A new Australian study has found that inherited cancer predisposition, or genetic cancer risk, is twice as prevalent in children with poor-prognosis cancers as routine clinical testing shows.
Published recently in the international journal, Clinical Cancer Research, the study’s findings have important implications for Australia’s current clinical genetic testing for cancer predisposition, and suggest that broad genetic screening of children with poor-prognosis cancers should be considered as a potential new standard of care.
For the study, 496 children with poor-prognosis cancer enrolled on the Zero Childhood Cancer Program (ZERO) — Australia’s national precision medicine program for children with cancer, jointly led by Children’s Cancer Institute and Kids Cancer Centre at Sydney Children’s Hospital, Randwick — had samples of normal tissue and tumour tissue genomically analysed.
By using in depth sequencing of the child’s germline DNA (the DNA they were born with) and tumour DNA, the researchers were able to identify a genetic cancer predisposition in one of every 6 children (15.5%) — half of which would have been missed using current clinical testing guidelines.
Germline pathogenic variants, or DNA changes, in cancer predisposition genes were found across all cancer types. Importantly, the findings were ‘clinically actionable’ in 63% of cases, meaning that they were relevant to the child’s clinical care, or the care of their at-risk relatives, and could impact management decisions.
According to Dr Noemi Fuentes-Bolanos, Paediatric Oncologist and Clinical Geneticist at Kids Cancer Centre, and co-lead author on the study, knowing if a child with cancer has an underlying genetic predisposition can play an important role in guiding their treatment, monitoring and long-term follow-up care.
“In this study, we generated an ultra-high resolution view of the heritable DNA in children with cancer by using whole genome sequencing,” she said. “Combining that with real-time information from the tumour itself allowed us to pinpoint certain genetic conditions with a level of accuracy we couldn’t achieve before.”
“Where a child is found to have a certain genetic variant that predisposes them to cancer, different therapies can increase the risk of unacceptable side effects and second cancers. Therefore, the diagnosis of genetic cancer risk in a child might help their doctor to adjust the intensity of anti-cancer therapies and provide a more personalised follow up plan once cancer treatment is completed.”
Detecting a genetic predisposition to cancer in a child can also have important implications for their family members, who may opt for genetic screening and counselling to help determine and manage their own risk.
“Among the most common questions parents ask when learning of their child’s cancer diagnosis are: why did this happen to my child, and is there a risk to my other children?” commented Eliza Courtney, Research Genetic Counsellor in the Genomic Childhood Cancer Risk Group at Children’s Cancer Institute, Senior Genetic Counsellor at Kids Cancer Centre, and co-lead author on the paper.
“Our findings help provide some answers for families, and more broadly how we might improve the approach to genetic testing in the clinical setting. The comprehensive paired tumour and germline data help us understand the contribution of genetic risk to cancer development, and guides genetic counselling for the family when making sense of the results.”
“What's particularly powerful, from my perspective, is the potential to intervene early with broader cancer surveillance in the child and their at-risk family members. This is the first step to improving outcomes for families living with genetic cancer risk.”
