Signalling in high-risk paediatric cancers – Genomic insights driving therapeutic possibilities

Abstract

Comprehensive genomic analyses of paediatric cancers has driven a rapid expansion of knowledge about the molecular drivers in these high-risk malignancies. The National Zero Childhood Cancer (ZERO) program aims to assess the feasibility of a translating genomic analyses into clinical recommendations. ZERO combines whole genome and transcriptome sequencing, DNA methylation profiling for CNS tumours and sarcomas, and until recently, a cancer associated gene panel. Where possible, in vitro drug screening and patient-derived xenograft drug efficacy testing is attempted. Recommendations are made – tiered by the strength of supporting evidence – through a national Multidisciplinary Tumour Board. The ZERO national trial (PRISM) is open at all 8 paediatric cancer centres in Australia. An emerging theme is that the combination of WGS and RNA-Seq provide orthogonal data that facilitate the identification of oncogenic driver events beyond the capacity of either approach alone. This includes the curation of splice-site mutations, imbalance in the expression of mutant alleles, the consequences of copy-number aberrations. Another key theme of PRISM is that high-risk paediatric cancers harbour novel, suspected oncogenic drivers for which no biology is currently known. Modelling these events and the responses to therapy are a high priority for the ZERO program.