Structural Variant Analysis of Complex Karyotype Myelodysplastic Neoplasia Through Optical Genome Mapping.

Area of Science:

• Genomics
• Cancer Biology
• Medical Diagnostics

Background:

• Myelodysplastic neoplasia with complex karyotype (CK-MDS) presents diagnostic challenges and poor prognosis.
• Standard-of-care cytogenetic testing often provides ambiguous results for CK-MDS.
• Accurate detection of structural variants (SVs) is critical for MDS management.

Purpose of the Study:

• To evaluate the utility of optical genome mapping (OGM) for detecting structural variants (SVs) in CK-MDS.
• To compare OGM's performance against standard-of-care (SOC) cytogenetics.
• To discover novel SVs and their potential clinical relevance in CK-MDS.

Main Methods:

• Applied optical genome mapping (OGM) to 15 CK-MDS cases with existing SOC cytogenetic data.
• Analyzed 85 chromosomes with reported abnormalities by SOC.
• Utilized transcriptome sequencing to confirm novel gene fusions identified by OGM.

Main Results:

• OGM detected corresponding alterations for 86% of SOC-reported abnormalities, offering higher resolution.
• OGM revealed multiple SVs or chromoanagenesis in 64% of altered chromosomes.
• OGM identified novel SVs in 93% of cases, including previously unreported gene fusions and gene repositioning impacting TP53, MECOM, and others.

Conclusions:

• OGM significantly enhances the diagnostic analysis of SVs in CK-MDS.
• OGM provides a more comprehensive understanding of complex genomic alterations in MDS.
• OGM is a powerful tool for discovering novel SVs in complex cancer genomes.