Copy-Neutral Loss of Heterozygosity in Myelofibrosis: Parallel Evaluation with Optical Genome Mapping and...

Area of Science:

• Hematologic Malignancies
• Genomic Instability
• Diagnostic Technologies

Background:

• Myelofibrosis (MF) is a complex blood cancer with variable outcomes.
• Copy-neutral loss of heterozygosity (CN-LOH) is implicated in MF progression by increasing homozygosity of mutations.
• Single-nucleotide polymorphism (SNP) arrays are standard for CN-LOH detection, but Optical Genome Mapping (OGM) presents a potential alternative.

Purpose of the Study:

• To evaluate the efficacy of Optical Genome Mapping (OGM) in detecting copy-neutral loss of heterozygosity (CN-LOH) in myelofibrosis (MF) patients.
• To compare the performance of different OGM analysis pipelines (de novo, guided assembly, VIA software) against SNP arrays.

Main Methods:

• A multicenter study involving 78 MF patients.
• CN-LOH detection using OGM with de novo (DN) and guided assembly (GA) pipelines, followed by VIA software re-analysis.
• Validation of OGM results against gold-standard SNP arrays.

Main Results:

• The VIA software demonstrated the highest concordance (90%) with SNP arrays for CN-LOH detection, significantly outperforming DN (37%) and GA (45%).
• VIA maintained high concordance across all CN-LOH event sizes, while DN and GA showed better performance for larger events (≥25 Mb).
• VIA identified six CN-LOH events involving the JAK2 gene on chromosome 9p that were missed by DN and GA pipelines.

Conclusions:

• Optical Genome Mapping, particularly when analyzed with VIA software, is a sensitive and reliable method for detecting CN-LOH in myelofibrosis.
• The VIA pipeline shows superior performance in identifying CN-LOH events, including those missed by other OGM assembly methods.
• Orthogonal validation with methods like SNP arrays is still recommended for comprehensive confirmation of CN-LOH findings in MF.