Mutations in two genes, ARID1A and PPP2R1A, appear to be linked to ovarian clear cell carcinoma, one of the most aggressive forms of ovarian cancer, investigators reported online Sept. 8 in Science Express.
In a separate study published online the same day in the New England Journal of Medicine, another team of researchers found an association between mutations in ARID1A and the development of ovarian clear cell and endometrioid carcinomas.
Although these two cancers are known to be associated with endometriosis, the genetic events tied to the transformation of endometriosis into cancer are unknown.
The ARID1A and PPP2R1A genes had not previously been linked to ovarian cancer, and the findings “may provide opportunities for developing new biomarkers and therapies that target those genes,” Siân Jones, Ph.D., lead author of the Science Express study, noted in a written statement.
The researchers speculated that ARID1A functions as a tumor suppressor gene and, when mutated, is “likely to directly lead to epigenetic changes in cancer cells.” PPP2R1A is an oncogene that, when altered, helps turn normal cells into tumor cells, they said.
Dr. Jones, a research associate at the Johns Hopkins Kimmel Cancer Center, Baltimore, and associates evaluated 18,000 protein-encoding genes in ovarian clear cell tumors from eight patients (Science 2010 Sept. 8 [doi:10.1126/science.1196333]). They purified the cancer cells and then analyzed the exomic sequences from those cells as well as normal cells obtained from the blood or unaffected tissues of the same patients.
There were 268 mutations in 253 genes among the eight tumors. The four genes with the most prevalent mutations were PIK3CA and KRAS, which had been previously linked to ovarian clear cell carcinoma, and ARID1A and PPP2R1A, which had not.
The researchers used polymerase chain reaction amplification and gene sequencing to determine the sequences of these four genes in an additional 34 patients with ovarian clear cell cancer. ARID1A mutations were identified in 57% of the 42 tumors, while 7.1% contained PPP2R1A mutations, 40% contained PIK3CA mutations, and 4.7% contained KRAS mutations.
“Discovery of tumor suppressor genes such as ARID1A that are mutated in cancers ... are likely to directly lead to epigenetic changes in cancer cells through specific modifications of chromatin proteins,” the researchers concluded. “They additionally provide a potential approach to determine which of the numerous epigenetic changes in cancers confer a selective growth advantage and which are simply ‘passengers’ that do not play a causal role. The identification of the genes whose expression is specifically modulated by ARID1A inactivation will be the next crucial step in this line of research.”
In the second study, investigators performed RNA sequencing on 18 ovarian clear cell carcinomas and one ovarian clear cell carcinoma cell line to identify variants in ARID1A. Next, they performed targeted exon resequencing in this cohort as well as in a validation cohort containing samples of ovarian clear cell carcinoma from 101 patients, endometrioid carcinoma from 33 patients, and high-grade serous carcinoma from 76 patients. The ovarian clear cell carcinoma-derived cell line ES2 also was included, wrote Kimberly C. Wiegand of the British Columbia Cancer Agency, Vancouver, and associates (N. Engl. J. Med 2010 Sept. 8 [doi:10.1056/NEJMoa1008433]).
ARID1A mutations were observed in 55 of 119 ovarian clear cell carcinoma (46%), 10 of 33 endometrioid carcinomas (30%), and none of the 76 high-grade serous ovarian carcinomas. Twelve of the ovarian clear cell carcinomas and five of the endometrioid carcinomas had two somatic mutations each.
Loss of BAF250a expression was seen in 42% of the ovarian clear cell carcinoma samples and 21% of the endometrioid carcinoma samples, compared with just 1% of the high-grade serous carcinoma samples. “This suggests that the mutations may be pathogenic, rather than random events,” they wrote.
The presence of ARID1A mutations was strongly correlated with loss of the BAF250a protein. Loss of BAF250a expression was seen in 73% and 50% of samples of ovarian clear cell carcinoma and endometrioid carcinoma with an ARID1A mutation, respectively, but in only 11% and 9% of samples without such a mutation.
The investigators suggested that defects in genes that alter the accessibility of transcription factors to chromatin, such as ARID1A, “will help to define ovarian clear cell carcinomas and endometrial carcinomas. If such a model is correct, other abnormalities affecting the ARID1A locus or dysregulation of other chromatin remodeling genes may be found in ovarian clear cell and endometrioid carcinomas that are negative for an ARID1A mutation. This idea is supported by the clinical similarities between ovarian clear cell carcinomas positive for and those negative for an ARID1A mutation.”