A research team from Uppsala University have successfully developed a new method of identifying cell mutations and their effect on the genes responsible for the development of glioblastoma brain tumours.
DNA strands containing non-coding regions hold important information and regulate whether a gene is active in different tissues, in different stages of development, and in diseases such as cancer. Cancer is caused by mutations that lead to uncontrolled cell division.
Little research has been conducted to assess how mutations in non-coding regions can affect one of the most aggressive types of cancer, glioblastomas. To address 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.
Intersecting thousands of mutations
The research team hypothesised that DNA sequences that have remained unchanged in mammals throughout evolution are likely to have important functions. Therefore, they intersected the thousands of mutations they had found with information about evolutionary conservation of the genetic regions where the mutations lie.
“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,” says Professor Karin Forsberg-Nilsson at the Department of Immunology, Genetics and Pathology, Uppsala University.
Linking mutations to poor brain tumours
The researchers validated their results using the gene SEMA3C, partly because they found a large number of mutations in non-coding regulatory regions near this gene, suggesting 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 also identifies more than 200 other genes enriched for non-coding mutations in the regions concerned. These likely have regulatory potential, thus further increasing the number of genes that are relevant to the development of brain tumours.