Abstract B011: Whole genome sequencing can reproduce all standard-of-care diagnostics for childhood cancer: Results from two national systems
Authors: Kennedy Jonathan , Leiter Sarah M. , Hodder Angus , Kan Sheng-Yuan , Bartram Jack , Barone Giuseppe , Gattens Michael , Murray Matthew J. , Behjati Sam , Tarpey Patrick , Cullen Matthew , Ceraulo Antony , Langenberg Karin , Molenaar Jan , Wessman Sandra , Abel Frida , Ljungman Gustaf , Giraud Geraldine , Blomstrand Hakon Anderson , Rohan Zdenek , Staffas Anna , Orsmark-Pietras Christina , Pandzic Tatjana , Golovleva Irina , Fogelstrand Linda , Abrahamsson Jonas , Norèn-Nyström Ulrika , Palle Josefine , Fioretos Thoas , Franco Lucia Cavelier , Barbany Gisela , Corradini Nadège , Schleirmacher Gudrun , Rosenquist Richard , Gisselsson David , Vedi Aditi 
Published: September 2024

Abstract
BACKGROUND Whole genome sequencing (WGS) is the most informative singular molecular assay in cancer diagnosis. Recent evidence demonstrates that WGS can add diagnostic information and change the management of childhood cancer, and thus is being increasingly employed in clinical settings globally. However, it remains unknown whether WGS can accurately recapitulate existing multi-assay standard-of-care (SOC) genomic testing used in pediatric cancer diagnostics. In this study we evaluate the concordance between WGS and SOC findings from an unselected cohort of children across 8 centres from two healthcare systems (England and Sweden) that offer routine WGS. METHODS We compared WGS and SOC genomic test reports for children under 18 years presenting with new or relapsed cancer between January 2021 and November 2023 across 2 English centres; Cambridge University Hospital and Great Ormond Street Hospital, and 6 Swedish centres; Gothenburg, Karolinska, Linköping, Lund, Umeå and Uppsala. Only WGS findings reported to clinicians were evaluated, without re-analysis of genomes. Tests were described as ‘concordant’ where WGS and SOC were in complete concordance (positive or negative) for all SOC-detected variants. Discordance described occasions where SOC detected findings not identified by WGS. ‘Additional findings’ described cases where WGS provided disease-relevant findings above SOC testing. Only disease-relevant variants were considered in the analysis. RESULTS A cohort of 1032 patients with 1841 SOC molecular tests was included – 436 with haematological malignancies and 596 with solid tumor malignancies (528 from England, and 504 from Sweden). WGS recapitulated 99.3% of SOC tests performed, across all types of genomic alteration (1829/1841). Of the 12 instances of discordance, 3 related to poor WGS sample purity, 5 were gene fusions, 1 low variant allele frequency (0.02) internal tandem duplication, 2 single nucleotide variants and 1 copy-number aberration. WGS provided additional disease relevant findings in 19.7% of cases (203/1032). DISCUSSION Deployment of available SOC genomic testing for cancer diagnostics is highly variable across nations, individual centres and disease entities, and is usually dictated by test availability, cost and likely clinical yield, in a non-agnostic manner. For the first time we demonstrate, across two national systems, that WGS faithfully recapitulates the vast majority of SOC findings irrespective of mutation class, cancer type and variant calling algorithm. Sample quality and intra-tumoral heterogeneity likely account for the few discrepancies observed. Barriers to implementation of routine WGS as the only molecular diagnostic assay for pediatric cancer are cost, analytical expertise, and turnaround time (TAT). Our group is systematically studying the health economic benefits of WGS as a single assay to replace all SOC testing. Finally, an ongoing collaborative project aimed at reducing TAT to under 48 hours using novel technology has demonstrated feasibility in a small number of patients to date.
Citation Format: Jonathan Kennedy, Sarah M. Leiter, Angus Hodder, Sheng-Yuan Kan, Jack Bartram, Giuseppe Barone, Michael Gattens, Matthew J. Murray, Sam Behjati, Patrick Tarpey, Matthew Cullen, Antony Ceraulo, Karin Langenberg, Jan Molenaar, Sandra Wessman, Frida Abel, Gustaf Ljungman, Geraldine Giraud, Hakon Anderson Blomstrand, Zdenek Rohan, Anna Staffas, Christina Orsmark-Pietras, Tatjana Pandzic, Irina Golovleva, Linda Fogelstrand, Jonas Abrahamsson, Ulrika Norèn-Nyström, Josefine Palle, Thoas Fioretos, Lucia Cavelier Franco, Gisela Barbany, Nadège Corradini, Gudrun Schleirmacher, Richard Rosenquist, David Gisselsson, Aditi Vedi. Whole genome sequencing can reproduce all standard-of-care diagnostics for childhood cancer: Results from two national systems [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 B011.