Researchers at Dana-Farber Cancer Institute, Boston, have identified an overactive gene that drives about one-third of high-grade serous ovarian tumors—the most common and malignant type of ovarian cancer. The gene, GAB2, isn’t mutated or abnormal, but triggers cancerous cell growth because the gene has been amplified, the investigators report in the Proceedings of the National Academy of Sciences.1
When the amplified gene was inserted into normal ovarian and fallopian tube cells in the laboratory, it powerfully transformed them into cancer cells, said the researchers, led by William C. Hahn, MD, PhD, of Dana-Farber and the Broad Institute of Harvard and MIT, who is the senior author of the report. The findings provide “strong evidence that GAB2 is a real oncogene—a driver of ovarian cancer,” Dr. Hahn said.
Innovative Screening Method
Dr. Hahn and his colleagues have devised a method for rapidly assessing the cancer-causing ability of large numbers of amplified genes. In the new study, they used data from The Cancer Genome Atlas to identify genes that were amplified in ovarian cancers. From these they selected 455 amplified genes for further testing.
After inserting segments of the genes into cells in the laboratory and then injecting them into mice, the scientists found that 26 of the genes were able to form tumors. Of these, GAB2 had the greatest tumor-forming capability and in further experiments, the amplified GAB2 gene potently transformed normal ovarian and fallopian tube cells into cancer cells.
Having successfully used the innovative screening method to identify the ovarian cancer oncogene, “This is a proof of principle that we can now systematically assess thousands of genes for their role in cancer on a large scale,” said Hahn.
The researchers determined that amplification of the GAB2 gene in ovarian cancer cells triggers the PI3K signaling pathway. Moreover, their experiments showed that cells with abnormal PI3K signaling because of amplified GAB2 could be killed with experimental drugs that inhibit the PI3K pathway. Such inhibitors are currently being tested in a number of cancers.
“This suggests that looking for GAB2 amplification in ovarian tumors could be helpful in identifying patients whose cancer may respond to PI3K inhibitors,” said Dr. Hahn. ■
1. Dunn GP, Cheung HW, Agarwalla PK, et al: In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene. Proc Natl Acad Sci USA. January 2, 2014 (early release online).