WGS trio sequencing at diagnosis of cancer: adult and paediatric patients show different genomic cancer risks

Abstract

The genetic risk landscapes of adult and paediatric cancers are quantitatively and qualitatively different. Adult cancer is a common but sporadic phenomenon: fewer than 10% of adult cancer patients carry a cancer risk allele, predominantly in genes involved in DNA maintenance. In contrast, paediatric cancer is a rare disease in which germline cancer risk alleles are observed at a higher frequency and in a broader set of genes, including regulators of signalling and development. Beyond these general observations, much remains unknown about the link between germline genotype and paediatric cancer risk. To address this, we report a systematic whole genome analysis and clinical curation of over 1,000 paediatric cancer patients and their relatives, incorporating the TARGET, PRISM, and PREDICT studies. In an interim analysis, we find that over 18% of unselected childhood cancer patients carry reportable germline cancer risk alleles. We discuss this result and related work expanding gene cancer relationships, examining the diagnostic utility of familial sequencing, and leveraging the trio design to establish whether polygenic risk might also contribute to childhood cancer.