Genetic Clue to Rare Ovarian Cancers Found
Canadian researchers have identified a gene mutation that appears to be common in a rare form of ovarian cancer known as granulosa-cell tumors. They discovered the mutation by sequencing RNA from the tumors of four women with the disease, which accounts for up to 5 percent of ovarian cancers.
Reporting their findings online in the New England Journal of Medicine last week, the researchers said that the mutation, which changes a single "letter" of DNA, appears to drive the most common form of the disease, the adult type.
They offered two lines of evidence. First, the mutation occurs in a gene (FOXL2) that is essential for the normal development of the cells where the tumors originate. And second, the mutation was found in nearly every granulosa-cell tumor the researchers tested.
"This study shows that virtually all adult type granulosa-cell tumors have exactly the same point mutation," said lead investigator Dr. David Huntsman of the British Columbia Cancer Agency. This knowledge, he added, could be used both to improve diagnostic tools and to develop targeted treatments that counter the effects of the mutation.
Beyond surgery, there are no standard treatments for the disease. In addition, these tumors are often misdiagnosed because they are relatively rare and can appear similar to other cancers. A molecular test based on FOXL2 could potentially improve the accuracy of current diagnostic methods and benefit patients, the researchers said.
Dr. Huntsman and his colleagues initially found the mutation by sequencing all of the messenger RNA—a chemical cousin of DNA—in the four tumors. The researchers went on to show that the mutation was present in 86 of 89 granulosa-cell tumors but not in more than 300 ovarian epithelial and breast tumors.
The mutation came as a surprise, as often happens when genomes are surveyed in an unbiased manner. The researchers were not expecting to find that a single letter of DNA from among the 3 billion in the human genome would be consistently changed in these tumors—or that the change would occur in a gene with a biological connection to the disease.
By focusing on RNA rather than DNA, the researchers uncovered a potentially important mutation for a fraction of the cost of conducting whole-genome sequencing on the same samples, noted an accompanying editorial that praised the study.
While sequencing RNA is less expensive than whole-genome sequencing, the approach also yields less information. In this case, the strategy worked because granulosa-cell tumors are relatively homogenous and have stable chromosomes. This is what made a genome-wide analysis of RNA feasible, the researchers said.
Most cancer genomes, by contrast, have such a range of genetic alterations that investigators may need to sequence hundreds of tumors in order to learn which changes are the most important for a given type of cancer.
The discovery of the FOXL2 mutation represents one of the first clinically relevant discoveries to emerge from the use of the powerful new technologies for sequencing cancer genomes, said Dr. Huntsman. But it will certainly not be the last, he continued, and it will probably not be the most important.
"This is just one example of how laying bare the wiring of cancer cells through sequencing will completely change the way we think about cancer and other diseases," he added.
—Edward R. Winstead