Proteins linked to the immune system, cell adhesion, blood vessel formation and known prostate cancer genes, were associated with the future risk of developing prostate cancer, including aggressive disease, in a new study led by researchers at Oxford Population Health.
The findings reveal biological differences between men who later developed prostate cancer and those who did not, and may help guide future studies aimed at identifying men at greater risk of the disease.
The study, published in European Urology and presented at the American Society of Human Genetics (ASHG) Annual Meeting, is the largest population-based investigation to date of blood proteins and future prostate cancer risk, with a particular focus on aggressive disease.
Prostate cancer is the most commonly diagnosed cancer in men worldwide, but relatively little is known about why some men develop the disease or why some cancers become aggressive. Most established risk factors, such as age and genetics, cannot be changed.
The researchers analysed blood samples from 982 men who subsequently developed prostate cancer and a randomly selected sample of 1,573 men from the European Prospective Investigation into Cancer and Nutrition (EPIC). They measured more than 6,000 proteins in the blood and looked for differences linked to the later development of prostate cancer, particularly aggressive disease. Participants were followed for around 16 years.
Twelve proteins were linked to prostate cancer diagnosed more than 15 years after the blood sample was collected. These included GZMK, a protein produced by immune cells involved in recognising and destroying abnormal cells, suggesting that immune processes may help keep prostate cancer in check long before it is diagnosed.
The researchers also identified seven proteins linked to aggressive prostate cancer. One protein, ANKRD1, was consistently linked to several serious forms of the disease, including cancers that had spread or were ultimately fatal. Other findings pointed to processes involved in how cancer cells interact with surrounding tissue and how new blood vessels form.
Dr Zhe Huang , first author of the study and a postdoctoral epidemiologist at Oxford Population Health, said: 'Prostate cancer is not one disease. Many prostate cancers grow slowly and may never cause harm, while others are aggressive and can be life-threatening.
'By measuring thousands of proteins in blood collected years before diagnosis, we can begin to investigate how men who later develop aggressive prostate cancer may differ from men who do not. Ultimately, we hope this will help us understand the biology of aggressive prostate cancer and identify markers that could improve how we assess risk in the future.'
The study also found links with blood levels of proteins produced by genes already known to be important in prostate cancer, including ERBB3, KRAS and NRAS. These proteins were particularly linked to aggressive prostate cancer diagnosed around a decade later. This does not mean cancer was already present when the blood was collected, but the findings may provide clues to biological changes associated with the future development of the disease.
Professor Karl Smith-Byrne (Oxford Population Health), a senior author of the study, said: 'Finding proteins linked to known prostate cancer driver genes in blood collected years before diagnosis gives us new insights into the earliest stages of the disease. Together with existing and future genetic evidence, these findings may help us identify biological pathways that could be targeted to prevent aggressive prostate cancer.'
The researchers compared their results with other large population studies and genetic evidence to test the robustness of their findings. Several findings were supported by these additional analyses, although not all could be confirmed. The proteins identified are not yet suitable for use as clinical tests; most associations were modest and further studies are needed to establish whether they could improve prediction of clinically significant prostate cancer.
Cancer Research UK part-funded the research and Dr Iain Foulkes, executive director of research and innovation at the charity, said: 'Prostate cancer is one of the biggest cancer killers of men, yet we still don't fully understand why some tumours grow slowly and may never cause harm, while others become aggressive and life-threatening. Understanding what drives these differences is crucial if we are to identify those most at risk and ultimately save more lives.
'This research offers important new clues. By analysing thousands of proteins in blood samples collected years before diagnosis, scientists have opened a fascinating window into the biology of the disease, including the possible role of our immune system. While there is more work to do, discoveries like this could pave the way for better ways to identify men at risk and, ultimately, prevent aggressive prostate cancer before it develops.'
Future research through the Prostate Cancer Aetiology and Prevention Programme (PCAP), funded by Cancer Research UK, will investigate whether these findings could ultimately contribute to better ways of predicting or preventing prostate cancer.
Professor Ruth Travis (Oxford Population Health), one of the PCAP programme leads, said: 'For the first time, technologies that allow us to measure thousands of proteins simultaneously are giving us unprecedented insight into the earliest stages of prostate cancer development.
'Combined with large, long-term population studies, they allow us to look back many years before diagnosis and investigate the biological changes associated with future cancer risk. Understanding these processes is a critical step towards developing new strategies to prevent prostate cancer.'
