The human genome contains nearly 22,000 genes and various studies have explored the nearly 2% of DNA that creates proteins. Far less is known about the remaining 98% of DNA that does not encode protein.
These non-coding regions contain important information and control whether a gene is active in different types of tissues, in different stages of development and in diseases like cancer.
Cancer is caused by mutations that result in uncontrolled cell division. Glioblastoma is one of the most aggressive forms of cancer. We know relatively little about how mutations in non-coding regions drive glioblastoma.
To combat this knowledge gap, researchers at Uppsala University have performed whole-genome sequencing of DNA in tumour tissues from patients with glioblastoma and analysed the identified mutations.
Professor Karin Forsberg-Nilsson explains "one of our key tasks was to identify functional mutations associated with regulatory elements and potential relevance to the development of cancer cells, and to distinguish them from all random variations without presumed significance.”
The researchers worked off the assumption that DNA sequences which haven’t changed in mammals throughout evolution will have important functions.
They intersected the thousands of mutations they had found with information about evolutionary conservation of the genetic regions where the mutations lie.
"We chose to focus on a subset of mutations in the best-preserved genetic regions that are likely to affect gene regulation," says Professor Kerstin-Lindblad-Toh.
The researchers verified their results using the gene SEMA3C, partly because they found many mutations in non-coding regulatory regions close to this gene, and partly because of other researchers’ findings that SEMA3C is linked to a poor cancer prognosis.
"We studied how mutations in non-coding regions affect SEMA3C's function and activity. Our results show that a specific, evolutionarily conserved, mutation in the vicinity of SEMA3C disrupts the binding of certain proteins whose task is to bind genes and regulate their activity," says Forsberg-Nilsson.
The study, in Genome Biology, also identifies over 200 genes enriched for non-coding mutations in the concerned regions.
These genes are likely to have regulatory potential that could further increase the number of genes identified as relevant to the development of brain tumours.
"Our results confirm the importance of the association between genetic alterations in non-coding regions, their biological function and disease pathology," concludes Forsberg-Nilsson.
More investment in research is needed to fully elucidate the genetic functioning within brain tumours which would help develop effective treatments for this devastating disease.
The Brain Tumour Charity has made a strategic commitment to fund world-class research to accelerate a cure.
To date, we have invested over £50 million in global research into brain tumours and won’t stop there. Because when you or someone you love has a brain tumour, a cure can’t wait.