Jul 26, 2022

Researchers discover DNA mutations no longer tell the whole story about cancer

Research: Brain & Neuroscience, Research: Cancer, Research: Genetics, Genomics & Proteomics, Research: Molecular & cell biology, Impactful research, Disruptive Innovation
Cynthia Hawkins

“How do we attack cancer? We need to look beyond just DNA alterations. The future of precision medicine will need to look at what other ways cancers use to spread and grow – that will be how we best choose therapies for patients”, says Dr. Cynthia Hawkins, Professor in Laboratory Medicine and Pathobiology in the Temerty Faculty of Medicine, and a neuropathologist clinician-scientist at SickKids.

In a recent paper published in Nature Communications, her team reported that gene splicing may be an important cancer-driving mechanism.

“For many years a lot of the initial characterization of tumors has been by looking at DNA and its mutations. We find a particular mutation and a particular gene that could be driving that cancer and choose therapies accordingly. However, for many patients, that targeted therapy doesn’t work well so it's not always predictive of what is really driving the cancer,” explains Hawkins.

Her team studies diffuse intrinsic pontine glioma, or DIPG, an aggressive childhood brain cancer. Fewer than 10% of children diagnosed with this type of brain tumor survive beyond two years from the date of their diagnosis. There are no effective treatments so researchers like Dr. Hawkins are looking beyond DNA mutations to seek therapies.

Proteins are vital for performing most cellular functions. DNA creates messenger RNA (or mRNA), a single strand of the double helix which contains information necessary for encoding proteins. Alternative splicing is a process that removes the intervening, non-coding sequences of genes (introns) from pre-mRNA and joins the protein-coding sequences (exons) together to enable translation of mRNA into a protein. Removing certain exons can change the function of the subsequent protein, for example if a protein’s function is to stop a cell from growing, by removing the necessary exons, that function could be reversed.

Splicing is well understood as a basic cell function, but the Hawkins lab have investigated it uniquely in gliomas, and the relationship between splicing and mutations in cancer overall.

“One of the most interesting things in our analysis was when we compared how many cancer genes were affected by a mutation versus alternative splicing - alternative splicing was much more frequent”, Hawkins explains. “Once we started looking at other types of cancer, we saw that overall cancers have a lot of alternative splicing, much more than in normal tissue and much more than the number of mutations in the genes that cause cancer”.

“We believe this is actually a common cancer mechanism - that cancer is taking advantage of these alternative splice forms,” says Hawkins. 

When the team looked at a specific example in gliomas, a cancer gene called NF1, they discovered that it is frequently alternatively spliced and that this spliced form was much less active at stopping cancer signaling pathways than the full gene form. 

This means that clinicians and molecular biologists can no longer depend on just the DNA mutations to make a diagnosis or plan a treatment path.

The Hawkins lab is already developing molecular tests in the clinical laboratory that use RNA and protein, rather than DNA mutations, to identify affected cancer pathways. “This helps us identify other potential pathways that drive the cancer, and therefore other ways we can target it”.

Read the paper "Splicing is an alternate oncogenic pathway activation mechanism in glioma" at Nature

This work has been funded by the Canadian Cancer Society Research Institute, Canadian Institutes of Health Research, ChadTough Foundation, DIPG Collaborative, Meagan’s Walk, and The Gilbert Family Foundation. 

Read more about Dr. Hawkin's research

Pathology and precision medicine: how research has transformed brain tumour diagnostics for children

LMP scientists receive CIHR funding

Dr. Hawkin's faculty profile