Diagnostic and Prognostic/Therapeutic Significance of Comprehensive Analysis of Bone and Soft Tissue Tumors Using Optical Genome Mapping and Next-generation Sequencing

Detecting somatic structural variants (SVs), copy number variants (CNVs), and mutations in bone and soft tissue tumors is essential for accurately diagnosing, treating, and prognosticating outcomes. Optical genome mapping (OGM) holds promise to yield useful data on SVs and CNVs but requires fresh or snap-frozen tissue. This study aimed to evaluate the clinical utility of data from OGM compared to current standard-of-care cytogenetic testing. We evaluated 60 consecutive specimens from bone and soft tissue tumors using OGM and karyotyping, FISH, gene fusion assays, and deep next-generation sequencing (NGS). OGM accurately identified diagnostic SVs/CNVs previously detected by karyotyping and FISH (specificity=100%). OGM identified diagnostic and pathogenic SVs/CNVs (∼23% of cases) undetected by karyotyping (cryptic/submicroscopic). OGM allowed detection and further characterization of complex structural rearrangements including chromoanagenesis (27% of cases) and complex 3-6-way translocations (15% of cases). In addition to identifying 321 SVs and CNVs among cases with chromoanagenesis events, OGM identified approximately 9 SVs and 12 CNVs per sample. A combination of OGM and deep NGS data identified diagnostic and pathogenic SVs, CNVs, and mutations in ∼98% of cases. Our cohort contained the most extensive collection of bone and soft tissue tumors profiled by OGM. OGM had excellent concordance with standard-of-care cytogenetic testing, detecting and assigning high-resolution genome-wide genomic abnormalities with higher sensitivity than routine testing. This is the first and largest study to provide insights into the clinical utility of combined OGM and deep sequencing for the pathologic diagnosis and potential prognostication of bone and soft tissue tumors in routine clinical practice.