Predicting pathogenic non-coding SVs disrupting the 3D genome in 1646 whole cancer genomes using multiple instance learning

Abstract

Abstract Over the past years, large consortia have been established to fuel the sequencing of whole genomes of many cancer patients. Despite the increased abundance in tools to study the impact of SNVs, non-coding SVs have been largely ignored in these data. Here, we introduce svMIL2, an improved version of our Multiple Instance Learning-based method to study the effect of somatic non-coding SVs disrupting boundaries of TADs and CTCF loops in 1646 cancer genomes. We demonstrate that svMIL2 predicts pathogenic non-coding SVs with an average AUC of 0.86 across 12 cancer types, and identifies non-coding SVs affecting well-known driver genes. The disruption of active (super) enhancers in open chromatin regions appears to be a common mechanism by which non-coding SVs exert their pathogenicity. Finally, our results reveal that the contribution of pathogenic non-coding SVs as opposed to driver SNVs may highly vary between cancers, with notably high numbers of genes being disrupted by pathogenic non-coding SVs in ovarian and pancreatic cancer. Taken together, our machine learning method offers a potent way to prioritize putatively pathogenic non-coding SVs and leverage non-coding SVs to identify driver genes. Moreover, our analysis of 1646 cancer genomes demonstrates the importance of including non-coding SVs in cancer diagnostics.