{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,7]],"date-time":"2026-07-07T20:38:38Z","timestamp":1783456718922,"version":"3.55.0"},"reference-count":43,"publisher":"Oxford University Press (OUP)","issue":"Supplement_2","license":[{"start":{"date-parts":[[2020,12,1]],"date-time":"2020-12-01T00:00:00Z","timestamp":1606780800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2020,12,30]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>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.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>All code for svMIL is publicly available on GitHub: https:\/\/github.com\/UMCUGenetics\/svMIL.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Supplementary information<\/jats:title>\n                  <jats:p>Supplementary data are available at Bioinformatics online.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btaa802","type":"journal-article","created":{"date-parts":[[2020,9,8]],"date-time":"2020-09-08T19:13:50Z","timestamp":1599592430000},"page":"i692-i699","source":"Crossref","is-referenced-by-count":7,"title":["svMIL: predicting the pathogenic effect of TAD boundary-disrupting somatic structural variants through\u00a0multiple instance learning"],"prefix":"10.1093","volume":"36","author":[{"given":"Marleen M.","family":"Nieboer","sequence":"first","affiliation":[{"name":"Center for Molecular Medicine, Oncode Institute, University Medical Center Utrecht , Utrecht 3584 CG, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeroen","family":"de Ridder","sequence":"additional","affiliation":[{"name":"Center for Molecular Medicine, Oncode Institute, University Medical Center Utrecht , Utrecht 3584 CG, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2020,12,29]]},"reference":[{"key":"2023062409324619600_btaa802-B1","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1038\/nature24277","article-title":"Genetic effects on gene expression across human tissues","volume":"550","author":"Aguet","year":"2017","journal-title":"Nature"},{"key":"2023062409324619600_btaa802-B2","doi-asserted-by":"crossref","first-page":"294","DOI":"10.1038\/s41588-019-0564-y","article-title":"Disruption of chromatin folding domains by somatic genomic rearrangements in human cancer","volume":"52","author":"Akdemir","year":"2020","journal-title":"Nat. Genet"},{"key":"2023062409324619600_btaa802-B3","doi-asserted-by":"crossref","first-page":"8004","DOI":"10.1038\/srep08004","article-title":"MBSTAR: multiple instance learning for predicting specific functional binding sites in microRNA targets","volume":"5","author":"Bandyopadhyay","year":"2015","journal-title":"Sci. Rep"},{"key":"2023062409324619600_btaa802-B4","doi-asserted-by":"crossref","first-page":"82","DOI":"10.1038\/s41586-020-1969-6","article-title":"Pan-cancer analysis of whole genomes","volume":"578","author":"Campbell","year":"2020","journal-title":"Nature"},{"key":"2023062409324619600_btaa802-B5","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1038\/ng.3950","article-title":"Reconstruction of enhancer-target networks in 935 samples of human primary cells, tissues and cell lines","volume":"49","author":"Cao","year":"2017","journal-title":"Nat. Genet"},{"key":"2023062409324619600_btaa802-B6","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/j.patcog.2017.10.009","article-title":"Multiple instance learning: a survey of problem characteristics and applications","volume":"77","author":"Carbonneau","year":"2018","journal-title":"Pattern Recogn"},{"key":"2023062409324619600_btaa802-B7","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1109\/TPAMI.2006.248","article-title":"MILES: Multiple-Instance Learning via Embedded Instance Selection","volume":"28","author":"Chen","year":"2006","journal-title":"IEEE Trans. Pattern Anal. Mach. Intell"},{"key":"2023062409324619600_btaa802-B8","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/s41586-020-2287-8","article-title":"A structural variation reference for medical and population genetics","volume":"581","author":"Collins","year":"2020","journal-title":"Nature"},{"key":"2023062409324619600_btaa802-B9","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1016\/S0004-3702(96)00034-3","article-title":"Solving the multiple instance problem with axis-parallel rectangles","volume":"89","author":"Dietterich","year":"1997","journal-title":"Artif. Intell"},{"key":"2023062409324619600_btaa802-B10","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/nature11082","article-title":"Topological domains in mammalian genomes identified by analysis of chromatin interactions","volume":"485","author":"Dixon","year":"2012","journal-title":"Nature"},{"key":"2023062409324619600_btaa802-B11","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1038\/s41588-018-0195-8","article-title":"Integrative detection and analysis of structural variation in cancer genomes","volume":"50","author":"Dixon","year":"2018","journal-title":"Nat. Genet"},{"key":"2023062409324619600_btaa802-B12","doi-asserted-by":"crossref","first-page":"D51","DOI":"10.1093\/nar\/gkw1069","article-title":"The eukaryotic promoter database in its 30th year: focus on non-vertebrate organisms","volume":"45","author":"Dreos","year":"2017","journal-title":"Nucleic Acids Res"},{"key":"2023062409324619600_btaa802-B13","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1038\/nature11247","article-title":"An integrated encyclopedia of DNA elements in the human genome","volume":"489","author":"Dunham","year":"2012","journal-title":"Nature"},{"key":"2023062409324619600_btaa802-B14","doi-asserted-by":"crossref","first-page":"265","DOI":"10.1038\/nature19800","article-title":"Formation of new chromatin domains determines pathogenicity of genomic duplications","volume":"538","author":"Franke","year":"2016","journal-title":"Nature"},{"key":"2023062409324619600_btaa802-B15","first-page":"33, 1083\u20131085","article-title":"SVScore: an impact prediction tool for structural variation","author":"Ganel","year":"2016","journal-title":"Bioinformatics"},{"key":"2023062409324619600_btaa802-B16","doi-asserted-by":"crossref","first-page":"3143","DOI":"10.1093\/hmg\/ddv065","article-title":"A large genomic deletion leads to enhancer adoption\u00a0by the lamin B1 gene: a second path to autosomal dominant adult-onset demyelinating leukodystrophy (ADLD)","volume":"24","author":"Giorgio","year":"2015","journal-title":"Hum. Mol. Genet"},{"key":"2023062409324619600_btaa802-B17","doi-asserted-by":"crossref","first-page":"2065","DOI":"10.1007\/s13277-014-2814-z","article-title":"MiR-218 regulates cisplatin chemosensitivity in breast cancer by targeting BRCA1","volume":"36","author":"He","year":"2015","journal-title":"Tumor Biol"},{"key":"2023062409324619600_btaa802-B18","doi-asserted-by":"crossref","first-page":"1454","DOI":"10.1126\/science.aad9024","article-title":"Activation of proto-oncogenes by disruption of chromosome neighborhoods","volume":"351","author":"Hnisz","year":"2016","journal-title":"Science"},{"key":"2023062409324619600_btaa802-B19","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1186\/s13059-019-1666-7","article-title":"TAD fusion score: discovery and ranking the contribution of deletions to genome structure","volume":"20","author":"Huynh","year":"2019","journal-title":"Genome Biol"},{"key":"2023062409324619600_btaa802-B20","doi-asserted-by":"crossref","first-page":"D164","DOI":"10.1093\/nar\/gkv1002","article-title":"dbSUPER: a database of super-enhancers in mouse and human genome","volume":"44","author":"Khan","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023062409324619600_btaa802-B21","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1038\/ng.2892","article-title":"A general framework for estimating the relative pathogenicity of human genetic variants","volume":"46","author":"Kircher","year":"2014","journal-title":"Nat. Genet"},{"key":"2023062409324619600_btaa802-B22","doi-asserted-by":"crossref","first-page":"D126","DOI":"10.1093\/nar\/gkv1203","article-title":"ORegAnno 3.0: a community-driven resource for curated regulatory annotation","volume":"44","author":"Lesurf","year":"2016","journal-title":"Nucleic Acids Res"},{"key":"2023062409324619600_btaa802-B23","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41586-019-1913-9","article-title":"Patterns of\u00a0somatic structural variation in human cancer genomes","volume":"578","author":"Li","year":"2020","journal-title":"Nature"},{"key":"2023062409324619600_btaa802-B24","doi-asserted-by":"crossref","first-page":"1012","DOI":"10.1016\/j.cell.2015.04.004","article-title":"Disruptions of topological chromatin domains cause pathogenic rewiring of gene-enhancer interactions","volume":"161","author":"Lupi\u00e1\u00f1ez","year":"2015","journal-title":"Cell"},{"key":"2023062409324619600_btaa802-B25","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1186\/s13059-016-0974-4","article-title":"The ensembl variant effect predictor","volume":"17","author":"McLaren","year":"2016","journal-title":"Genome Biol"},{"key":"2023062409324619600_btaa802-B26","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1021\/acs.jproteome.5b00883","article-title":"Genome-wide functional annotation of human protein-coding splice variants using multiple instance learning","volume":"15","author":"Panwar","year":"2016","journal-title":"J. Proteome Res"},{"key":"2023062409324619600_btaa802-B27","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1038\/s41586-019-1689-y","article-title":"Pan-cancer whole-genome analyses of metastatic solid tumours","volume":"575","author":"Priestley","year":"2019","journal-title":"Nature"},{"key":"2023062409324619600_btaa802-B28","doi-asserted-by":"crossref","first-page":"1665","DOI":"10.1016\/j.cell.2014.11.021","article-title":"A 3D map of the human genome at kilobase resolution reveals principles of chromatin looping","volume":"159","author":"Rao","year":"2014","journal-title":"Cell"},{"key":"2023062409324619600_btaa802-B29","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/ng.3720","article-title":"The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies","volume":"49","author":"Redin","year":"2017","journal-title":"Nat. Genet"},{"key":"2023062409324619600_btaa802-B30","doi-asserted-by":"crossref","first-page":"102","DOI":"10.1038\/s41586-020-1965-x","article-title":"Analyses of non-coding somatic drivers in 2,658 cancer whole genomes","volume":"578","author":"Rheinbay","year":"2020","journal-title":"Nature"},{"key":"2023062409324619600_btaa802-B31","doi-asserted-by":"crossref","first-page":"R25","DOI":"10.1186\/gb-2010-11-3-r25","article-title":"A scaling normalization method for differential expression analysis of RNA-seq data","volume":"11","author":"Robinson","year":"2010","journal-title":"Genome Biol"},{"key":"2023062409324619600_btaa802-B32","doi-asserted-by":"crossref","first-page":"511","DOI":"10.1093\/bioinformatics\/btx536","article-title":"FATHMM-XF: accurate prediction of pathogenic point mutations via extended features","volume":"34","author":"Rogers","year":"2018","journal-title":"Bioinformatics"},{"key":"2023062409324619600_btaa802-B33","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/nature15394","article-title":"An integrated map of structural variation in 2,504 human genomes","volume":"526","author":"Sudmant","year":"2015","journal-title":"Nature"},{"key":"2023062409324619600_btaa802-B34","doi-asserted-by":"crossref","first-page":"1421","DOI":"10.1101\/gr.163485.113","article-title":"Reconfiguration of nucleosome-depleted regions at distal regulatory elements accompanies DNA methylation of enhancers and insulators in cancer","volume":"24","author":"Taberlay","year":"2014","journal-title":"Genome Res"},{"key":"2023062409324619600_btaa802-B35","doi-asserted-by":"crossref","first-page":"D941","DOI":"10.1093\/nar\/gky1015","article-title":"COSMIC: the Catalogue Of Somatic Mutations In Cancer","volume":"47","author":"Tate","year":"2019","journal-title":"Nucleic Acids Res"},{"key":"2023062409324619600_btaa802-B36","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.gde.2016.03.008","article-title":"TAD disruption as oncogenic driver","volume":"36","author":"Valton","year":"2016","journal-title":"Curr. Opin. Genet. Dev"},{"key":"2023062409324619600_btaa802-B37","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.humpath.2017.10.032","article-title":"BRCA1 and BRCA2 expression patterns and prognostic significance in digestive system cancers","volume":"71","author":"Wang","year":"2018","journal-title":"Hum. Pathol"},{"key":"2023062409324619600_btaa802-B38","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1186\/s13059-018-1519-9","article-title":"The 3D Genome Browser: a web-based browser for visualizing 3D genome organization and long-range chromatin interactions","volume":"19","author":"Wang","year":"2018","journal-title":"Genome Biol"},{"key":"2023062409324619600_btaa802-B39","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1038\/ng.3722","article-title":"Pan-cancer analysis of somatic copy-number alterations implicates IRS4 and IGF2 in enhancer hijacking","volume":"49","author":"Weischenfeldt","year":"2017","journal-title":"Nat. Genet"},{"key":"2023062409324619600_btaa802-B40","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.celrep.2018.06.025","article-title":"A pan-cancer compendium of genes deregulated by somatic genomic rearrangement across more than 1,400 cases","volume":"24","author":"Zhang","year":"2018","journal-title":"Cell Rep"},{"key":"2023062409324619600_btaa802-B41","doi-asserted-by":"crossref","first-page":"5356","DOI":"10.1038\/s41467-018-07766-x","article-title":"Local and global chromatin interactions are altered by large genomic deletions associated with human brain development","volume":"9","author":"Zhang","year":"2018","journal-title":"Nat. Commun"},{"key":"2023062409324619600_btaa802-B42","first-page":"295","author":"Zhou","year":"2010"},{"key":"2023062409324619600_btaa802-B43","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1038\/nmeth.3547","article-title":"Predicting effects of noncoding variants with deep learning-based sequence model","volume":"12","author":"Zhou","year":"2015","journal-title":"Nat. Methods"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/Supplement_2\/i692\/50693422\/btaa802.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/36\/Supplement_2\/i692\/50693422\/btaa802.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T23:55:03Z","timestamp":1687650903000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/36\/Supplement_2\/i692\/6055921"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12]]},"references-count":43,"journal-issue":{"issue":"Supplement_2","published-print":{"date-parts":[[2020,12,30]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btaa802","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2020,12]]},"published":{"date-parts":[[2020,12]]}}}