Abstract B030: Whole genome sequencing provides practice-changing benefits when performed on consecutive, unselected children with suspected cancer
Authors: Hodder Angus , Leiter Sarah M. , Kennedy Jonathan , Addy Dilys , Ahmed Munaza , Ajithkumar Thankamma , Allinson Kieren , Ancliff Phil , Bailey Shivani , Barnard Gemma , Burke GA Amos , Burns Charlotte , Cano-Flanagan Julian , Chalker Jane , Coleman Nicholas , Cheng Danny , Clinch Yasmin , Dryden Caryl , Ghorashian Sara , Griffin Blanche , Horan Gail , Hubank Michael , May Phillippa , McDerra Joanna , Nagrecha Rajvi , Nicholson James , O'Connor David , Pavasovic Vesna , Quaegebeur Annelies , Rao Anupama , Roberts Thomas , Samarasinghe Sujith , Stasevich Iryna , Tadross John A. , Trayers Claire , Trotman Jamie , Vora Ajay , Watkins James , Chitty Lyn S , Bowdin Sarah , Armstrong Ruth , Murray Matthew J. , Hook Catherine E. , Tarpey Patrick , Vedi Aditi , Bartram Jack , Behjati Sam 
Published: September 2024

Background Whilst large scale paediatric whole genome sequencing (WGS) projects have been performed, these studies have been limited to children with high-risk disease, non-consecutive patients, and/or assessing potential benefits, rather than determining the actual impact on patient care. In England, where children with suspected cancer have universal access to WGS, we set out to assess the real-world impact of WGS on consecutive, unselected patients. Methods To assess this, we collected WGS reports, clinical and diagnostic information from children who presented to two large paediatric centres in England, where WGS became routine. We evaluated the overlap between standard of care (SOC) genetic tests and WGS, and the actual impact WGS results had on clinical practice, only counting those instances where findings were solely attributable to WGS. Results We studied 281 children (282 tumours), across 75 diagnoses – 130 solid malignancies (from Cambridge University Hospitals), and 152 haematological malignancies (from Great Ormond Street Hospital). Both centres performed extensive SOC tests, including targeted DNA and/or RNA sequencing panels on many diagnoses. Median turn-around time (TAT), from DNA availability to the release of Genomic England reports was 20.3 days (range 9-71). We found that consecutive WGS was feasible, and faithfully reproduced all 738 SOC genetic tests. Beyond this, in 108 instances for 83 (29%) children, WGS provided additional disease-relevant (diagnostic, risk-defining, mutation-target or germline) information. In 80 instances, from 69 (24%) cases, WGS provided direct clinical benefit above SOC. In 40 (14%) cases it provided accelerated genetic findings compared to SOC, leading to a modified or clarified diagnosis but without a substantive change to management. In 20 (7%) of cases WGS findings made children eligible for mutation-targeting medication during treatment/relapse. Our key finding was that in 20 (7%) cases, unique WGS findings directly changed the clinical care that children received. This was through the discovery of tumour findings that changed the diagnosis or risk category of patients and their management, or through unexpected germline findings that led to cascade testing and/or predisposition-directed therapy. ConclusionsOur study demonstrates that WGS can be delivered as part of routine clinical care to children with cancer and reproduces SOC genetic tests, providing opportunities for assay consolidation. Beyond this we evidence that WGS can provide clinical benefit, and in a substantial minority change the care children receive.

Citation Format: Angus Hodder, Sarah M. Leiter, Jonathan Kennedy, Dilys Addy, Munaza Ahmed, Thankamma Ajithkumar, Kieren Allinson, Phil Ancliff, Shivani Bailey, Gemma Barnard, GA Amos Burke, Charlotte Burns, Julian Cano-Flanagan, Jane Chalker, Nicholas Coleman, Danny Cheng, Yasmin Clinch, Caryl Dryden, Sara Ghorashian, Blanche Griffin, Gail Horan, Michael Hubank, Phillippa May, Joanna McDerra, Rajvi Nagrecha, James Nicholson, David O'Connor, Vesna Pavasovic, Annelies Quaegebeur, Anupama Rao, Thomas Roberts, Sujith Samarasinghe, Iryna Stasevich, John A. Tadross, Claire Trayers, Jamie Trotman, Ajay Vora, James Watkins, Lyn S Chitty, Sarah Bowdin, Ruth Armstrong, Matthew J. Murray, Catherine E. Hook, Patrick Tarpey, Aditi Vedi, Jack Bartram, Sam Behjati. Whole genome sequencing provides practice-changing benefits when performed on consecutive, unselected children with suspected cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pediatric Cancer Research; 2024 Sep 5-8; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl):Abstract nr B030.