Epigenetic modifications are changes to the DNA molecule that can affect gene expression without altering the underlying genetic sequence. In recent years, researchers have identified several epigenetic markers that are associated with prostate cancer, including changes in DNA methylation and histone modification patterns.
Scientists at the Garvan Institute of Medical Research have discovered new epigenetic biomarkers to predict more aggressive forms of prostate cancer. The biomarkers can be used in conjunction with traditional clinical tools to predict whether a man will develop a more metastatic and lethal form of the disease, potentially assisting clinicians in developing a better treatment plan.
“There is a need for men with prostate cancer to have more personalised treatments guided by the nature of their tumors, and they can’t get that without new biomarkers that can better predict the risk of developing the lethal form of the disease,” says Professor Susan Clark, Head of the Epigenetic Research lab at Garvan and the study’s lead researcher.
There is a need for men with prostate cancer to have more personalised treatments guided by the nature of their tumors, and they can’t get that without new biomarkers that can better predict the risk of developing the lethal form of the disease.
Professor Susan Clark
Prostate cancer is the second most common cancer diagnosed in men worldwide. After being diagnosed, approximately half of all men will develop metastatic cancer during their lifetime. Metastasis typically takes 15 years or more to develop, but a small percentage of men develop a fatal, metastatic form much sooner after diagnosis. Clinicians could begin more aggressive treatments earlier if they could identify patients who may develop this type of prostate cancer in the early stages.
The new research was published in Clinical and Translational Medicine. This is one of the most comprehensive and long-term molecular studies of prostate cancer progression. The disease’s slow progression makes studying its biology difficult.
The researchers were able to analyze samples from 185 men who had their prostate removed due to a prostate cancer diagnosis in the 1990s and 2000s thanks to a bank of biopsies kept at Garvan and St Vincent’s Hospital for the last 20 years. The team then tracked the number of men who survived the disease and those who died from it, some of whom died more than 15 years later.
The researchers looked at their genomes and identified 1420 regions specific to the prostate cancer where they could see epigenetic changes – marks on the DNA, known as DNA methylation. The methylation process can turn a gene’s activity up or down without altering its DNA sequence like a mutation does.
Of those regions, 18 genes were studied further, with one, the CACNA2D4 gene, which is involved in calcium channel regulation, standing out as a key biomarker.
“We know very little about this gene and it’s not typically profiled, so we really need to understand how the methylation process may suppress the gene’s activity,” says Dr. Ruth Pidsley, the study’s first author.
The comprehensive epigenome sequencing data has been made available to other researchers for use in future prostate cancer research by the team. Not only did the epigenome analysis reveal differences between men with lethal and non-lethal prostate cancer, but the biomarkers also improved existing clinical tools for prognosis.
The new findings offer hope for a more personalized cancer treatment.
“What you really want to know on the day a patient is diagnosed is who has the potential for lethal prostate cancer and who doesn’t, because it will change the way you treat the cancer,” says Professor Lisa Horvath, the clinical lead on the study and an oncologist and researcher at Garvan.
“These epigenetic biomarkers have the potential to help us figure out who has lethal prostate cancer and who doesn’t right away,” she says. The next step is to expand the study and see if the biomarkers can be detected in blood samples at the outset.
