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In Bioinformatics (Oxford, England)

MOTIVATION : Despite the fact that structural variants (SVs) play an important role in cancer, methods to predict their effect, especially for SVs in non-coding regions, are lacking, leaving them often overlooked in the clinic. Non-coding SVs may disrupt the boundaries of Topologically Associated Domains (TADs), thereby affecting interactions between genes and regulatory elements such as enhancers. However, it is not known when such alterations are pathogenic. Although machine learning techniques are a promising solution to answer this question, representing the large number of interactions that an SV can disrupt in a single feature matrix is not trivial.

RESULTS : We introduce svMIL: a method to predict pathogenic TAD boundary-disrupting SV effects based on multiple instance learning, which circumvents the need for a traditional feature matrix by grouping SVs into bags that can contain any number of disruptions. We demonstrate that svMIL can predict SV pathogenicity, measured through same-sample gene expression aberration, for various cancer types. In addition, our approach reveals that somatic pathogenic SVs alter different regulatory interactions than somatic non-pathogenic SVs and germline SVs.

AVAILABILITY AND IMPLEMENTATION : All code for svMIL is publicly available on GitHub:

SUPPLEMENTARY INFORMATION : Supplementary data are available at Bioinformatics online.

Nieboer Marleen M, de Ridder Jeroen