High-resolution detection of structural variants in cancer cell lines using electronic genome mapping Free

Introduction:

Structural variants (SVs) are often associated with adverse outcomes in hematologic malignancies, making reliable detection essential for risk stratification and treatment planning. Among these, deletions affecting the tumor suppressor gene TP53 are particularly notable, as they are associated with unfavorable clinical outcomes across a range of cancers, including leukemias. Similarly, gene fusions involving the promyelocytic leukemia (PML) and retinoic acid receptor alpha (RARA) genes, most notably the canonical PML::RARA fusion, are core determinants of acute promyelocytic leukemia (APL) and remain central to diagnosis and therapeutic decision-making. Despite their clinical significance, precise detection of SVs remains a major challenge. Existing methods often face trade-offs between resolution, sensitivity, scalability, and cost, limiting their ability to comprehensively characterize these aberrations in hematologic malignancies. In this study, we demonstrate the utility of the OhmX™ Platform, powered by electronic genome mapping (EGM), for detecting clinically relevant TP53 deletions and PML::RARA translocations in commercially available cancer cell lines.

Methods:

EGM, a solid-state nanochannel-based platform, was used to detect TP53 deletions and PML::RARA gene fusions in commercially available leukemia and cancer cell lines. Extracted DNA underwent simultaneous dual-enzyme nicking and labeling, followed by data acquisition on the OhmX Analyzer. SVs were explored using Human Chromosome Explorer™ de novo assembly and confirmed with SV-Verify™, a targeted, alignment-based variant detection application.

Results:

In this study, we applied EGM using the OhmX Platform to analyze two leukemia-derived cell lines (HL-60 and NB-4) and a non-small cell lung cancer (NSCLC) cell line (H1299) to demonstrate the detection of homozygous TP53 deletions ranging in size from approximately 3.8 kb to 87 kb, as well as a canonical reciprocal PML::RARA translocation. These results highlight the OhmX Platform's capacity to detect a diverse range of SVs across cancer models, demonstrating its utility in structural variant research.

Conclusion:

EGM enabled high-confidence mapping of homozygous TP53 deletions and a reciprocal PML::RARA translocation using a sequence-specific tagging strategy and an electronic detection system with approximately 300 bp resolution. The EGM-powered OhmX Platform demonstrates utility in translational cancer research through its ability to detect diverse classes of genomic aberrations that are often difficult to identify with other methods.