Target-enhanced whole-genome sequencing (TE-WGS) shows clinical validity equivalent to commercially available targeted oncology panel

Cancer poses a significant global health challenge, with increasing incidence rates demanding precise genomic testing for individualized treatment strategies. Targeted-panel sequencing (TPS) has improved personalized oncology but often lacks comprehensive coverage of crucial cancer alterations. Whole-genome sequencing (WGS) addresses this gap, offering extensive genomic testing. This study demonstrates the potential medical application of WGS. Methods This study evaluates the power of target-enhanced WGS (TE-WGS), a clinical-grade WGS method sequencing both cancer and matched normal tissues. A cohort of forty-nine patients with various solid cancer types underwent both TE-WGS and TruSight Oncology 500 (TSO500), one of the mainstream TPS approaches currently used in the clinic. Results TE-WGS methods detected all the variants reported from TSO500 (100%, 498/498). A high correlation in the detection of variant allele fractions (VAF) was observed between the TE-WGS and TSO500 methodologies (r=0.977). Notably, within the pool of 498 variants commonly detected by both approaches, 223 variants (44.8%) were discerned within peripheral blood samples exclusively through the TE-WGS technique, suggesting their presence as constitutional variants inherent to the germline. Conversely, the remaining subset of 275 variants (55.2%) were not detected in peripheral blood using the TE-WGS method, signifying them as bona fide somatic variants. Further, TE-WGS provided accurate copy number profiles, fusion-genes, MSI- and homologous-recombination deficiency (HRD) scores, which were essential for clinical decision making. Conclusion TE-WGS proves to be a comprehensive approach in personalized oncology, matching the key biomarker detection capabilities of the established TSO500 panel. Additionally, TE-WGS uniquely identifies germline variants and genomic instability markers, offering additional clinical actions. Its adaptability and cost-effectiveness further underscore its clinical utility, making TE-WGS a valuable tool in personalized cancer treatment. ### Competing Interest Statement M.K. currently holds a consultancy/advisory role for MSD and Genome Insight Inc., and M.K. has received grant/research funding from Genome Insight Inc. These affiliations may present potential conflicts of interest related to the submitted manuscript. ### Funding Statement This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (No. NRF-2022R1F1A1074910). This research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (HR22C1734, HI23C1589). ### 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: Institutional Review Board of Ajou University Hospital (AJOUIRB-SMP-2022-271) 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 data produced in the present study are available upon reasonable request to the authors.