Optical Genome Mapping: A Promising New Tool to Assess Genomic Complexity in Chronic Lymphocytic Leukemia (CLL)

Abstract

Novel treatments in chronic lymphocytic leukemia (CLL) have generated interest regarding the clinical impact of genomic complexity, currently assessed by chromosome banding analysis (CBA) and chromosomal microarray analysis (CMA). Optical genome mapping (OGM), a novel technique based on imaging of long DNA molecules labeled at specific sites, allows the identification of multiple cytogenetic abnormalities in a single test. We aimed to determine whether OGM is a suitable alternative to cytogenomic assessment in CLL, especially focused on genomic complexity. Cytogenomic OGM aberrations from 42 patients were compared with CBA, FISH, and CMA information. Clinical–biological characteristics and time to first treatment (TTFT) were analyzed according to the complexity detected by OGM. Globally, OGM identified 90.3% of the known alterations (279/309). Discordances were mainly found in (peri-)centromeric or telomeric regions or subclonal aberrations (<15–20%). OGM underscored additional abnormalities, providing novel structural information on known aberrations in 55% of patients. Regarding genomic complexity, the number of OGM abnormalities had better accuracy in predicting TTFT than current methods (C-index: 0.696, 0.602, 0.661 by OGM, CBA, and CMA, respectively). A cut-off of ≥10 alterations defined a complex OGM group (C-OGM, n = 12), which included 11/14 patients with ≥5 abnormalities by CBA/CMA and one patient with chromothripsis (Kappa index = 0.778; p < 0.001). Moreover, C-OGM displayed enrichment of TP53 abnormalities (58.3% vs. 3.3%, p < 0.001) and a significantly shorter TTFT (median: 2 vs. 43 months, p = 0.014). OGM is a robust technology for implementation in the routine management of CLL patients, although further studies are required to define standard genomic complexity criteria.

Optical Genome Mapping in Routine Cytogenetic Diagnosis of Acute Leukemia

“…It could be challenging, therefore, to count the number of reported abnormalities in each clone as described in ISCN and to unravel the clonal hierarchy. These limitations could be of critical importance in some other hematological malignancies like chronic lymphocytic leukemia [ 41 , 42 ]. However, the relevance of OGM counting of abnormalities should be confirmed by further studies.…”

Optical Genome Mapping for Cytogenetic Diagnostics in AML

“…They analyzed 42 patients, reaching a 90% concordance rate with standard diagnostics (CBA, FISH, and CMA) and additional information in 55% of patients. Furthermore, they showed that the classification of patients according to the obtained OGM results was more precise in predicting the time to first treatment compared to standard diagnostics, which is a clinically relevant prognostic marker in CLL [ 23 ].…”

TP53 Abnormalities Are Underlying the Poor Outcome Associated with Chromothripsis in Chronic Lymphocytic Leukemia Patients with Complex Karyotype

“…Thirty patients with cth and the control cohort were selected from a previous work from our group [ 15 ]. The three additional cases with chromothripsis were identified in another study from our group [ 39 ].…”