Discovery could help select drugs for ovarian cancer patients
Researchers at Dana-Farber Cancer Institute 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 – excessive copies of it are present in the cancer cells, the scientists report in the Proceedings of the National Academy of Sciences. 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,” Hahn said. Several other genes are known to contribute to ovarian cancer, including the inherited mutant BRCA1 and BRCA2 genes.
Normal cells contain two copies of each gene. Ovarian cancer cells contain a striking amount of copy number variation – regions of DNA that have been amplified or are missing – but whether such a region is relevant to cancer requires further study. 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 a federal project called 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. (Many high-grade serous ovarian cancers begin in the fallopian tubes.)
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.
In its normal, un-amplified state, the GAB2 gene makes a protein that helps transmit biochemical signals to the cell from the outer cell membrane – where they are received from the external environment – into the cell nucleus, where the signals turn genes on and off to perform different functions. This signaling cascade is made up of many proteins that form the molecular equivalent of a bucket brigade, passing the signals from one to the other. The GAB2 protein serves as one of the buckets.
The researchers determined that amplification of the GAB2 gene in ovarian cancer cells triggers a signaling pathway, PI3K, that is frequently abnormal in ovarian and other types of cancer. 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 Hahn.
First authors of the report are Gavin Dunn, MD, of Massachusetts General Hospital and Dana-Farber, and Hiu Wing Cheung, PhD, of Dana-Farber and the Broad Institute.
The research was supported by National Institutes of Health grants RC2 CA148268, U01 CA176058, U54 CA143798, U54 CA112962, U01 CA152990, and NIH R25. Additional support was provided by the American Brain Tumor Association, a Canadian Institutes of Health Research Fellowship, a Kaleidoscope of Hope Foundation Young Investigator Research Award, The Mary Kay Foundation, The Sandy Rollman Ovarian Cancer Research Foundation, The Robert and Deborah First Fund, The Executive Council of the Susan F. Smith Center for Women’s Cancers at Dana–Farber Cancer Institute, The V Foundation for Cancer Research, American Cancer Society Institutional Research Grant IRG-97-219-14, and The Marsha Rivkin Center for Ovarian Cancer Research.