Most people take it for granted that, should they or their child develop a medical condition, they will be quickly and accurately diagnosed – the first step to getting effective treatment. But that is not always possible, particularly in the case of childhood cancers and other rare genetic diseases.
To help address this shortcoming, researchers at Children's Cancer Institute have developed a new suite of tools and resources accessible to scientists worldwide.
These new resources assist scientists to identify mutations or changes in a patient’s genes (known as ‘genetic variants’) that may be causing a medical condition or, in the case of a cancer, driving the growth of that cancer. This information is especially vital for uncovering the cause of rare inherited diseases that often leave patients, parents and their clinician searching for answers. For childhood cancers, knowledge of the specific genetic variants found in a cancer can now guide clinicians to choose the most effective treatment tailored to the individual child in their care.
Currently, many of the genetic variants that cause disease are not well understood. In particular, very little is known about a group known as ‘splice-altering variants’, despite research showing that up to one third of all disease-causing genetic variants belong to this group.
This is where Children’s Cancer Institute is making a major contribution. Its Computational Biology Group has recently published three important pieces of research in high-impact international journals. Each of these offer valuable new insights and tools that help identify and understand splice-altering variants.
The first in this trio of papers, published in Genome Biology in 2023, details ‘Introme’, a highly innovative machine learning tool. Lead author, Patricia Sullivan, explains: “We developed Introme to help identify genetic variants that affect an often-overlooked process, gene splicing, which other tools have not been able to pick up on. With Introme now available, we expect to see a substantial increase in diagnosis rates of rare genetic diseases.”
The team then published two papers in the American Journal of Human Genetics. The first of these presents a large database of often-overlooked variants, SpliceVarDB, which medical professionals can use to efficiently identify splice-altering variants affecting their patients, eliminating the need for extensive laboratory testing. Enabled by SpliceVarDB, the team’s third paper leverages data-driven insights to identify genetic variants that may cause abnormal splicing. By uncovering common patterns, the team developed practical rules to streamline variant assessment.
For the first time, clinicians now have clear and detailed guidance to evaluate the splicing potential of observed variants. This is crucial for those treating cancer or rare disease patients, where identifying whether a variant in a key gene contributes to the disease can be a decisive factor in diagnosis and treatment.
The true value of these studies becomes clear when viewed in the context of precision medicine (aka personalised medicine), which is revolutionising the way genetic diseases, including cancer, are being treated. To provide an accurate diagnosis and treatment recommendation for a patient, precision medicine programs rely on detailed knowledge of which of that patient’s genes are altered, how they are altered, and the significance of these alterations.
“The promise of personalised medicine is that each patient receives a rapid and accurate diagnosis, leading to the right treatment at the right time” explained Associate Professor Mark Cowley, Head of the Computational Biology Group at Children’s Cancer Institute. “However, to successfully diagnose a genetic disease, we need tools that help us sift through thousands or even millions of genetic changes in each patient’s genes, allowing us to focus on the few that that could be driving the disease.”
The Zero Childhood Cancer Program (ZERO) − Australia’s national precision medicine program for children with cancer − has shown that using genetic analysis in this way, it is possible to identify disease-causing genetic variants in more than 90% of children with cancer. In many cases, this knowledge can be used to provide an accurate diagnosis, and often personalised treatment recommendations as well, leading to improved survival.
“We want to know how we can close the gap to enable personalised care for every child,” said Associate Professor Cowley. “We believe the answer lies in being able to identify every genetic variant that could be causing a patient’s disease – something that’s not currently possible because our understanding of the genome is incomplete.”
“Introme and the other resources developed by our team represent a huge step forward. These powerful new tools not only help us to accurately pinpoint clinically relevant genetic variants in individual patients, but are also allowing us to learn more about the mechanisms that drive childhood cancer, paving the way for the development of new targeted therapies.”
Introme and associated resources are freely available to clinicians and researchers online here.
Media Contact
Tuhina Pandey
tpandey@ccia.org.au
0452070757
