is specifically affected by ARID1A inactivation.