Optical Genome Mapping in Pediatric Hematologic Malignancies: High Diagnostic Yield and Unique Insights Across...

Hematologic neoplasms in pediatric patients have different genomic profiles compared with the same malignancies in adults, with copy number abnormalities (CNAs) and balanced structural variants (SVs) being the most prevalent types of oncogenic drivers. Consequently, we hypothesized that optical genome mapping (OGM), as a new method for genome-wide, high-resolution detection of CNAs and balanced SVs, could represent a powerful testing approach for pediatric leukemias. This study compared the performance of OGM in the detection of clinically significant variants with current standard-of-care (SOC) diagnostic methodologies, including karyotyping, fluorescence in situ hybridization (FISH), chromosomal microarray, and a custom pediatric next-generation sequencing panel, OncoKids. In a retrospective review of results from SOC genetic testing and OGM for 100 de novo or relapsed pediatric hematologic neoplasms, full concordance was observed in 71% of cases. A clinically significant finding (tier 1 or 2 based on the Association for Molecular Pathology/American Society of Clinical Oncology/College of American Pathologists guidelines) was missed by OGM in 7 cases, but in 22 cases, OGM identified additional tier 1 or 2 findings missed by SOC testing. The highest increase in diagnostic yield was noted in T-lymphoblastic leukemia/lymphoma (T-ALL), with nearly 40% (9/23) of T-ALL cases having additional tier 1 or 2 findings detected using OGM. The main advantage of OGM was the ability to detect cytogenetically cryptic, balanced rearrangements not targeted by routine FISH probes or OncoKids, whereas its main limitation was low resolution for identifying copy-neutral loss of heterozygosity. As a single assay, OGM detected the majority (92%) of clinically significant variants identified by the combined use of karyotyping, FISH, chromosomal microarray, and OncoKids, and revealed additional tier 1 or 2 variants missed by SOC testing in 22% of the cases. Our study shows that OGM represents a powerful assay for detection of CNAs and balanced SVs in pediatric hematologic neoplasms.