Abstract 3492: Comprehensive analysis of hematological malignancies with optical genome mapping and Bionano VIA™Software

Abstract The current standard for analysis of samples with suspected hematological cancer is karyotyping, fluorescence in situ hybridization (FISH), and/or chromosomal microarray (CMA). However, these methods have several limitations for the detection of structural variants (SVs) or copy number variants (CNV) that are smaller than 5 Mbp (karyotyping). Additionally, they are limited in their ability to detect low allele fraction (LAF) events and cannot detect the absence of heterozygosity (AOH) or the loss of heterozygosity (AOH/LOH - FISH and karyotyping). Optical genome mapping (OGM) from Bionano can enable accurate detection of SV and CNV events of sizes down to 5 kbp, with high sensitivity to detect LAF events down to 5% variant allele fraction. Bionano’s VIA™ software provides visualization and analysis support for OGM SV events including an improved Circos plot and ideogram for whole genome review. VIA incorporates CNV calling from OGM data using the SNP-FASST3 algorithm which also allows for accurate copy number calling at allele fractions as low as 10%. CNV detection performance was evaluated using 280 CNV events ranging in size from 175 kbp to 8 Mbp on the 22 autosomal chromosomes. Sensitivity and PPV were calculated for each size range separately. Using SNP-FASST3, VIA also adds the ability to detect AOH/LOH events from OGM data. By analyzing locations where known SNPs disrupt the specific nucleotide sequence motif used by the DLE-1 labeling enzyme, a B-allele frequency can be calculated and enable AOH/LOH detection at low allelic fractions. AOH/LOH performance using SNP-FASST3 was evaluated using a cohort of constitutional and cancer samples analyzed with orthogonal methods as well as with simulated events. Sensitivity for 20-25 Mbp AOH events was 92% with PPV greater than 90% at 25% aberrant cell fraction. The VIA 7. 0 release also includes the ability to create a customizable decision tree using supplied reference annotation files for CNV, AOH and SV event pre-classification. VIA resources include a panel of target variants derived from various medical societies for clinical analysis guidelines specific to Acute Myeloid Leukemia (AML), Myelodysplastic Syndrome (MDS) and an aggregation of all hematological malignancy guidelines (pan-heme). These methods, combined with tools for expert review and reclassification of variants, allow users to conduct whole genome interpretation and report results. These new features in VIA provide a streamlined workflow for analyzing heterogeneous hematological cancer samples and demonstrate the analytical performance of updated approaches for detection of CNV and AOH/LOH regions at low allele fractions using optical genome mapping alone. Citation Format: Jacob Wisotsky, Aliz Raski, Westley Sherman, Megan Roytman, Samer Al-Saffar, Jen Hauenstein, Andy Wing Chun Pang, Viren Wasnikar, Neil Miller. Comprehensive analysis of hematological malignancies with optical genome mapping and Bionano VIA™Software abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 3492.