Researchers studying ovarian cancer have discovered that, in a substantial fraction of ovarian tumors, a gene closely related to the estrogen receptor is broken and fused to an adjacent gene by a chromosome rearrangement; a finding that could shed light on how these deadly tumors develop and spread. Identifying a gene fusion in ovarian cancer may provide scientists with a new opportunity to specifically identify ovarian cancers early in their development and perhaps to develop new treatments.
The gene fusion was found by searching through a vast pile of data from "deep sequencing" of the genes active in ovarian tumors. "Although this is the first time that a rearrangement of neighboring genes has been found to occur repeatedly in a cancer, we suspect that these local rearrangements may be more common and important that we had realized" said Patrick O. Brown, senior author of the study and Howard Hughes Medical Institute investigator. The study, which appears in the September 20 issue of the online, open access journal PLoS Biology, was funded by the National Cancer Institute, the Howard Hughes Medical Institute and the Canary Foundation - a non-profit dedicated to developing technology for early detection of potentially deadly cancers.
Serous ovarian cancer, the most common form of ovarian cancer, is a particularly lethal cancer because it is usually only detected at a late stage in its progression, after the cancer has spread to other tissues. The Stanford team of Julia Salzman, Robert J. Marinelli, Peter Wang and Brown identified a recurrent gene fusion between ESRRA, a gene related to the estrogen receptor, and a nearby gene called C11orf20, in about 15% of serous ovarian cancer cases tested. This very specific genetic change might provide a marker for detection of some cancers at a curable stage. The fact that ovarian tumors in many patients share the same genetic change suggests it may be important for the way they behave. "More study will reveal if this gene fusion contributes to the tumor's aggressive growth and spread" said Brown.
The research leading to the discovery was performed at Stanford University School of Medicine and combined a relatively new technology—"deep sequencing"—with tools from genetics, computer science and statistics. The researchers were specifically looking for evidence that the tumor had rearranged its DNA so that two distinct genes were now fused together in the tumor. Julia Salzman explained, "Many groups have hoped to find recurrent gene fusions in different cancers using deep sequencing, but it has been proved more difficult than expected. Doing the experiment to obtain the data is just the beginning—analyzing the data poses significant challenges. We spent months designing computer and statistical algorithms to sort out signal from noise". Then, the challenge was to establish whether the finding was more than a fluke. Collaborators in the Canary network at the Fred Hutchinson Cancer Research Center in Seattle and the British Columbia Cancer Research Agency in Victoria, BC independently confirmed the presence of the gene fusion in multiple ovarian cancers.
Finding that ESRRA and C11orf20 are fused together may give insight into what happens as ovarian cancers develop, and gives researchers a target to study. It also serves as a proof of principle that deep sequencing of the genes expressed in cancer can uncover recurrent gene fusions. By using similar methods, future studies are in process that will test whether additional important genes can be found in ovarian tumors. The work also has broader potential: millions of dollars have been spent by the NIH, universities and other organizations on deep sequencing of tumors. Because much of the resulting data is public, essentially anyone can apply new methods to analyze it. Brown said that the work is continuing: "We are testing our algorithms on publicly available data and hope it might lead to more discoveries."
Funding: Work in POB's lab was supported by the Canary Foundation, Howard Hughes Medical Institute, and US National Institutes of Health grant CA77097. POB is an investigator of the Howard Hughes Medical Institute. Work in CWD's lab was supported by the Pacific Ovarian Cancer Research Consortium and National Cancer Institute award number P50 CA083636. Work in BHN's lab was supported by the British Columbia Cancer Foundation and US Department of Defense grant OC080380. JSN is supported by a fellowship from the Canadian Institutes of Health Research. JS received partial salary support from National Science Foundation grant DMS-0940077. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Citation: Salzman J, Marinelli RJ, Wang PL, Green AE, Nielsen JS, et al. (2011) ESRRA-C11orf20 Is a Recurrent Gene Fusion in Serous Ovarian Carcinoma. PLoS Biol 9(9): e1001156. doi:10.1371/journal.pbio.1001156
Link to the freely available text: http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001156
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