Optical genome mapping in acute myeloid leukemia: a multicenter evaluation

Abstract

Detection of hallmark genomic aberrations in acute myeloid leukemia (AML) is essential for diagnostic subtyping, prognosis and patient management. However, cytogenetic/cytogenomic techniques used to identify those aberrations, such as karyotyping, fluorescence in situ hybridization (FISH) or chromosomal microarray analysis (CMA), are limited by the need for skilled personnel as well as significant time, cost and labor. Optical genome mapping (OGM) provides in a single, cost-effective assay significantly higher resolution than karyotyping with comprehensive genome-wide analysis comparable to CMA and the added unique ability to detect balanced structural variants (SVs). Here, we report in a real-world setting the performance of OGM in a cohort of 100 AML cases, which were previously characterized by karyotype alone or karyotype and FISH or CMA. OGM identified all clinically relevant SVs and copy number variants (CNVs) reported by these standard cytogenetic methods when representative clones were present in >5% allelic fraction. Importantly, OGM identified clinically relevant information in 13% of cases that had been missed by the routine methods. Three cases reported with normal karyotypes were shown to have cryptic translocations involving gene fusions. In 4% of cases, OGM findings would have altered recommended clinical management and in an additional 8%, OGM would have rendered the cases potentially eligible for clinical trials. The results from this multi-institutional study indicate that OGM effectively recovers clinically relevant SVs and CNVs found by standard of care methods and reveals additional SVs not reported. Furthermore, OGM minimizes the need for labor-intensive multiple cytogenetic tests while concomitantly maximizing diagnostic detection through a standardized workflow.

Multisite Study of Optical Genome Mapping of Retrospective and Prospective Constitutional Disorder Cohorts

“…To address this important barrier, two of the senior authors (from Augusta University and Praxis Genomics) on this study have gone through the process of LDT (laboratory developed test) validation and implementation of OGM and obtaining a proprietary laboratory analyte (PLA) code from the American Medical Association (AMA) for CPT™ coding and pricing determination on the Clinical Laboratory Fee Schedule (CLFS) from the Centers for Medicaid and Medicare Services (CMS) (constitutional PLA codes: 0260U, 0264U, 0265U, and oncology PLA codes: 0299U, 0300U, 0331U). Not only is the increase in diagnostic yield by OGM demonstrated in the constitutional setting, but similar increases have been reported by multiple investigators in the heme-onc setting 45,47,48 .…”

“…This challenge has become acute during and after the COVID-19 pandemic affecting turnaround time and workflow efficiencies. Multiple reports demonstrate that OGM can be seamlessly implemented in a routine lab workflow without the need of specialized training for SV detection (as compared to legacy methods) and the end-to-end solution of this assay including the software for data analysis allows for the uniform assessment and interpretation of disease associated structural variants 15,44,45,47,48 . As shown earlier, board certified laboratory directors, geneticists or pathologists performed the final director review in this study thereby demonstrating the effective value of OGM to be used in the detection of structural variants potentially causative of rare diseases 18 .…”

Optical Genome Mapping for Cytogenetic Diagnostics in AML

“…In 13% of samples, additional information could be detected by OGM. In 12% of cases, the information gained by OGM led to changes in classification and hence therapeutic decision making [ 30 ].…”

Optical Genome Mapping Reveals and Characterizes Recurrent Aberrations and New Fusion Genes in Adult ALL

“…The previous karyotyping result in patient 8 was 45,X,-Y [ 11 ]/46,XY [ 14 ], indicating the loss of chromosome Y. OGM revealed a large CN loss of about 22 Mbp on chromosome 20q as well as translocation SVs between chromosomes 20 and Y (VAF 0.07–0.21), redefining the karyotyping result as a rearrangement between chromosomes Y and 20. This OGM result adds additional structural information, suggesting that in fact chromosome 20q instead of Y material is lost.…”

“…In contrast, optical genome mapping (OGM) allows a genome-wide approach with a resolution of up to 500 bp depending on the analysis settings for somatic aberrations or germline variants, respectively. The benefit of OGM analysis was studied in patients with acute myeloid leukemia (AML) before [ 11 , 12 , 13 , 14 , 15 ]: It enables a genome-wide analysis in one single workflow without the necessity to preselect target regions to be analyzed by multiple FISH probes or RT-PCR assays. In addition, OGM analysis was already performed in a few studies examining ALL patients: Lestringant et al compared OGM with a combination of conventional methods in 7 pediatric and 3 adult ALL patients.…”