A recent review in Cancers explores the growing role of optical genome mapping (OGM) in the genomic characterization of acute lymphoblastic leukemia (ALL), underscoring its utility as a high-resolution method for detecting structural variants (SVs), copy number variations (CNVs), and gene fusions. As the genomic landscape of ALL becomes increasingly central to risk stratification and treatment planning, OGM is emerging as a complementary tool to conventional cytogenetic and molecular assays.
ALL is a genetically heterogeneous malignancy characterized by diverse structural abnormalities that affect prognosis and guide therapy. Traditional methods—including karyotyping, fluorescence in situ hybridization (FISH), and polymerase chain reaction (PCR)—often fail to detect cryptic or complex rearrangements, particularly in cases with normal or uninformative karyotypes. OGM addresses these gaps by enabling direct visualization of ultra-high-molecular-weight DNA without the need for cell culture or amplification, thereby preserving native genomic architecture and minimizing diagnostic artifacts.
The review highlights several contexts in which OGM provides diagnostic advantages. In particular, it allows for high-resolution mapping of gene fusions relevant to risk stratification and therapeutic targeting, such as KMT2A rearrangements, IKZF1 deletions, and kinase fusions involving ABL1, PDGFRB, JAK2, and EPOR. In the case of intrachromosomal amplification of chromosome 21 (iAMP21), a high-risk pediatric B-ALL subtype, OGM has shown the ability to detect both the amplification and associated chromothripsis, which are difficult to characterize fully with conventional FISH.
OGM also facilitates the identification of novel and rare genomic rearrangements. The review describes several newly characterized gene fusions—such as TMEM272::KDM4B, WDFY2::ARID2, and OSBPL3::NRIP1—that may have biological or therapeutic relevance but are undetectable with standard testing. In some cases, OGM has provided structural resolution for complex translocations that previously lacked complete characterization, such as a three-way t(2;12;21) rearrangement involving ETV6 and RUNX1.
Despite these advantages, the authors note several limitations. OGM has reduced sensitivity in repetitive genomic regions, such as centromeres and pseudoautosomal areas, and cannot reliably detect certain events like Robertsonian translocations. It also performs less effectively in identifying structural variants in low-frequency subclones and cannot determine chromosomal ploidy with the accuracy of karyotyping. For example, masked hypodiploidy—an important adverse prognostic marker—may be misclassified by OGM due to its inability to distinguish between duplicated and homologous chromosomes.
Turnaround time is another consideration. While OGM can consolidate multiple tests into a single workflow, its longer processing time compared to FISH or PCR limits its use in urgent clinical scenarios, such as rapid initiation of tyrosine kinase inhibitors in BCR::ABL1-positive cases. As a result, the authors emphasize that OGM should be used in conjunction with, rather than as a replacement for, established diagnostic platforms.
When paired with next-generation sequencing (NGS), OGM enhances comprehensive genomic profiling. While NGS excels at detecting small variants and point mutations, OGM captures large-scale structural events, offering a more complete view of the leukemic genome. This integrated approach may support more informed clinical decisions, particularly in complex or high-risk subtypes of ALL.
Overall, the review positions OGM as a valuable adjunct in the evolving diagnostic landscape of ALL, particularly for uncovering cryptic structural variants and refining genomic risk models. Ongoing technological improvements and clinical validation are likely to expand its role in personalized leukemia care.