The Clinical Utility of Optical Genome Mapping for the Assessment of Genomic Aberrations in Acute Lymphoblastic Leukemia

Abstract

Acute lymphoblastic leukemia (ALL) is the most prevalent type of cancer occurring in children. ALL is characterized by structural and numeric genomic aberrations that strongly correlate with prognosis and clinical outcome. Usually, a combination of cyto- and molecular genetic methods (karyotyping, array-CGH, FISH, RT-PCR, RNA-Seq) is needed to identify all aberrations relevant for risk stratification. We investigated the feasibility of optical genome mapping (OGM), a DNA-based method, to detect these aberrations in an all-in-one approach. As proof of principle, twelve pediatric ALL samples were analyzed by OGM, and results were validated by comparing OGM data to results obtained from routine diagnostics. All genomic aberrations including translocations (e.g., dic(9;12)), aneuploidies (e.g., high hyperdiploidy) and copy number variations (e.g., IKZF1, PAX5) known from other techniques were also detected by OGM. Moreover, OGM was superior to well-established techniques for resolution of the more complex structure of a translocation t(12;21) and had a higher sensitivity for detection of copy number alterations. Importantly, a new and unknown gene fusion of JAK2 and NPAT due to a translocation t(9;11) was detected. We demonstrate the feasibility of OGM to detect well-established as well as new putative prognostic markers in an all-in-one approach in ALL. We hope that these limited results will be confirmed with testing of more samples in the future.

Optimizing the diagnostic workflow for acute lymphoblastic leukemia by optical genome mapping

“…16,18 Following this finding the OGM analytical soft- this study. 16,18 Moreover, Lestringant et al also reported cross-contamination between samples, a problem we did not encounter. 16 Besides potentially missing important alterations, OGM sometimes also provides false-positive results.…”

“…This technology has already been applied to different cohorts of patients with hematological neoplasms with promising results. [15][16][17][18] Here, we examine the application of OGM for the genetic characterization of newly diagnosed ALL patients to determine whether this approach can eventually replace all, or part of, the current testing strategy. It is expected that OGM will not only lead to an improved detection rate of chromosome abnormalities but could also facilitate the identification of novel aberrations and contribute to the betterindividualized treatment of patients.…”

Optical genome mapping reveals additional prognostic information compared to conventional cytogenetics in AML/MDS patients

“…14,15 In a cohort of 12 pediatric ALL patients, Lühmann et al recently proved the feasibility of OGM in detecting relevant variants in ALL. 19 Preliminary OGM results for MDS and AML arising from MDS in 12 patients are available from Yang et al 16 In our study, bone marrow and peripheral blood samples from patients with AML and MDS with excessive blasts were analyzed by OGM. Routine analysis by karyotyping took place in parallel to OGM in order to assess the logistics and practicability of OGM as well as the concordance in this group of diseases.…”

“…[14][15][16][17] Recent analysis showed a high concordance of OGM results compared to other cytogenetic methods in hematological malignancy genomes 14,16 and ALL patients. 18,19 In our study we asked in a proof-of-principle design, whether OGM can replace conventional cytogenetic diagnostics and provides additional information with potential impact on treatment in a clinical setting. Overall, 27 cases of AML and MDS were analyzed by OGM parallel to standard diagnostic workup, including conventional karyotyping, molecular diagnostics, such as multiplex PCR assays and FISH for some cases.…”

“…Theoretically, OGM has the ability to yield the information obtained from a combination of karyotyping, FISH and microarrays in one diagnostic work up 14–17 . Recent analysis showed a high concordance of OGM results compared to other cytogenetic methods in hematological malignancy genomes 14,16 and ALL patients 18,19 …”