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RNA Sequencing Study Uncovers Recurrent Gene Fusion in Ovarian Cancer

NEW YORK (GenomeWeb News) – A US and Canadian research team reported in PLoS Biology last night that it has identified a gene fusion that occurs in a subset of serous ovarian cancer cases.

The California and British Columbia-based investigators found the fusion through RNA sequencing studies of a dozen late-stage serous ovarian tumors, followed by deep sequencing of the corresponding DNA in affected samples. The fusion, which involves an estrogen receptor-related gene called ESRRA and another chromosome 11 gene of unknown function, showed up in around 15 percent of the cases that the researchers screened in their follow-up experiments.

"The ESRRA-C11orf20 fusion is, to our knowledge, the first recurrent gene fusion to be identified in serous ovarian cancer," senior author Patrick Brown, a biochemistry researcher at Stanford University, and co-authors wrote. "This fusion gene and its components are now high-priority targets for further investigation of their potential roles in pathogenesis and as potential diagnostic or therapeutic targets."

Serous ovarian cancer is a histology-based subtype of the disease that often eludes detection until it has already spread to other parts of the body. Because this form of the disease is associated with the most ovarian cancer deaths each year, researchers are keen to find clues for diagnosing and treating it prior to metastasis.

For the current study, Brown and his colleagues focused on finding recurrent gene fusions in serous ovarian cancer using Illumina GAII paired-end sequencing to sequence complementary DNA libraries made using messenger RNA from 12 late-stage serous ovarian cancer samples.

By analyzing this RNA sequence data in an analysis pipeline that compared potentially fused exons to both the RefSeq database and to a database of potential fusion genes developed for the study, the team identified two potential gene fusions supported by several sequence reads.

They focused their attention on a fusion involving two chromosome 11 genes: ESRRA, an estrogen receptor related alpha gene associated with poor breast cancer outcome in a past study, and C11orf20, a gene of unknown function.

Though there was some variation in the exons involved, this fusion included the 5' end of ERSSA and exons from the 3' end of the C11orf20 gene. In the human reference genome, researchers explained, C11orf20 is on the other side of ERSSA, just upstream of it.

Deep Illumina paired-end sequencing of the affected region of the genome in two fusion-positive tumors and one matched normal sample uncovered copy number alterations in the region in one of the tumors and chromosomal rearrangements in the other, the study authors reported.

"The results provide strong evidence that a fusion transcript arose from genomic rearrangement of the C11orf20-ESRRA region of chromosome 11 in one tumor and copy number variation evidence of rearrangement in the second tumor."

When the researchers screened 67 serous ovarian samples from the Pacific Ovarian Cancer Research Consortium, Fred Hutchinson Cancer Research Center, and the British Columbia Cancer Agency using RT-PCR and Sanger sequencing, they found that 10 of the tumors carried similar fusion ESRRA-C11orf20 fusions.

The study authors noted that that might slightly underestimate the number of fusions, since they did not consider a sample to be fusion-positive unless the fusion turned up in most PCR replicates for that sample.

Even so, with a frequency nearing 15 percent, the ESRRA-C11orf20 fusion is the most common genetic change detected in serous ovarian cancer so far. That has fueled speculation that intra-chromosomal fusions may be more common in cancers, in general, than currently appreciated.

"This kind of genetic lesion — a chromosomal rearrangement involving pairs of genes located near one another on the same chromosome — can escape detection by any of the methods traditionally used to detect chromosome rearrangements in cancer," Brown said in a statement. "But I think these local rearrangements … might actually turn out to be among the most frequent genetic lesions in cancer."

More studies are needed to determine the prevalence of the ESRRA-C11orf20 fusion in larger serous ovarian cancer cohorts and to determine whether it has any ties to ovarian cancer outcome. Researchers are also interested in figuring out whether tumor DNA, specifically the newly identified fusion, can be detected in blood samples from women with ovarian cancer.

"It's potentially the case that this fusion is an early event in the cancer," co-first author Julia Salzman, a biochemistry and statistics researcher at Stanford University, said in a statement. "If so, it's possible that it could be used as a biomarker for the cancer before it has become clinically apparent, or that we can learn more about what causes the cancer by studying what we expect will be a new protein product."