Researchers identify genetic clues that could reveal aggressive prostate cancer

Prostate cancer is the second most common form of cancer among men globally. Yet, we still know relatively little about why the disease develops or why some men live with it for years while in others it progresses aggressively.

In a new study from the University of Copenhagen and Rigshospitalet as well as University of Konstanz in Germany, Ontario Institute for Cancer Research (OICR) in Canada and Centro Nacional de Investigaciones Oncológicas (CNIO) in Spain, researchers analysed the genetic material of 1,000 prostate cancer patients and identified a new way of tracking how the disease develops. The approach could help identify patients at high risk of developing aggressive prostate cancer.

“We have effectively created a map of the biological processes that drive prostate cancer,” says Joachim Weischenfeldt, Professor at the Biotech Research & Innovation Centre (BRIC) at the University of Copenhagen and Rigshospitalet, and lead author of the study, which has just been published in the journal Nature.

The biggest challenge in prostate cancer is not detecting the disease, but determining which patients have a harmless form of cancer and which are at risk of developing a life-threatening disease.

“Once the cancer has spread, the five-year survival rate drops to 30 per cent. That makes it critically important to identify which patients are developing aggressive, life-threatening prostate cancer,” says Jüri Reimand, Principal Investigator at Onatario Institute for Cancer Research and co-author on the study..

Analysing the crime scene

In the study, researchers analysed samples from almost 1,000 prostate tumours. Rather than focusing solely on cancer-causing genes, they examined the genetic traces the disease leaves across the entire genome.

Cancer arises when cells accumulate uncontrolled mutations in their DNA. Each mutation leaves behind a particular context, or ‘fingerprint’, that can reveal the process responsible for causing the cancer.

“It is a bit like a crime scene. The cancer gene is the culprit, while the genetic signatures are the fingerprints left behind. By analysing those signatures, we can understand why and how the cancer cells emerged,” says Joachim Weischenfeldt.

DNA replication errors play a major role

The researchers found that eight types of genetic fingerprints account for 85 per cent of all prostate cancer cases.

Four of the eight patterns were associated with a higher risk of the cancer spreading, particularly in tumours driven by the male sex hormone testosterone.

The team also discovered that errors occurring during DNA replication appear to play a much greater role in the development of prostate cancer than previously recognised. Around one-third of tumours are caused by damage that occurs when DNA is copied.

“From a biological perspective, it is important to understand why so many men develop prostate cancer, and we are the first to show how common this mechanism is. This opens an entirely new field for understanding the underlying biology and for developing new treatments,” says Joachim Weischenfeldt.

Knowing which types of mutations are driving a tumour could eventually make it possible to predict whether a patient's cancer is likely to become aggressive.

“It is remarkable how much clinical significance these eight fingerprints appear to have. They can actually help distinguish between patients who are developing life-threatening cancer and those who are not,” says Joachim Weischenfeldt.

A step towards more personalised treatment

The researchers also found evidence that the genetic fingerprints could eventually be used to predict which patients are most likely to benefit from different treatments. The same principles may also be applicable to other cancers, including breast, ovarian and pancreatic cancer.

“What is particularly exciting is that these eight signatures may help doctors determine whether patients with advanced cancer are likely to respond to chemotherapy, or whether treatments such as hormone therapy would be a better option,” says Joachim Weischenfeldt.

He stresses, however, that the findings will not change patient treatment in the immediate future. The results must first be validated in clinical studies before the approach can be implemented in healthcare.

On the other hand, the method is based on data and sequencing technologies that are already widely used in cancer diagnostics. For that reason, he believes it could be used for risk assessment within the next few years.

“Our goal is to tailor treatment to each individual patient's disease, and this brings us one
step closer to making that a reality,” says Joachim Weischenfeldt.