Genes underpinning predisposition to childhood cancer

The genetic changes underpinning cancer predisposition in children are not clearly defined and warrant further research, as identification of a genetic contribution to a patient’s disease can be beneficial for patients and their families. With technological advances, it is now possible to discover a broad spectrum of genetic changes implicated in cancer predisposition by sequencing the genome. An analytical review of six publications utilising germline genome sequencing in paediatric oncology found that these studies differed in the selected childhood cancer diagnoses and the genes considered for interpretation, resulting in differences in the proportions of childhood cancer patients that were reported to carry clinically relevant pathogenic germline variants. In this study, childhood cancer patients that presented with phenotypes indicative of a genetic susceptibility to cancer, such as multiple cancer diagnoses, a family history of cancer and/or a genetic diagnosis, underwent germline exome sequencing. Sequencing data were analysed for rare germline variants in over 1000 cancer predisposition, cancer associated and DNA repair genes, that were predicted to cause a loss of function or to be deleterious. Almost one quarter of childhood cancer patients with features suggestive of a genetic predisposition to cancer were found to carry pathogenic or likely pathogenic germline variant/s in 12 known cancer predisposition genes. A rare variant burden analysis of 31 autosomal dominant cancer predisposition genes found that deleterious germline variants were significantly enriched in a cohort of 63 childhood cancer patients compared to a cohort of 1107 genetically matched healthy aged controls. Novel germline variants not previously associated with cancer predisposition were also detected in 10 genes in 16 childhood cancer patients. This study has expanded our understanding of cancer predisposition in children, by discovering the diagnostic potential of sequencing patients with defined phenotypic features, and by linking pathogenic or likely pathogenic germline variants in known predisposition genes with new cancer diagnoses. Ultimately, by combining the analysis of family pedigrees with functional gene studies and data-sharing, the significance of novel germline variants associated with the onset of cancer in childhood will be established. As more childhood cancer predisposition genes are identified and characterised, screening processes may be more routinely incorporated into paediatric clinical care

Protocol for a comprehensive prospective cohort study of trio-based whole-genome sequencing for underlying cancer predisposition in paediatric and adolescent patients newly diagnosed with cancer: the PREDICT study

Introduction Identifying an underlying germline cancer predisposition (CP) in a child with cancer has potentially significant implications for both the child and biological relatives. Cohort studies indicate that 10%–15% of paediatric cancer patients carry germline pathogenic or likely pathogenic variants in cancer predisposition genes, but many of these patients do not meet current clinical criteria for genetic testing. This suggests broad tumour agnostic germline testing may benefit paediatric cancer patients. However, the utility and psychosocial impact of this approach remain unknown. We hypothesise that an approach involving trio whole-genome germline sequencing (trio WGS) will identify children and families with an underlying CP in a timely fashion, that the trio design will streamline cancer risk counselling to at-risk relatives if CP was inherited, and that trio testing will not have a negative psychosocial impact on families.Method and analysis To test this, we present the Cancer PREDisposition In Childhood by Trio sequencing study (PREDICT). This study will assess the clinical utility of trio WGS to identify CP in unselected patients with cancer 21 years or younger in New South Wales, Australia. PREDICT will perform analysis of biological parents to determine heritability and will examine the psychosocial impact of this trio sequencing approach. PREDICT also includes a broad genomics research programme to identify new candidate genes associated with childhood cancer risk.Ethics and dissemination By evaluating the feasibility, utility and psychosocial impact of trio WGS to identify CP in paediatric cancer, PREDICT will inform how such comprehensive testing can be incorporated into a standard of care at diagnosis for all childhood cancer patients.Trial registration number NCT04903782