Science Editor

Bcr-Abl is the root cause of most cases of chronic myelogenous leukemia (CML) and the target of Gleevec (imatinib, Novartis AG) and several second-generation agents. It was the first gene fusion that was identified as a cause of cancer, and its success story continues to be a motivator for researchers looking for similar fusions.

But it has hardly been the last; less than a month ago, the FDA approved Xalkori (crizotinib, Pfizer Inc.), which targets a gene fusion, EML4-ALK, that is behind about 5 percent of all cases of non-small-cell lung cancer.

Now researchers have identified another gene fusion that is present in about 15 percent of all serous ovarian cancers. They hope their findings could lead both to a way to detect those ovarian cancers where it is present before the disease has spread, and, possibly, to a therapeutic target.

The fusion gene's biological contribution to ovarian cancer, if any, still has to be worked out. But the details of the two fused genes certainly make it plausible that there would be such a connection: One of the genes is the ESRRA, which is "a fairly well-studied gene in the context of breast and ovarian cancer" because of its similarities to the estrogen receptor, lead author Julia Salzman told BioWorld Today.

The biological function of the other gene, C11orf20, is not clear at this time, but it is under positive selective pressure in mammals, making it likely that there is a biological role to be discovered. Salzman, who is a research associate at Stanford University, said that deciphering that role, as well as looking for correlations of the fusion gene with clinical outcomes in ovarian cancer patients, are on her team's to-do list.

Salzman said she and her team believe that gene fusions such as the one they have identified are "an underappreciated phenomenon."

Most of them are harder to see than the Bcr-Abl fusion, which is, to put it in nontechnical terms, enormous: It involves a whole-scale rearrangement between two separate chromosomes that is visible "even under a microscope," Salzman said.

In contrast, ESRRA and C11orf20 usually live fairly near each other on chromosome 11, and the rearrangement that leads to their fusion is only a few thousand bases large. It is invisible under a microscope, and "even most microarray approaches would miss it," Salzman said.

Salzman and her team were able to identify the fusion by basically taking the entire RNA transcriptome and using sequencing followed by bioinformatics methods to detect unusual sequence variations that could point to a gene fusion.

Using that technique, the team analyzed nearly 70 samples from serous ovarian tumors. They found fusions between ESRRA and C11orf20 in 10 of those samples, or about 15 percent – a number that is nowhere near the 90 percent of CML cases the have the Bcr-Abl fusion, but higher than the 5 percent of lung cancer patients with EML4-ALK fusions. More detailed analysis of two of those tumors found the fusion gene in the majority of tumor cells in one of them, and copy number variations, which are also indicative of a gene rearrangement, in the other.

Their findings appeared in the Sept. 20, 2011, online edition of PLoS Biology.

The work identified a potential prospect for a biomarker that could be used for early detection of serous ovarian cancer. "Potentially, this gene fusion codes for a protein," Salzman said. If it does, such a protein might be secreted and, therefore, be detectable in the bloodstream.

Serous ovarian cancer is in bitter need of such an early warning signal. It's the most frequent subtype of ovarian cancer, accounting for about half of all cases. And 80 percent of all ovarian cancer deaths are due to that subtype, because it usually is diagnosed only after it has spread.

In their paper, Salzman and her colleagues acknowledged that "it remains possible that the ESRRA-C11orf20 fusion is an incidental consequence of another, functionally important, genetic event or that it is merely a 'passenger'" mutation. But they don't buy it.

"The apparent frequency with which this rearrangement occurs in serous ovarian cancer," they added, "and the lack of evidence that it accompanies large-scale structural variation (such as gene amplification) are more suggestive of a direct role." If that is the case, the fusion gene might also make a therapeutic target.