113. Optical Genome Mapping: Clinical validation and diagnostic utility for cytogenomic analysis of Hematological Neoplasms

Abstract

Hematological neoplasms are predominantly defined by chromosomal aberrations that includes structural variants (SVs) and copy number variations (CNVs). The current standard-of-care (SOC) methods [karyotyping, fluorescence in-situ hybridization (FISH), and chromosomal microarrays (CMA)] employed for the detection of SVs and CNVs are labor intensive, time and cost-prohibitive, and often does not reveal the genetic complexity of the tumor. Optical genome mapping (OGM) is an emerging technology that can detect all classes of SVs in a single assay. We report the results from our clinical validation (in a CLIA setting) of the OGM technique for hematological neoplasms. The study included 94 sample runs (including replicates) using 71 well characterized unique samples (61 hematological neoplasms and 10 controls). The analytical performance showed a sensitivity of 98.7%, specificity of 100%, accuracy of 98.7%, PPV of 100% and NPV of 98%, that included the detection of 61 aneuploidies, 35 deletions, 28 translocations, 11 duplications/amplifications, 15 insertions/additional material not identified with karyotyping, 12 marker chromosomes, 1 each of ring chromosome, inversion and isochromosome. OGM showed high (robust) technical and analytical reproducibility with a limit of detection of 5% allele fraction for the variant classes evaluated in the study. In addition, OGM demonstrated higher resolution to refine breakpoints, identify the additional material, marker and ring chromosomes. This first CLIA validation report demonstrates the technical and analytical advantages of OGM compared to the current SOC methods used for chromosomal characterization, and we recommend OGM as a potential first-tier cytogenetic test for the evaluation of hematological neoplasms. Hematological neoplasms are predominantly defined by chromosomal aberrations that includes structural variants (SVs) and copy number variations (CNVs). The current standard-of-care (SOC) methods [karyotyping, fluorescence in-situ hybridization (FISH), and chromosomal microarrays (CMA)] employed for the detection of SVs and CNVs are labor intensive, time and cost-prohibitive, and often does not reveal the genetic complexity of the tumor. Optical genome mapping (OGM) is an emerging technology that can detect all classes of SVs in a single assay. We report the results from our clinical validation (in a CLIA setting) of the OGM technique for hematological neoplasms. The study included 94 sample runs (including replicates) using 71 well characterized unique samples (61 hematological neoplasms and 10 controls). The analytical performance showed a sensitivity of 98.7%, specificity of 100%, accuracy of 98.7%, PPV of 100% and NPV of 98%, that included the detection of 61 aneuploidies, 35 deletions, 28 translocations, 11 duplications/amplifications, 15 insertions/additional material not identified with karyotyping, 12 marker chromosomes, 1 each of ring chromosome, inversion and isochromosome. OGM showed high (robust) technical and analytical reproducibility with a limit of detection of 5% allele fraction for the variant classes evaluated in the study. In addition, OGM demonstrated higher resolution to refine breakpoints, identify the additional material, marker and ring chromosomes. This first CLIA validation report demonstrates the technical and analytical advantages of OGM compared to the current SOC methods used for chromosomal characterization, and we recommend OGM as a potential first-tier cytogenetic test for the evaluation of hematological neoplasms.