By probing the DNA of brain tumours, a Québec researcher is hoping to find a way to increase the survival rate of children suffering from aggressive forms of brain cancer.

In recent decades, medicine has been able to improve the survival rates for many types of cancer, but sadly, it remains powerless when it comes to brain cancer. This is especially true in children and young adults: their survivorship three years after diagnosis is not even 10% with certain particularly aggressive forms of the disease. In fact, it is the leading cause of death by cancer in people under the age of 20. Less malignant forms can be cured, but survivors are often left with severe and permanent brain damage caused by the life-saving therapies they received.

Heavily Guarded Tumours

Through her work in genomics, Nada Jabado, pediatric hemato-oncologist at the Montreal Children’s Hospital and researcher at the McGill University Health Centre Research Institute, has recently discovered why conventional chemotherapy and radiation therapy have no impact on the most lethal types of brain tumours, particularly in children. “My colleagues and I have identified two genetic mutations: one prevents healthy cells from replicating normally, the other protects cancer cells from the treatments we currently use,” she explained.

Dr. Jabado and her colleagues, Michael Taylor of SickKids Hospital in Toronto and Jacek Majewski of the Department of Human Genetics at McGill University, were the first to identify these two genetic mutations, which account for nearly 40% of glioblastomas in children, a particularly malignant form of brain tumour. They made another important discovery: pediatric and adult glioblastomas may look identical under the microscope, but the mechanisms that drive them are completely different. “It is clearer now why these tumours resist treatment in young patients,” added Dr. Jabado, who sees in this progress new targets for personalized therapies.

This is why the World Health Organization has recently decided to include in its classification of brain tumours the mutations identified by Dr. Jabado and her team. From now on, they will be used to determine the subgroups of aggressive tumours in order to predict their response to radiation and chemotherapy.

Dissecting Cancer Cells

When studying cancer cells, the researchers noted that these genetic mutations most likely occur during brain development and that they affect histones in particular. Histones are essential proteins that compact the long DNA molecule into the nucleus of each cell and, most importantly, orchestrate all the functions of the genome by interpreting both the genetic and epigenetic (the epigenome) code. The epigenome refers to a set of chemical changes, called epigenetic markers, that build up over time in response to lifestyle and environmental factors. The epigenetic markers affect how the genetic code is read by determining whether a gene is switched on or off. Any modification in the histones will alter the epigenome and how it is read. In the case of glioblastomas, Dr. Jabado and her team demonstrated that the histones affected by these mutations cause the growth, survival and spread of tumours. Since epigenetic markers can be repaired or even removed, Dr. Jabado believes that a sub-group of patients could benefit from a specific therapy targeting the epigenome.

The researchers are continuing their foray into brain tumours in order to increase the survival rate and quality of life of children and young adults. They have started analyzing the genome and epigenome of cancer cells for different categories of tumours to identify their specific characteristics in the hope of discovering their Achilles’ heel.

The end game? To find reliable indicators that would lead to the early detection of genetic mutations and weak points of brain tumours and start treatment before the disease has a chance to progress. Dr. Jabado and her team are working with clinicians, the families of children with cancer, bioethicists and health economists on finding in the DNA of cancer cells some targets that could respond to specific drugs. She hopes that one day any cancer diagnosis she gives will be accompanied by a favourable prognosis.

The Epigenome: Our Genome’s Orchestra Conductor

Think of the epigenome as the orchestra conductor and the histones as the musicians. They all play their scores, but instead of reading musical notes, they read the genetic code. Lifestyle and environmental factors, which mark our genes, leave temporary or permanent annotations on these scores, causing the orchestra to change the way the music is read. At times, some musicians may make a mistake when reading the score or the annotations (e.g., histones affected by a mutation) and the symphony played by the orchestra then becomes a cacophony.