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

Abstract

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.

Keywords: cancer genetics; molecular aspects; molecular biology; paediatric clinical genetics & dysmorphology; paediatric oncology; protocols & guidelines.

Figure 1

Regional demographics of the PREDisposition In Childhood by Trio-based whole-genome sequencing (PREDICT) recruiting sites compared with the state of New South Wales (NSW) and the overall Australian population, according to the 2021 Australian census. (A) The age distribution of recruiting sites for PREDICT, in relation to NSW and Australia. (B) The top five ancestries of each recruiting site in PREDICT, in relation to NSW and Australia. Ancestry is self-reported and not mutually exclusive; each census respondent could select up to two ancestries.

Figure 2

Sequential stages in curation of variants and reporting. MDT, multidisciplinary team; MGCT, multidisciplinary cancer genetic team; MGT, multidisciplinary genomics team.

Figure 3

The research firewall concept for clinical-research separation in PREDisposition In Childhood by Trio-based whole-genome sequencing. Genomic, clinical and patient identity data proceed through the clinical domain, with variants curated and ultimately reported following expert review (left panel). Separately, deidentified clinical and genomic data are passed to the research domain (right panel), where broad-ranging research analyses are performed with no pathway to report. In exceptional circumstances, variants of potential clinical relevance identified in the research arm will be returned to a designated expert review panel comprising clinical and laboratory representatives. This review panel will assess the potential reportability of the variant, and if reporting is advised, the sample will be reidentified and details forwarded to the clinical arm for second review and potential reporting. MDT, multidisciplinary team.