Childhood cancer is the leading cause of disease related death in the western world. In Australia, there are 950 newly diagnosed children, adolescents and young adults diagnosed with cancer each year. 150 of these have high-risk cancers with <30% chance of surviving 5 years. The Kid’s Cancer Centre and Children’s Cancer Institute established the Zero Childhood Cancer Program in 2015, which applies a comprehensive molecular profiling approach to diagnose, identify treatment options and inherited cancer predisposition syndromes in children with high-risk cancer, from around Australia. Deep whole genome sequencing (100x depth) of the tumour and germline (35x depth), with RNA-sequencing and methylation profiling is performed in real-time, analysed, interpreted, discussed in a molecular tumour board and a report is returned with a median time of 6 weeks from enrolment. To date, >90% of children receive a diagnosis, >70% receive a targeted treatment recommendation, and of the children who receive the recommended treatment, >70% had an objective response (Wong et al, 2020). From 2023, ZERO2 will expand to all children adolescents and young adults with newly diagnosed cancers, and at relapse or progression. We aim to determine the utility of a comprehensive precision medicine in all childhood cancer subtypes.
To deliver ZERO at national scale, we have developed a suite of analysis tools including pipelines, curation and reporting tools, a knowledgebase, and data sharing portals. Precision medicine demands the accurate identification all the clinically relevant inherited and acquired mutations in each child’s cancer, including single nucleotide variants, short indels and structural variants (SVs), which include copy number alterations (CNVs), translocations, inversions and insertions. Many children’s cancers are driven by SVs, for which there are no best practice analytical approaches yet established. With collaborators at Hartwig Medical Foundation, we have developed and optimised tools for the accurate detection of CNV and SV from childhood cancers, including PURPLE, GRIDSS2 and LINX.
Here we will discuss insights from the ZERO program into the molecular genetics of childhood cancer, the impact of correctly identifying SVs and intragenic SVs in tumours, and the expansion of ZERO2.