Optical Genome Mapping and Comprehensive Next Generation Sequencing Panel for Myeloid Cancers: New Era of Complimentary Profiling

The standard-of-care (SOC) for genomic testing of myeloid cancers primarily relies on karyotyping/ fluorescent in situ hybridization (FISH) (cytogenetic analysis) and targeted gene panels (≤54 genes) that harbor hotspot pathogenic variants (molecular genetic analysis). Both cytogenetic and molecular testing workup is necessary for the identification and detection of large structural variants (SVs), single nucleotide variants (SNV), and indels. Despite this combinatorial approach, ~50% of myeloid cancer genomes remain cytogenetically normal, and the limited sequencing variant profiles obtained from targeted panels are unable to resolve the genetic etiology of these myeloid tumors.

In this study, we evaluated the performance and clinical utility of optical genome mapping (OGM) by comparison to SOC methods (karyotype and FISH) in 50 myeloid samples, and comparison of a 523-gene next-generation sequencing (NGS) panel with a 54-gene targeted panel in 140 cases. Additionally, we evaluate the utility of combined analysis with OGM and 523-gene NGS panels in a subset of 31 cases.

OGM and the 523-gene NGS panel were found to have an analytical concordance of 100% with karyotyping, FISH, and the 54-gene panel, respectively. In the cytogenetic analysis, OGM detected cytogenetic aberrations in 40% (4/10) cases that were negative with karyotyping and FISH. In the molecular analysis, the 523-gene NGS panel detected additional clinically relevant SNVs in 19% of cases. The combined analysis with OGM and 523-gene NGS panel detected clinically relevant compound heterozygous events in 19% of cases.

This study demonstrates the higher sensitivity, resolution, accuracy, and ability to reveal cryptic and clinically relevant novel variants in myeloid cancers as compared to SOC methodologies. This cost-effective approach of using OGM and a 523-gene NGS panel for comprehensive genomic profiling of myeloid cancers will not only increase the yield of actionable targets leading to improved clinical outcomes but also help resolve our ongoing conundrum of apparently genomically normal myeloid cancers by providing more answers.

Kolhe:Cepheid: Honoraria; PGDx: Honoraria, Research Funding; Agena: Honoraria, Research Funding; Qiagen: Honoraria, Research Funding; Bioanano INc: Honoraria, Research Funding, Speakers Bureau; Illumina: Research Funding; Perkin Elmer: Honoraria, Research Funding.