Integrated germline and somatic molecular profiling to detect cancer predisposition has a high clinical impact in poor-prognosis paediatric cancer

Germline predisposition has a significant role in paediatric cancer. However, the optimal approach to identifying cancer-causing germline pathogenic variants (GPV) in children, and even the prevalence of GPV among children with cancer, remain unclear. Here we report our findings from a comprehensive survey of GPV in 496 children with poor-prognosis cancer. By integrating tumour and germline molecular profiling we identified GPV in 15.5% of patients, 48.1% of whom had not met clinical genetic testing criteria. Although the cancer type was outside the recognised phenotypic spectrum for 43.7% of reported GPV, 63.2% of these were clinically actionable for cancer risk. Integrated germline-tumour analysis increased the GPV detection rate by 8.5%, and informed germline interpretation in 14.3% of patients with GPV, highlighting the value of integrated analyses. Our findings establish the benefit of broad integrated tumour-germline screening, over targeted phenotype-driven testing, to detect GPV in children with poor prognosis cancers. ### Competing Interest Statement L.M.S.L has received advisory board fees from Bayer. D.S.Z. reports consulting/advisory board fees from Bayer, Astra Zeneca, Accendatech, Novartis, Day One, FivePhusion, Amgen, Alexion, and Norgine and research support from Accendatech. P.G.E. is recipient of a share in milestone and royalty payments paid to the Walter and Eliza Hall Institute of Medical Research for the development of venetoclax. The remaining authors have no conflicts of interest to declare. ### Funding Statement The Medical Research Future Fund, the Australian Brain Cancer Mission, the Minderoo Foundation's Collaborate Against Cancer Initiative and funds raised through the Zero Childhood Cancer Capacity Campaign, a joint initiative of the Children's Cancer Institute and the Sydney Children's Hospital Foundation, supported the national clinical trial and associated clinical and research personnel. Lions International and the Australian Lions Children's Cancer Research Foundation (ALCCRF) provided funding to perform whole genome sequencing and for key personnel. The Cure Brain Cancer Foundation supported RNA sequencing of patients with brain tumours; the Kids Cancer Project supported molecular profiling and molecular and clinical trial personnel; and the University of New South Wales, W. Peters, and the Australian Genomics Health Alliance for provided personnel funding support. Infrastructure and personnel were funded by grants from the Australian Federal Government Department of Health, the New South Wales Ministry of Health-funded Luminesce Alliance, the Australian Cancer Research Foundation, the Kinghorn Foundation, Tour de Cure, the Kids Cancer Alliance. M.J.C is supported by the Cancer Institute of New South Wales, Cancer Australia, and My Room. G.M.M and P.G.E are supported by the Steven Walter Children's Cancer Foundation and The Hyundai Help 4 Kids Foundation. M.P is supported by National Health and Medical Research Council Investigator Grant APP1176265. D.S.Z is supported by grants from the National Health and Medical Research Council (Synergy Grant #2019056, and Leadership Grant APP2017898) and Cancer Institute New South Wales Program Grant (TPG2037). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics approval for this research was granted by the Sydney Children's Hospitals Network Human Research Ethics Committee (LNR/14/SCH/497), the Hunter New England Human Research Ethics Committee of the Hunter New England Local Health District (17/02/015/4.06) and the New South Wales Human Research Ethics Committee (HREC/17/HNE/29). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All interim data produced in the present study are available upon reasonable request to the authors. Patient molecular data are available through application to the ZERO Data Access Committee, see https://www.zerochildhoodcancer.org.au/clinicians-researchers/for-researchers/data-and-sample-resources