Unlocking the code of rare diseases

DNA is the molecular code for all life on Earth.

The human genome is made up of approximately 25,000 protein-coding genes, and many more non-coding sequences that control the expression of these genes. The amount of information contained in our genome is so vast that our understanding of genetic determination is far from complete.

Dr. Bekim Sadikovic is an Associate Scientist with Lawson and Head of the Molecular Genetics Division at London Health Sciences Centre (LHSC). “Even though our knowledge has exploded in the last decade, we are just scratching the surface of what there is to know about our DNA,” he cautions. “We have the capability to sequence human genomes in a single day, but we are limited by our ability to interpret the clinical impact of this information.”

Many diseases and their potential therapies are studied at a population level. With a large number of people affected, discoveries and improvements are more likely. But what about diseases that are rare? Or those that have a high degree of variability among individuals? This is where genetic profiling can make a difference.

Paediatric oncology research

Approximately 20 per cent of children diagnosed with cancer do not respond positively to treatment. While many other areas of cancer research have made great progress, in the last three decades the needle has barely moved for our smallest and most vulnerable patients. Incidences of childhood cancer continue to go up.

Very few breakthroughs have been made impacting the treatment of childhood cancer, but it’s not for lack of trying. Existing drugs and their various combinations have been tested. Still, many children are not recovering.

Dr. Alexandra Zorzi is an Associate Scientist at Lawson and Chief of Paediatric Oncology at Children’s Hospital, LHSC. “I often tell families that I loathe statistics. We can cite that the cure rate of a particular cancer is 80 per cent, but in reality, there is only one child in front of us with their own story,” she shares.

Dr. Zorzi is part of a research network known as PROFYLE – Precision Oncology for Young People. PROFYLE is a Canadian initiative that brings together the country’s top scientists, clinicians and experts, all with a united goal of understanding childhood cancers, finding cures and improving outcomes for affected kids and their families. The initiative is supported by The Terry Fox Foundation and locally by the Fight Like Mason Foundation.

Jacob's Story

Jacob Seltzer was born in May 2018. His parents, Jennifer and Adam, felt everything was developing normally until a family member noticed a small bump on Jacob’s belly. It seemed like nothing to worry about, but they soon noticed that it was growing.

Jacob’s family physician referred them to Dr. Zorzi. After multiple tests, they were able to determine what was going on with the odd mark under the skin.

Jacob’s bump was the visible outward sign of a neuroblastoma – a type of cancer that develops from immature nerve cells, and is most commonly found in the adrenal gland near the kidneys. Inside, it was invading his bones, organs and bone marrow. He was only five months old.

Neuroblastomas in infancy typically respond well to conventional treatment. After Jacob started his treatment, Dr. Zorzi closely monitored the results of his physical exams, scans and tumour markers secreted in his urine. After four months, nothing was changing.

Dr. Zorzi knew this neuroblastoma was different.

Unlocking the genetic code of Jacob’s cancer helped Dr. Zorzi and her team find the key that would rewrite the story for Jacob and his family.

As a PROFYLE collaborator, Dr. Zorzi was able to send a sample to a lab in Toronto, where they sequenced the genome of the tumour. Now knowing the DNA profile of the tumour, experts were able to determine that he had a mutation in the gene that codes for anaplastic lymphoma kinase (ALK). This mutation causes cells to divide uncontrollably, resulting in cancer.

Precision and personalized medicine is now a reality, and many targeted drug therapies exist for multiple diseases. “It is bittersweet that paediatric cancers represent only one per cent of all cancer diagnoses in Ontario. Due to the rarity of these diseases, they do not receive the same attention or the same funding and drug development as, for example, adult lung cancer,” says Dr. Zorzi.

It turns out that the same ALK mutation is commonly found in the tumours of lung cancer patients, with a targeted medicine already developed for adults.

“By understanding the genomic landscape of Jacob’s tumour, we were able to make the case that this drug could help him and received compassionate access. We were cautious, because this drug has not been thoroughly tested in children. Given the alternatives we were facing, it was our best option,” explains Dr. Zorzi.

Today, Jacob’s lab tests show almost no trace of the cancer and his scans have normalized. “We feel so fortunate to have been assigned Dr. Zorzi as our doctor. She’s one of the best out there and she has connections to other experts. This research has changed our lives. Jacob can do normal things now, like visit with family and friends. Before, the risk of infection was too high,” says Jennifer.

Deintensifying cancer treatment

Dr. Anthony Nichols, a Lawson Scientist and Chief of Head and Neck Surgical Oncology at LHSC, focuses his research on improving outcomes for patients with head and neck cancer.

Head and neck squamous cell carcinoma (HNSCC) is the fifth most common cancer worldwide. The disease, as well as its treatment, has a profoundly negative impact on the patient’s quality of life due to physical disfigurement and difficulty speaking and swallowing.

Approximately 25 per cent of HNSCC cases are caused by oral infection with the human p apillomavirus (HPV) and tend to respond well to treatment. Most HPV-negative tumours are caused by smoking, but one thir d of these patients are non-smokers.

Dr. Nichols and his team conducted a genomic analysis of HPV-negative tumours to determine the connection between smoking and cancer recovery. They discovered that two genes, NSD1 and COL1A11, were more frequently mutated in heavy smokers. Surprisingly, they found that patients carrying the NSD1 mutation experienced significantly better outcomes when compared to those carrying the non-mutated gene. These findings were later validated in a cohort of patients at LHSC.

“Having the genetic profile of these tumours can help inform physicians on how their patient’s disease will respond to treatment, and in many cases a less intense cancer treatment can be used effectively,” says Dr. Nichols.

Beyond the genome

Part of Dr. Sadikovic’s research concentrates on diagnosing extremely rare, heritable diseases. Children with developmental delay are commonly referred to the Medical Genetics Program at LHSC for genome sequencing. The medical team must then attempt to determine which of the 25,000 genes is responsible for the condition.

For some, there are no genetic abnormalities detected.

Many people believe our genes determine our destiny, but there’s another layer, the epigenome, that controls the expression of our genes – whether a gene is turned on or off. The patterns of genes being turned off can now be tested, facilitating the diagnosis of previously unsolved cases of congenital abnormalities.

“Families may spend years going through repeated tests and exams, hoping for a diagnosis. This process is very hard on them and is costly for our health care system,” explains Dr. Sadikovic.

While there are still limited treatment options for many of these conditions, a diagnosis can help physicians better predict the course of the disease, allowing families to plan more accurately for the future.

“It is important for everyone to understand the other layers of life that contribute to the observable characteristics of our genes. It’s not about our particular collection of genes, it’s the different ways those genes are expressed and the environment we are exposed to.”