Study of intronic variant provides critical information about the size and growth speed of gliomas
MoGen scientists stride towards a better understanding of the biology of non-coding genomic alterations
Research co-led by MoGen Professor Dr. Daniel Schramek at Lunenfeld-Tannenbaum Research Institute (LTRI), in collaboration with Mount Sinai Hospital, Toronto, Mayo Clinic Comprehensive Cancer Center and Mayo Clinic Center for Individualized Medicine, identified the biologic mechanism of a germline alteration that may be critical for developing new therapies to treat and prevent a type of brain tumor. In this multicenter study, the team of investigators found that animal models who carry the germline alteration, called rs55705857 developed larger gliomas faster, compared to animal models that did not carry the alteration. Their findings were published in the journal Science and the results have relevance to other cancers and diseases.
The studied genomic variant is interesting because it is not an alteration that affects a gene that codes for proteins. The biology of such “intronic” variants in a noncoding gene is poorly understood. Understanding how such germline alterations interact with other mutations in cells to accelerate tumor formation is crucial, and future research may lead to novel and specific therapies that target the rs55705857 alteration.
Consequently, such therapies could be used to treat patients with low-grade glioma as well as prevent low-grade glioma in susceptible people and families. In addition, some people have an imaging evaluation of the brain that coincidently reveals an abnormality that could represent an early glioma. Knowledge of the rs55705857 genotype can help clinicians determine, pre-surgery, whether the imaging abnormality may in fact be a glioma.
"We expected that rs55705857 would accelerate low-grade glioma development; but we were surprised by the magnitude of that acceleration," says Dr. Schramek.
For the study, Dr. Schramek’s team developed an animal model of low-grade glioma. Animal tumour models are generated by incorporating the mutations from human tumours into animal cells. The special characteristic of the model is that the animals who carry the rs55705857 germline alteration develop tumours that are larger, occur much more frequently and at a much younger age.
Dr. Schramek shares that there are many alterations (likely thousands) outside of genes that are associated with the development of cancer and other diseases. However, the mechanism of action is only understood for very few of these alterations.
This study demonstrates that with the tools of modern molecular/cell biology, it is possible to decipher much of the mechanism of action of such alterations.