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Team IDs New Gene Fusions in Prostate and Other Cancers

By Andrea Anderson

NEW YORK (GenomeWeb News) – An international research team led by investigators at the University of Michigan has used transcriptome sequencing to find previously unidentified gene fusions in prostate cancer.

In a paper appearing online yesterday in Nature Medicine, researchers from the US, Germany, Canada, and Singapore reported on the results of a transcriptome sequencing study involving 15 individuals with prostate cancer. After identifying two tumors containing RAF kinase pathway-related gene fusions, the team screened hundreds more tumors for similar rearrangements, uncovering RAF family gene fusions in one to two percent of prostate cancer, gastric cancer, and melanoma samples.

Those involved say the results not only reveal a new type of gene fusion in solid cancers, but may also point to new treatments for a subset of prostate and other cancer cases, since treatments aimed at curbing RAF kinase pathway activity are already being tested for melanoma, which frequently contains RAF point mutations.

"[O]ur results emphasize the key role of the RAF family gene rearrangements in cancer, suggest that RAF and MEK inhibitors may be useful in a subset of gene fusion-harboring solid tumors, and demonstrate that sequencing of tumor transcriptomes and genomes may lead to the identification of rare targetable fusions across cancer types," senior author Arul Chinnaiyan, director of the University of Michigan's Michigan Center for Translational Pathology, and his co-authors wrote.

"The clinical implications of this are actually pretty significant," co-author Christopher Maher, a research investigator with the Michigan Center for Translational Pathology and former post-doctoral researcher in Chinnaiyan's lab, told GenomeWeb Daily News. "We definitely want to take this into the clinic to start screening patients."

Last spring, Chinnaiyan and his team reported in the Proceedings of the National Academy of Sciences that they had used transcriptome sequencing of prostate cancers to detect fusions involving the TMPRSS2 gene and transcription factors in the ETS family. Now, the researchers have shown that alternative fusions can also occur in cancers lacking such ETS fusions.

Chinnaiyan, Maher, and their co-workers sequenced transcripts from 15 prostate cancers — five known to contain gene fusions affecting the ETS gene and another 10 that did not contain such fusions — using paired-end sequencing with the Illumina GAII platform.

In the process, the team identified two tumors that did not have ETS fusions, but which contained gene fusions involving BRAF and RAF1 genes in RAF signaling pathways.

The first of these tumors contained a fusion between an untranslated exon from the prostate-specific gene SLC45A3 and a BRAF exon. The other prostate tumor, meanwhile, contained two non-ETS fusions — one between ESRP1 exon 13 and RAF1 exon 6 and a reciprocal RAF1-ESRP1 fusion between RAF1 exon 5 and ESRP1 exon 14.

After verifying the new fusions by quantitative RT-PCR and fluorescence in situ hybridization, the researchers looked for the same rearrangements in three other prostate cancer cohorts, identifying six BRAF rearrangements and four RAF1 rearrangements in 349 prostate cancer samples tested. Overall, they say, roughly two percent of individuals with prostate cancer appear to carry a RAF-related rearrangement.

And based on their examination of 49 breast, 26 endometrial, 85 gastric, 131 melanoma, and 42 liver tumors, the researchers estimate that roughly one to two percent of gastric cancers contain BRAF rearrangements.

By sequencing transcripts from one of these gastric tumors, for instance, they identified a fusion between BRAF exon 8 and exon5 of AGTRAP, which codes for an angiotensin II, type I receptor-associated protein.

The team's screen also turned up one BRAF rearrangement and one RAF1 rearrangement in melanoma.

On the other hand, while they found that some 59 percent of the melanoma samples contain known oncogenic point mutations in BRAF, the researchers did not find any such point mutations when they screened 274 prostate cancer samples.

Together, the team argued, their findings indicate that RAF activation can occur not only through mutations, but also as a consequence of genomic rearrangements in certain solid tumors. That has researchers hopeful that they will be able to use fusion status as a method for further screening and sub-dividing prostate cancer patients, Maher explained.

Because at least four compounds targeting the RAF kinase signaling pathway are already being tested against melanoma, researchers say, it should be possible to test these drugs against the subset of prostate and other cancers containing RAF-related rearrangements as well.

For example, the team reported that both RAF kinase and MEK inhibitors curbed the invasiveness of cell lines expressing SLC45A3-BRAF or ESRP1-RAF1 fusion genes.

In addition, finding such fusions in at least three cancer types suggests understanding and treating cancer will increasingly rely on finding pathways affected across cancer types, Maher noted, instead of focusing primarily on the organs affected.

"Rather than treating cancer as just an entity classified under the microscope as a 'prostate tumor' or a 'gastric tumor,' it needs to be thought of as a 'RAF mutant tumor,'" Chinnaiyan said in a statement. "We need to think about what the driving molecular basis for each tumor is and what oncologists can then do about that for the patients."