Abstract

While genomic analysis of tumors has stimulated major advances in cancer diagnosis, prognosis and treatment, current methods fail to identify a large fraction of somatic structural variants in tumors. We have applied a combination of whole genome sequencing and optical genome mapping to a number of adult and pediatric leukemia samples, which revealed in each of these samples a large number of structural variants not recognizable by current tools of genomic analyses. We developed computational methods to determine which of those variants likely arose as somatic mutations. The method identified 97% of the structural variants previously reported by karyotype analysis of these samples and revealed an additional fivefold more such somatic rearrangements. The method identified on average tens of previously unrecognizable inversions and duplications and hundreds of previously unrecognizable insertions and deletions. These structural variants recurrently affected a number of leukemia associated genes as well as cancer driver genes not previously associated with leukemia and genes not previously associated with cancer. A number of variants only affected intergenic regions but caused cis-acting alterations in expression of neighboring genes. Analysis of TCGA data indicates that the status of several of the recurrently mutated genes identified in this study significantly affect survival of AML patients. Our results suggest that current genomic analysis methods fail to identify a majority of structural variants in leukemia samples and this lacunae may hamper diagnostic and prognostic efforts.