Although Grade Group 5 cancers (Gleason score 9 and 10 cancers) have similar features when examined under a microscope, a recent study published in the journal European Urology suggests that they are quite different when their gene expression patterns are examined. This study was led by researchers at the University of California Los Angeles (UCLA).
In this study, researchers examined prostate cancer tissue samples from 2138 patients with Grade Group 5 prostate cancer. The researchers wanted to know if there were differences in gene expression patterns between the patient samples and if these differences affected the patients’ prognosis and long-term outcome.
Gene expression patterns (profiles) are determined by looking at the products of genes called RNA. When a gene (made of DNA) is activated, it serves as a template to create an RNA molecule in a process called gene transcription. The RNA in turn serves as the template to create the specific protein product encoded by the original gene. Through examining the different types of RNA molecules present in a cell, researchers can define the expression pattern or profile for that cell. Comparing the gene expression profiles of normal cells with cancer cells, provides insight into the changes that occur in cancer cells that could be contributing to their behaviour.
The UCLA researchers compared the expression profiles of different patients with Grade Group 5 prostate cancer. To do this, they used sophisticated microdissection techniques to dissect cells from Gleason pattern 5 areas of prostate cancer biopsy tissue. They then extracted RNA from the cells which was used to determine the gene expression profiles. The scientist also used data and information available from a previous clinical trial called GRID (Decipher Genomics Resources Information Database) which was conducted from 2014 to 2017.
After comparing the expression profiles for 2138 patients, the researchers found four distinct groups or clusters based on specific expression profile information. Cluster 1, they referred to as a high genomic risk cluster. This cluster seen in 325 of the patients (15%) had expression profiles enriched for genes related to the cell proliferation, metabolic pathways, androgen response pathways, and DNA repair, and had a higher average genomic risk than the other clusters.
Cluster 2, with the lowest genomic risk, was seen in 383 of the patients (18%). This cluster was associated with expression of genes important for immune response and various other metabolic pathways.
Clusters 3 (624 men, 29%) and 4 (806 men, 38%) showed an intermediate pattern of gene expression compared to clusters 1 and 2. Cluster 3 had slightly higher expression of genes related to cell proliferation and metabolic pathways then cluster 4, while cluster 4 showed higher expression of immune related genes then cluster 3.
The researchers wanted to be sure that what they were observing was correct, so they examined the expression profiles of a separate group of 1921 patients. Again, they found four clusters with the high genomic risk cluster showing upregulation of pathways related to androgen receptor signalling, DNA repair, and proliferation, while the low genomic risk cluster showed upregulation of immune response pathways.
Finally, the researchers wanted to know if the different clusters would provide information on clinical outcome for prostate cancer. For this part of the study, they examined a third separate group of 201 men for whom the disease outcome was known. In these men, it was found that those in the high genomic risk cluster (Cluster 1) had significantly worse metastasis-free survival than the other clusters.
The researchers showed that Grade Group 5 prostate cancers can be divided into 4 different subgroups based on their gene expression profiles. They showed that those with expression profiles consistent with high genomic risk (cluster 1) had a poorer outcome and suggested that this group “may be the most likely to derive benefit from treatment intensification, and rational approaches may include the use of interventions active against the pathways that are dysregulated”. They conclude that further investigation into Grade Group 5 disease “and particularly into this aggressive subgroup, is clearly warranted”.
This important study shows us that not all prostate cancers are the same. Studies like this one and developments in precision medicine are bringing us closer to a future where treatments for prostate cancer are more personalised.