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

Abstract

Simple SummaryGenome complexity, detected by chromosome banding analysis or chromosomal microarray analysis, is a poor prognostic factor for chronic lymphocytic leukemia (CLL). Herein, we aimed to assess the performance of optical genome mapping (OGM) for the cytogenomic characterization of CLL patients, with a special focus on risk stratification based on genomic complexity. A cohort of 42 patients enriched in complex karyotypes was assessed by OGM, and the results were compared with those obtained from current methods. Moreover, clinical–biological characteristics and time to first treatment were analyzed according to the OGM-defined complexity. Globally, OGM identified 90% of the known alterations and provided novel structural information about these aberrations in 55% of patients. Regarding genomic complexity, OGM allowed us to identify a complex group (≥10 alterations) displaying enrichment of TP53 abnormalities and poorer evolution. Altogether, we confirmed that OGM is a valuable tool for the cytogenomic assessment and prognostic stratification of CLL patients.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.