SickKids study demonstrates how comprehensive genetic sequencing informs a new standard of cancer care

In a first for Canadian precision oncology, a research team at The Hospital for Sick Children (SickKids) has led the largest genome sequencing study for Canadian paediatric cancer patients that changes the way clinicians, researchers and other care providers can work together to diagnose and treat rare tumours.

For young patients with rare, relapsed, metastatic or treatment-resistant cancers, survival rates are low with few, if any established effective treatment.

As part of the SickKids Cancer Sequencing program (KiCS), the study used next generation sequencing to deeply sequence over 860 cancer-associated genes. They also sequenced the complete genomes and transcriptomes, the complete set of both coding and non-coding RNAs of tissue, of 300 paediatric, adolescent and young adult patients with rare, relapsed and hard-to-cure cancers, using a novel machine learning algorithm.

In the findings published on December 30, 2022 in Nature Cancer, the sequencing identified at least one clinically actionable variant in 56 per cent of patients and variants targetable by specific treatments in 54 per cent of patients. Six per cent of variants were instrumental in changing or refining the diagnosis for patients in the study and had a direct impact on their treatment.

“Knowledge really is power,” says Dr. Anita Villani, lead author, co-Director of KiCS and the Cancer Genetics Program, Project Investigator in the SickKids Research Institute and Staff Oncologist in the Division of Haematology/Oncology. “The more data we have about these tumours, the more we are able to provide the most effective and individualized care possible for children with cancer, whether that means clarifying a diagnosis and starting a child on the correct care pathway, providing more treatment options for children with relapsed cancers, or identifying a predisposition which may inform care for their family.”

‘Cancer genomics is ready for primetime’

From the methods to the computational framework, every aspect of this project was developed, validated and analyzed at SickKids and led by Villani and the other KiCS co-Directors Drs. David Malkin and Adam Shlien, Senior Scientists in the Genetics & Genome Biology program. The study is a step forward toward achieving SickKids’ vision for Precision Child Health, a movement to provide individualized care for every patient and to ensure that every patient can engage in, and benefit from, research.

“Until now, the cancer care pipeline has been relatively siloed, but Precision Child Health is changing the way we practice medicine,” says Malkin, who holds the CIBC Children's Foundation Chair Child Health Research, co-leads the SickKids Precision Child Health Initiative and is co-Director of the Cancer Genetics Program. 

Each week, a SickKids Molecular Tumour Board brings together clinicians, analysts, genetic counsellors, geneticists, genomic scientists, bioinformaticians and other specialists to discuss specific paediatric cancer cases. This multidisciplinary group uses KiCS data to identify which treatments and therapies may be appropriate to consider for each patient, with patients involved from across Canada and around the world. To date, oncologists from over 30 hospitals worldwide have referred their patients to KiCS for genome analysis.

The meetings also inform new learnings for both research and clinicians, with the goal that cancer genomics should be a standard part of clinical care.

“Cancer genomics is ready for primetime,” says Shlien, who holds a Canada Research Chair in Childhood Cancer Genomics and is an Associate Director in the Department of Paediatric Laboratory Medicine. “Our research shows that full genome and transcriptome sequencing can support novel care strategies and should be available for everyone at the time of diagnosis.”

Collecting data throughout the cancer journey

For each participant, researchers took snapshots of the tumours over time and noted how those changes may impact a patient’s prognosis and trajectory of care. For children with relapsed cancers, for whom survival rates remain low, this information can inform the frequency of care and support new interventions.

“Tumour sequencing is usually done once during a patient’s cancer diagnosis, if at all,” says Shlien. “But we saw tumour genomes changing substantially over the course of the disease. Further sequencing can help us support the provision of treatment that is not only unique to each tumour type, but to each patient’s stage in the cancer journey."

Eventually, the team hopes to make conducting biopsies at multiple stages throughout a patient’s experience a standard part of care.

Learnings from the genomic data collected from patients in the study also had implications for family members and relatives. For the 17 per cent of patients who had previously undiagnosed variants in cancer predisposition genes, the sequencing allowed physicians to take the necessary steps to inform relatives and implement any tumour surveillance measures.

In the future, whole genome analysis may be used to identify individuals at risk for cancer and begin surveillance for tumour detection earlier, with the goal to eventually lead to better outcomes.

“These families are giving us a gift in allowing us to comprehensively sequence their tumours, and that gift will impact the health of future generations,” says Villani.

The KiCS program is supported by the Garron Family Cancer Centre through funding from SickKids Foundation, including key donors like CIBC. Additional support was provided by Alex’s Lemonade Stand Foundation for Childhood Cancer, Ontario Ministry of Research and Innovation, V Foundation, St. Baldrick’s Foundation Robert J. Arceci Innovation Award, and CureSearch for Children’s Cancer.