Sequencing the genome of cancer tumours is often used to help identify the type of cancer a person has and the best treatment for it.
Although cancer genomics has been used for a few years now, scientists are still learning about the best way to use genomic information to grade and categorize cancers.
One area that has received little attention until now is the methylation status of the cancer genome around specific genes.
Levels of expression of certain genes can also be affected by copy number variants (CNVs). CNVs arise because some sections of DNA are repeated, and the number of repeats varies between individuals due to deletions or duplications of DNA.
This leaves some people with many copies of a particular DNA sequence, whilst others have far fewer. These variations between individuals can be normal and harmless — however, they can also underpin disease.
A type of brain cancer called meningioma is known for the diversity of CNVs that occur between the genomes of different tumors. CNVs can also affect methylation, which further affects gene expression.
In a study by researchers at Northwestern University in Evanston, IL, the scientists decided to look at both the level of methylation in the meningioma genomes and the number of repeats in different CNVs. They included certain genes in the cancer genome known to control growth and repair to see if this provided any insight into outcomes.
The findings are published in the journal
Using genomic data from 565 tumors taken from two cohorts of patients who had been followed up for 5–6 years, researchers profiled the DNA methylation of the cancer genomes. They then analyzed this alongside the presence of DNA repeats at certain points in the genome and also looked at the RNA present in the tumors to determine which genes had and hadn’t been expressed.
They found that looking at the number of repeats within certain genes alone did not predict patient outcomes accurately, but looking at the number of repeats of genes alongside the level of methylation revealed three different grades of tumor.
Just over one-third of the tumors in the cohort were designated “merlin intact” meningiomas, where patients had the best outcomes. These tumors did not involve abnormal numbers of repeats on the gene that codes for a protein called merlin, which
Conversely, 38% had immune-enriched meningiomas where patients had intermediate outcomes. These tumors were characterized by loss of the gene that codes for merlin and downregulation of other tumor-suppressing genes due to methylation.
This allowed them to overcome normal responses from the immune system.
A further 28% had hypermitotic meningiomas where the patient not only had fewer repeats of the gene that codes for merlin but a number of other gene repeats that caused either increased growth or decreased tumor suppression.
They also had methylation that allowed the increased expression of a gene known to promote cell growth. These patients had the least favorable outcomes.
Using this information, the researchers then tested the drug abemaciclib, a cancer drug already used for breast cancer, on tumor cells in cell lines, organoids, and xenografts in mice.
Results from these experiments indicated the drug could be used to treat individuals who had been identified as having either immune-enriched tumors or hypermitotic tumors.
Previously trials have failed to identify drugs that could reliably treat meningioma, but the identification of a biomarker could help identify patients who could benefit from certain treatments, said lead study author Dr. Stephen Magill.
Dr. Magill is an assistant professor of neurological surgery at Northwestern University Feinberg School of Medicine. He told Medical News Today in an interview: “Some of our findings are really raising the possibility that the more we know about the biology, [the more] we can then say: this isn’t just a meningioma, you have a hypermitotic meningioma.”
“So we can really use that as a biomarker to stratify who would go into a clinical trial.”
Cancer researcher professor Noam Shomron from the Sackler Faculty of Medicine from Tel Aviv University, Israel, who was not involved in the research told Medical News Today:
“I think it’s a wonderful study, because it’s so comprehensive, and it spans molecular and clinical findings and structural variations and methylation — which is epigenetics — [and something that] doesn’t often take center stage.”