Optical Genome Mapping Reveals Novel Structural Variants in Pediatric Brain Tumors

Brain tumors are a leading cause of cancer-related mortality in children. Research shows that structural variants (SVs) play an important role in tumorigenesis and growth. However, most genetic studies have relied on short-read based exome/genome sequencing (SRS) that have limited ability to detect SVs. Optical genome mapping (OGM) utilizes ultra-long DNA molecules to construct and evaluate much longer genomic fragments, making it effective in identifying large SVs. We utilized OGM for the detection of novel clinically relevant SVs in pediatric brain tumors. Ultra high molecular weight DNA was extracted from a cohort of pediatric brain tumors and matched normal samples (n=50). OGM was performed using nanochannel chip arrays on a Saphyr instrument and SVs (large insertions/deletions, inversions, translocations) were identified. We then used nanotatoR to subclassify SVs into functional pathways and determined which genes impact specific cell developmental functions. Tumor-associated, low population frequency SVs were identified in all samples. The most common SV events were deletions and translocations. Nearly all samples had a SV that overlapped with a gene known to have clinical significance. CDKN2A/B deletions were most common in high grade tumors. OGM also detected clinically relevant, previously unknown fusions (i.e. NTRK2-KANK1, C11orf95-NCOA1 fusion) and deletions (NF1, ATRX) that may have affected therapeutic management. We also discovered novel SVs overlapping genes and miRNAs that could impact tumorigenesis. OGM effectively identifies novel clinically relevant SVs in pediatric brain tumor samples, including SVs that were not discovered other methods of testing. This is a promising new method to map the full SV spectrum of pediatric brain tumors. Future studies will expand testing to a larger cohort of samples to better understand the full spectrum of SVs and begin clinical analysis to determine the effect of SVs on response to treatment/prognosis.