Benefits for children with suspected cancer from routine whole-genome sequencing

Abstract

Clinical whole-genome sequencing (WGS) has been shown to deliver potential benefits to children with cancer and to alter treatment in high-risk patient groups. It remains unknown whether offering WGS to every child with suspected cancer can change patient management. We collected WGS variant calls and clinical and diagnostic information from 281 children (282 tumors) across two English units (n = 152 from a hematology center, n = 130 from a solid tumor center) where WGS had become a routine test. Our key finding was that variants uniquely attributable to WGS changed the management in ~7% (20 out of 282) of cases while providing additional disease-relevant findings, beyond standard-of-care molecular tests, in 108 instances for 83 (29%) cases. Furthermore, WGS faithfully reproduced every standard-of-care molecular test (n = 738) and revealed several previously unknown genomic features of childhood tumors. We show that WGS can be delivered as part of routine clinical care to children with suspected cancer and can change clinical management by delivering unexpected genomic insights. Our experience portrays WGS as a clinically impactful assay for routine practice, providing opportunities for assay consolidation and for delivery of molecularly informed patient care.

Fig. 1. Study recruitment.

a,b, Recruitment of patients was split by site and study phase (a) and by tumor type (b). The patients were recruited from two sites where WGS became routine. The octothorpe indicates that a low tumor cell fraction in Hodgkin’s disease precludes any somatic molecular test (be it SOC or WGS). The asterisks indicate that one patient (CUH_0034) underwent WGS twice: at diagnosis during the implementation phase and at relapse during the routine phase (Supplementary Table 1).

Fig. 2. NHS England WGS centralized workflow.

There are seven regional GLHs in England. Genomics England is a private company owned by the UK government, responsible for WGS, variant calling and annotation. GLH scientists pull this information from a centralized portal in the form of an automated WGS report (with pertinent variants stratified by potential actionability), interpreting results within their clinical context, before cases are brought to a GTAB. GTABs include, at a minimum, reporting scientists, clinical geneticists and treating clinicians. GTAB reports are made available as a part of patient notes, informing clinical practice. The asterisk indicates that DNA extraction is performed in GLHs and is submitted for centralized WGS via a centralized plating service located elsewhere. The dagger indicates that sequencing is carried out in a central facility to a depth of approximately 100× for tumors and 40× for germlines.

Fig. 3. WGS findings compared with SOC genomic test results, split by study site.

Each case shows which SOC tests were performed (green if successful, ‘X’ if failed). We highlight where tests should have been performed, or would have, had it not been for WGS (as defined in Extended Data Table 1). Where genomic findings provided disease-relevant information, we highlight cases where WGS matched SOC (blue) or provided additional information (yellow). There were no cases in which WGS did not match SOC. Definitions of benefit and numbers in each category can be found in Table 1. A full case-by-case breakdown of all SOC and WGS findings can be found in Extended Data Table 1. For mutation-specific IHC, the following three mutations were included: BRAF V600E, IDH1 R132H and H3F3A K27M. GCT, germ cell tumors.