Enabling whole genome sequencing analysis from FFPE specimens in clinical oncology

Dylan Domenico, Gunes Gundem, Max F. Levine, Juan Esteban Arango-Ossa, Pauline Robbe, Georgios Asimomitis, Cassidy Cobbs, Emily Stockfisch, Tara O’Donohue, Charlotte Brierley, Janine Senz, Dawn Cochrane, Neeman Mohibullah, Umesh Bhanot, Joachim Silber, Neerav Shukla, Sohrab P. Shah, Britta Weigelt, Oliver Zivanovic, Andrew McPherson, Anna Schuh, Andrew L. Kung and Elli Papaemmanuil ()
Additional contact information
Dylan Domenico: Memorial Sloan Kettering Cancer Center, Department of Pediatrics
Gunes Gundem: Memorial Sloan Kettering Cancer Center, Department of Pediatrics
Max F. Levine: Memorial Sloan Kettering Cancer Center, Department of Pediatrics
Juan Esteban Arango-Ossa: Memorial Sloan Kettering Cancer Center, Department of Pediatrics
Pauline Robbe: RIKEN Center for Integrative Medical Sciences
Georgios Asimomitis: Memorial Sloan Kettering Cancer Center, Department of Pediatrics
Cassidy Cobbs: Memorial Sloan Kettering Cancer Center, Integrated Genomics Operation Core, Center for Molecular Oncology
Emily Stockfisch: Memorial Sloan Kettering Cancer Center, Department of Pediatrics
Tara O’Donohue: Memorial Sloan Kettering Cancer Center, Department of Pediatrics
Charlotte Brierley: University of Oxford, Medical Research Council Weatherall Institute of Molecular Medicine
Janine Senz: BC Cancer, Department of Molecular Oncology
Dawn Cochrane: BC Cancer, Department of Molecular Oncology
Neeman Mohibullah: Memorial Sloan Kettering Cancer Center, Integrated Genomics Operation Core, Center for Molecular Oncology
Umesh Bhanot: Memorial Sloan Kettering Cancer Center, Department of Pathology and Laboratory Medicine
Joachim Silber: Memorial Sloan Kettering Cancer Center, Department of Pathology and Laboratory Medicine
Neerav Shukla: Memorial Sloan Kettering Cancer Center, Department of Pediatrics
Sohrab P. Shah: Memorial Sloan Kettering Cancer Center, Halvorsen Center for Computational Oncology
Britta Weigelt: Memorial Sloan Kettering Cancer Center, Department of Pathology and Laboratory Medicine
Oliver Zivanovic: Memorial Sloan Kettering Cancer Center, Gynecology Service, Department of Surgery
Andrew McPherson: Memorial Sloan Kettering Cancer Center, Halvorsen Center for Computational Oncology
Anna Schuh: University of Oxford, Oxford Molecular Diagnostics Centre, Radcliffe Department of Medicine
Andrew L. Kung: Memorial Sloan Kettering Cancer Center, Department of Pediatrics
Elli Papaemmanuil: Memorial Sloan Kettering Cancer Center, Department of Pediatrics

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract The adoption of whole genome sequencing (WGS) in clinical oncology is challenged by low data quality and increased artifacts in standard-of-care formalin-fixed paraffin-embedded (FFPE) samples. Analysis of 56 fresh frozen (FF) and FFPE matched pairs demonstrates that FFPE processing results in a median 20-fold enrichment in artifactual calls across mutation classes and impairs detection of clinically relevant biomarkers such as homologous recombination deficiency (HRD). We demonstrate that implementation of consensus calling reduces artifactual structural variant (SV) calls by 98% but is not sufficient in mitigating artifactual calls for single nucleotide variants (SNVs) and indels as compared to FF data. We develop FFPErase, a machine learning framework that filters SNV/indel artifacts and delivers clinical grade variant reporting allowing accurate quantification of clinically relevant biomarkers. Comparison of FFPErase WGS calls to clinical reporting by FDA-approved panel tests demonstrates 99% sensitivity and enables reporting of 24% more clinically relevant findings.

Date: 2025
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DOI: 10.1038/s41467-025-65654-7

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