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Exome Meta-Analysis Uncovers Copious Prostate Cancer Drivers

NEW YORK (GenomeWeb) – A new meta-analysis of prostate cancer exomes has identified dozens of potential driver genes, including genes mutated in just a fraction of the cancer cases considered.

In an effort to expand on prior genomic studies of prostate cancer, researchers from the US and UK used the same analytical strategy to assess protein-coding sequence data for more than 1,000 primary or metastatic prostate cancer cases. Their findings, published in Nature Genetics yesterday, revealed nearly 100 significantly mutated genes.

That set included 70 genes not implicated as prostate cancer drivers previously, the team noted, and pointed to a previously unappreciated class of tumors with epigenetic regulator pathway changes that were missing ETS transcription factor fusions. Moreover, the authors emphasized, a broad swath of the driver candidates were altered in fewer than 3 percent of the tumors.

"While many of the significantly altered genes and pathways are mutated at low frequencies, given the incidence of prostate cancer, these alterations still impact large patient populations," co-corresponding authors Eliezer Van Allen, a medical oncology researcher affiliated with Dana-Farber Cancer Institute and the Broad Institute, and Nikolaus Schultz, an oncology and pathogenesis researcher at Memorial Sloan Kettering Cancer Center, and their colleagues wrote.

For their analyses, Schultz, Van Allen, and colleagues focused on whole-exome sequenced data for matched tumor and normal germline samples from 680 individuals with primary prostate cancer and 333 metastatic cancer cases originally profiled at several academic centers and/or through large studies spearheaded by Stand Up to Cancer or the Cancer Genome Atlas.

The team's standardized alignment, mutation calling, and mutational significance analyses led to 97 significantly mutated genes. Along with representatives from androgen signaling, DNA repair, and PI3 kinase-AKT and other signaling pathways already implicated in prostate cancer previously, for example, it uncovered recurrent mutations affecting members of ubiquitin and spliceosome pathways.

All told, some 70 candidate drivers had been linked to other cancer types in the past, while nine did not appear to be recurrently mutated in prostate or other cancers until now.

Just over half of tumors contained ETS gene fusions, the researchers reported. Another 11 percent contained mutations in CUL3, SPOP, or IDH1 (genes known to contribute to the disease) and 4 percent had FOXA1 mutations. The remaining ETS fusion-negative tumors contained mutations in epigenetic regulator, chromatin remodeling, and other pathways.

While mutations in known driver genes such as TP53 and SPOP were relatively common, the team cautioned that many genes were recurrently altered in less than 3 percent of prostate cancers, leading to a "long tail" of apparent oncogenes.

"As predicted by prior power analyses," the authors wrote, "the majority of these new [significantly mutated genes] occurred in less than 5 percent of the overall cohort and could not be discovered in cohorts with over 900 samples."

By comparing primary and metastatic tumors, meanwhile, the researchers narrowed in on genomic markers that may ultimately aid in stratifying prostate cancer risk by systematically comparing the protein-coding alterations in primary and metastatic prostate cancer tumors.

Metastatic tumors appeared more prone to copy number alterations, for example, and consistent with past findings, they also tended to be marked by significantly higher mutational loads relative to the primary prostate cancers. 

"[W]hereas expanded analysis of primary indolent prostate cancer suggests near saturation for gene discovery," the authors noted, "this analysis, which includes more advanced cases, has identified new and biologically and clinically relevant events and creates an opportunity to prospectively assess a metastasis-associated genomic marker for clinical stratification in localized prostate cancer."