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Keywords: cancer; diagnostics; DNA sequencing; whole genome sequencing Biomarker; precision oncology Abstract The current increase in number and diversity of targeted anticancer agents poses challenges to the logistics and timeliness of molecular diagnostics (MolDx), resulting in underdiagnosis and treatment. Whole-genome sequencing (WGS) may provide a sustainable solution for addressing current as well as future diagnostic challenges. The present study therefore aimed to prospectively assess feasibility, validity, and value of WGS in routine clinical practice. WGS was conducted independently of, and in parallel with, standard of care (SOC) diagnostics on routinely obtained tumor samples from 1,200 consecutive patients with metastatic cancer. Results from both tests were compared and discussed in a dedicated tumor board. From 1,200 patients, 1,302 samples were obtained, of which 1,216 contained tumor cells. WGS was successful in 70% (854/1,216) of samples with a median turnaround time of 11days. Low tumor purity ( Article Note: Equal first authors. Co-senior authors. Conflict of interest statement: AL reports grants from BMS, MSD, AstraZeneca, and Boehringer, nonfinancial support from Merck Serono and Roche. HS and EC report consultancy fees and support for attending meetings and traveling from Illumina. EV is member of the supervisory board of Hartwig. GM is cofounder and a board member (CSO) of CRCbioscreen BV, he has a research collaboration with CZ Health Insurances (cash matching to ZonMW grant) and he has research collaborations with Exact Sciences, Sysmex, Sentinel Ch. SpA, Personal Genome Diagnostics (PGDX), DELFi; these companies provide materials, equipment, and/or sample/genomic analyses. GM is an Advisory Board member of 'Missie Tumor Onbekend.' KM reports research grants from AstraZeneca and speakers' fees from MSD, Roche, AstraZeneca. and Benecke. KM received consultancy fees from Pfizer, BMS, Roche, MSD, Abbvie, AstraZeneca, Diaceutics, Lilly, Bayer, Boehringer Ingelheim and nonfinancial support from Roche, Takeda, Pfizer, PGDx and DELFi. KS, LS, PR, LB, FL, EK, TB, IR, LS, DS, VN, JB, EB, JH, and LK report no conflicts of interest. CAPTION(S): Supplementary materials and methods Figure S1. Predefined workflow for resolving discordant results between WGS and SOC molecular diagnostics Figure S2. Optimizations of the workflow during the course of the study Figure S3. Feasibility of WGS on biopsies per localization Figure S4. Clinical value of prospective WGS: actionable events Figure S5. Clinical value of prospective WGS: number of therapy options per patient Figure S6 Clinical value of prospective WGS: therapy options Figure S7. Pathogenic germline variants with somatic loss Figure S8. Pathogenic germline variants per tumor type Figure S9. Pathogenic germline variants with therapy options Figure S10. Cascade strategy for molecular diagnostics Table S1. Genes for which pathogenic germlines were analyzed Table S2. NGS modified Ampliseq panel Table S3. Archer Fusionplex - Lung v1.0 Table S4. Archer Fusionplex - (Expanded) Sarcoma v2.0 Table S5. Information per WGS attempt Table S6. Additional variants detected by WGS Table S7. Clinical validity Table S8. Pathogenic germline variants detected by WGS Table S9. Correlation signatures in BRCA and Lynch patients Byline: Kris G Samsom, Luuk J Schipper, Paul Roepman, Linda JW Bosch, Ferry Lalezari, Elisabeth G Klompenhouwer, Adrianus J Langen, Tineke E Buffart, Immy Riethorst, Lieke Schoenmaker, Daoin Schout, Vincent Noort, Jose G Berg, Ewart Bruijn, Jacobus JM Hoeven, Hans Snellenberg, Lizet E Kolk, Edwin Cuppen, Emile E Voest, Gerrit A Meijer, Kim Monkhorst