Illustration of the prostate organ in blue surrounded by red cancer cells to symbolize prostate cancer
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A U.K. study has shown that prostate cancer can be classified into two distinct prostate cancer subtypes according to how gene mutations evolve within the tumors, with one type linked to more aggressive disease than the other.

The discovery was made by an international team, led by the University of Oxford and the University of Manchester, that used whole genome sequencing and artificial intelligence to study changes in the DNA of tumor samples taken from 159 men with untreated low- or intermediate-risk prostate cancer.

Study co-author Colin Cooper, from the University of East Anglia says that prostate cancer has always been thought of as one disease. “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.”

This is important because for other cancers, like breast cancer, different classifications exist that help guide treatment and have ultimately resulted in decreased mortality rates. “For prostate cancer this has never been possible,” Cooper tells Inside Precision Medicine.

The researchers explain in Cell Genomics that the development of cancer is a dynamic process involving the sequential accumulation of genetic alterations that disrupt normal biological processes, enabling tumor cells to rapidly proliferate and eventually invade and metastasize to other tissues.

For the current study, they first classified the tumors by three different aspects of tumor evolution: patterns of co-occurring genomic features, mechanism of DNA double-strand breaks, and the evolutionary order in which genetic alterations occur. In each case, the results were grouped in to two clusters.

The investigators then integrated the results of the three classification methods and showed that the tumors could be divided in to two groups, termed evotypes, according to their evolutionary trajectories.

More than three-quarters (78.6%) of the tumors evolved via the standard route and were assigned to the canonical-evotype, while the remaining 21.4% belong to the alternative evotype that results in a distinct form of disease. The shift away from the canonical trajectory was characterized by androgen receptor dysregulation, the researchers note.

However, they also point out that although each prostate cancer subtype had a different tendency for certain aberrations, no single aberration was either necessary or sufficient for assignment to either evotype.

“The lack of consistent genetic alterations indicates that there may be multiple individual routes of progression for each evotype,” they write.

The team, led by Dan Woodcock from the University of Oxford, also investigated whether classifying tumors by evotype could be used to model disease risk. The data showed that individuals with alternative evotype tumors had a significant 2.3-fold higher risk for biochemical recurrence than those with canonical evotype tumors. In addition, when evotype was combined with tumor mutational burden, a commonly used risk prediction marker, the model outperformed the use of TMB alone.

The researchers now plan to further validate the use of evotype in risk prediction models.

Cooper says: “We hope that the findings will not only save lives through better diagnosis and tailored treatments in the future, but they may help researchers working in other cancer fields better understand other types of cancer too.”

The evotype project is part of the The Pan Prostate Cancer Group, set up by scientists from the University of Oxford, the University of Manchester, the University of East Anglia, and the Institute of Cancer Research, London. They are working together to analyze genetic data from thousands of prostate cancer samples across nine countries that they hope will address many of the clinical problems experienced by men diagnosed with this disease.

Dr. Rupal Mistry, Cancer Research UK’s senior science engagement manager, notes: “The work published today by this global consortium of researchers has the potential to make a real difference to people affected by prostate cancer.”

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