Detection of structural DNA variants in medulloblastomas using optical genome mapping.

Medulloblastoma (MB) is the most common malignant brain tumor in children that is subdivided into distinct MB groups characterized by specific genetic, epigenetic, and transcriptional profiles. In addition to single nucleotide variants, structural variants (SVs), including DNA deletions, duplications, focal gene amplifications, translocations and inversions, may contribute to MB pathogenesis. However, comprehensive profiling of SVs is challenging, as established cytogenetic methods such as karyotyping and fluorescence in situ hybridization (FISH) are limited by low resolution or restricted to detection of predefined SVs. Moreover, commonly used molecular diagnostic techniques like gene panel next-generation sequencing and microarray-based DNA copy number (CN) analysis may not reveal complex SVs. To more comprehensively characterize SVs in MB, we applied optical genome mapping (OGM) for genome-wide SV detection in 29 MB tissues and six MB cell lines. We found that OGM reliably detected genome-wide DNA CN changes in these samples, as validated by comparison to microarray-based DNA CN profiling. In addition, OGM allowed for the characterization of novel genomic alterations, including amplification and overexpression of the GPC5 gene on chr13q31.3 in a Group 3 MB tumor, as well as recurrent SVs affecting the NRXN1 gene on chr2p16.3 by deletion or translocation in subsets of MB Group 3 and 4 tumors. Taken together, our data indicate that OGM represents a promising approach for comprehensive profiling of SVs in pediatric brain tumors.