Whole-Genome Analyses Expand Genetic Picture of Prostate Cancer

April 25, 2018
Dave Levitan
Dave Levitan

A study found some mutations that are already targeted by approved or investigational drugs for prostate cancer, along with dozens of targets that should be considered as candidates for future trials.

Researchers have found a number of previously unidentified genes that may act as drivers of prostate cancer. A new study found some mutations that are already targeted by approved or investigational drugs, along with dozens of targets that should be considered as candidates for future trials.

“[Prostate cancer] is difficult to manage clinically due to a poor current understanding of what dictates its highly variable natural history and of what underlies the development of castration-resistant disease,” wrote study authors led by David C. Wedge, PhD, of Oxford University in the United Kingdom. Previous work has identified genetically distinct subgroups of prostate cancer, but the ordering of genetic events in the disease’s course remains poorly understood.

For the new analysis, the researchers sequenced the whole genomes of 112 primary and metastatic prostate cancer samples, and combined these with previously sequenced samples for a total of 930 cancers. They compared them with normal control samples. The results were published in Nature Genetics.

They found a significantly higher mutational burden among primary samples than among metastatic samples; within the metastatic subset, those treated with androgen deprivation therapy had a higher mutational burden.

The analysis revealed a total of 22 putative driver genes harboring coding mutations that had not been previously identified. They also found that NEAT1, which was recently reported to be associated with prostate cancer progression, had a noncoding mutation in 13 of the 112 samples, and these mutations were significantly overrepresented in those with metastatic disease. The FOXA1 gene was also noted to be of importance, with a coding mutation seen in 14 samples and a noncoding mutation seen in 6 samples.

They also were able to establish mutations likely to be involved in specific steps of the progression of prostate cancer. For example, the loss of CHD1 and BRCA2 are likely early events in cancer development in ETS fusion–negative cancers. A combination of several genes including CDH12, ANTXR2, SPOP, IL6ST, DLC1, and MTUS1 was found to be a predictor of biochemical recurrence, with better prognostic value than a combination of Gleason score, prostate-specific antigen level at prostatectomy, and pathologic T stage.

The driver genes identified were found to be related to druggable targets as well. This includes 11 targets of currently approved therapies, and 7 targets of investigational drugs, along with dozens of potential novel targets. In total, 80 of the 156 proteins central to development of the disease were deemed to either be targets of existing drugs or of potential future agents.

“Network analyses identified, in addition to previously known drivers, targets that could be exploited for clinical investigation with existing drugs as well as targets for new drug discovery, giving potential for the results of genome analysis to be translated rapidly into therapeutic innovation and patient benefit,” the authors concluded.