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Prostate Cancer Subtypes Found by Analyzing Tumor Evolutionary Trajectories

Abstract molecular cancer

NEW YORK – An international team led by investigators in the UK has delved into prostate cancer evolution, defining two prostate cancer "evotypes" with alternative evolutionary paths.

Using genomic data collected through the Pan Prostate Cancer Group, the researchers used artificial intelligence approaches to interrogate mutation trajectories in whole-genome sequences for 159 intermediate- or low-risk, treatment-naive prostate adenocarcinoma tumors collected in nine countries from patients treated with radical prostatectomy — work they reported in Cell Genomics on Thursday.

"We investigated the genomic evolution of prostate cancer through the application of three separate classification methods, each designed to investigate a different aspect of tumor evolution," the authors wrote, noting that their results indicated that "alternative-evotype tumors diverge from those of the canonical evotype through the stochastic accumulation of genetic alterations associated with disruptions to androgen receptor DNA binding."

Building on prior studies that have uncovered specific genetic alterations that are prone to arise early on in the prostate cancer development process, the team characterized evolutionary subtypes turning up in prostate cancer due to gene mutations that occur due to the presence of earlier mutation events, co-senior author David Wedge, a researcher affiliated with the University of Oxford, University of Manchester, Oxford NIHR Biomedical Research Centre, and Manchester NIHR Biomedical Research Centre, explained in an email.

"Within this study we have unified many of the previous observations to define [two] different evolutionary subtypes, each of which is made up of a set of gene mutations, which tend to occur in a particular order," he said.

Based on evolutionary trees assembled from the available prostate cancer sequence data, the team defined evotypes marked by divergent mutation accumulation patterns and distinct levels of aggressiveness.

"We have … linked the separation of the two subtypes to specific behavior of the cancer cells in the two [prostate cancer] subtypes," Wedge said. "This means that we can predict which tumors will evolve to the more aggressive subtype and potentially deliver appropriate treatment tailored to the future aggressiveness of a patient's tumor."

Together, he explained, the results revealed the distinct behaviors of prostate cancer cells with typical or atypical androgen receptor binding site behavior, highlighting the possibility of predicting tumor evolution, aggressiveness, and potential targeted treatment options.

"Our research demonstrates that prostate tumors evolve along multiple pathways, leading to two distinct disease types," first author Dan Woodcock, a surgical sciences researcher affiliated with the University of Oxford and the University of Oxford's Big Data Institute, said in a statement, adding that the results make it possible to "classify tumors based on how the cancer evolves rather than solely on individual gene mutations or expression patterns."

For his part, co-senior author Colin Cooper suggested that the findings may provide avenues for improving prostate cancer diagnoses and tailored treatment development down the road.

"[U]ntil now, we thought that prostate cancer was just one type of disease. But it is only now, with advancements in artificial intelligence, that we have been able to show that there are actually two different subtypes at play," Cooper said in a statement, adding that results from this study and the strategy used "may help researchers working in other cancer fields better understand other types of cancer, too."