The fifth deadliest cancer among women across the United States, ovarian clear cell carcinoma has proven to be an elusive killer and one which does not respond well to traditional therapies. To gain a better understanding into the genetic origins of this cancer, two independent research teams - using different approaches - embarked on efforts to examine the protein-coding regions (or exons) of ovarian tumor cells.

Dr. Nickolas Papadopoulos, of Johns Hopkins Kimmel Cancer Center, led one team in sequencing all 18,000 protein-coding genes from eight ovarian clear cell carcinoma patients. Comparing both tumor and normal cells, the group identified four (4) genes that were mutated in the tumors but not in the normal cells. Of these, the most common was the gene ARID1A, which had never before been linked to ovarian cancer.

The scientists then sequenced the four implicated genes in normal and tumor cells from an additional thirty-four patients. Most of the tumor samples had mutations in ARID1A (57% of the 42 tumors). Two other genes that had previously been tied to ovarian cancer—PIK3CA and KRAS—were found in 40% and 5% of the tumors, respectively. The fourth gene, PPP2R1A, hadn't previously been associated with ovarian cancer. It was found in 7% of the tumors.

As reported in the online issue of Science on September 8, 2010, the researchers conclude that ARID1A must act as a tumor suppressor gene. Its protein product is known to play a role in chromatin remodeling, which is a process that changes how DNA is packaged in the cell's nucleus. Chromatin remodeling can affect how and when certain genes are transcribed. When ARID1A is mutated, genes may be incorrectly switched on or off, which can cause cells to grow and flourish unchecked.

In the second study, published that same day in the New England Journal of Medicine, a Canada-based research team led by Dr. David Huntsman took a slightly different approach. Rather than sequencing protein-coding DNA regions, they sequenced the transcriptome—the complete set of expressed RNAs. They analyzed different types of tumors from several tumor banks, including an NCI-funded bank at Johns Hopkins. The scientists found that the ARID1A gene was mutated in 46% (55 out of 119) of ovarian clear cell tumors and in 30% (10 out of 33) of endometrioid ovarian tumors, a different subtype of ovarian cancer. In contrast, the gene wasn’t altered in any of the 76 samples of a different type of ovarian tumor.

Both ovarian clear cell cancer and endometrioid cancer can arise from endometriosis, a condition in which cells from the uterine lining migrate and grow in other locations, such as the ovaries. The scientists say their findings may help to shed light on molecular events that transform endometriosis into ovarian cancer.

"The interesting thing about this gene [ARID1A] is that it's tied to something called epigenetic changes, which include changes in how the DNA is packed and regulated," says Papadopoulos. Epigenetic factors affect gene activity—in this case by altering chromatin—without altering the DNA sequence. "The next step will be to understand this pathway better," he says.

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