{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T19:47:51Z","timestamp":1781380071161,"version":"3.54.1"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2024,1,20]],"date-time":"2024-01-20T00:00:00Z","timestamp":1705708800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100015754","name":"Stiftung der Deutschen Wirtschaft","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100015754","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100021828","name":"German Academic Exchange Service","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100021828","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Berlin School of Integrative Oncology"},{"DOI":"10.13039\/100001680","name":"Charles H. Hood Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001680","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000885","name":"Children's Cancer Research Fund","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000885","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001368","name":"V Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001368","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,2,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:sec>\n                  <jats:title>Motivation<\/jats:title>\n                  <jats:p>Copy-number variations (CNVs) are common genetic alterations in cancer and their detection may impact tumor classification and therapeutic decisions. However, detection of clinically relevant large and focal CNVs remains challenging when sample material or resources are limited. This has motivated us to create a software tool to infer CNVs from DNA methylation arrays which are often generated as part of clinical routines and in research settings.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>We present our R package, conumee 2.0, that combines tangent normalization, an adjustable genomic binning heuristic, and weighted circular binary segmentation to utilize DNA methylation arrays for CNV analysis and mitigate technical biases and batch effects. Segmentation results were validated in a lung squamous cell carcinoma dataset from TCGA (n\u2009=\u2009367 samples) by comparison to segmentations derived from genotyping arrays (Pearson\u2019s correlation coefficient of 0.91). We further introduce a segmented block bootstrapping approach to detect focal alternations that achieved 60.9% sensitivity and 98.6% specificity for deletions affecting CDKN2A\/B (60.0% and 96.9% for RB1, respectively) in a low-grade glioma cohort from TCGA (n\u2009=\u2009239 samples). Finally, our tool provides functionality to detect and summarize CNVs across large sample cohorts.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Availability and implementation<\/jats:title>\n                  <jats:p>Conumee 2.0 is available under open-source license at: https:\/\/github.com\/hovestadtlab\/conumee2.<\/jats:p>\n               <\/jats:sec>","DOI":"10.1093\/bioinformatics\/btae029","type":"journal-article","created":{"date-parts":[[2024,1,21]],"date-time":"2024-01-21T01:14:30Z","timestamp":1705799670000},"source":"Crossref","is-referenced-by-count":78,"title":["Conumee 2.0: enhanced copy-number variation analysis from DNA methylation arrays for humans and mice"],"prefix":"10.1093","volume":"40","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0237-8694","authenticated-orcid":false,"given":"Bjarne","family":"Daenekas","sequence":"first","affiliation":[{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute , Boston, MA 02115, United States"},{"name":"Broad Institute of MIT and Harvard , Cambridge, MA 02142, United States"},{"name":"Department of Neuropathology, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eil\u00eds","family":"P\u00e9rez","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , 10117 Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fabio","family":"Boniolo","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute , Boston, MA 02115, United States"},{"name":"Broad Institute of MIT and Harvard , Cambridge, MA 02142, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabina","family":"Stefan","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute , Boston, MA 02115, United States"},{"name":"Broad Institute of MIT and Harvard , Cambridge, MA 02142, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4439-3136","authenticated-orcid":false,"given":"Salvatore","family":"Benfatto","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute , Boston, MA 02115, United States"},{"name":"Broad Institute of MIT and Harvard , Cambridge, MA 02142, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7616-7665","authenticated-orcid":false,"given":"Martin","family":"Sill","sequence":"additional","affiliation":[{"name":"Hopp Children\u2019s Cancer Center Heidelberg (KiTZ) , 69120 Heidelberg, Germany"},{"name":"Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) , 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dominik","family":"Sturm","sequence":"additional","affiliation":[{"name":"Hopp Children\u2019s Cancer Center Heidelberg (KiTZ) , 69120 Heidelberg, Germany"},{"name":"Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) , 69120 Heidelberg, Germany"},{"name":"Department of Pediatric Oncology, Hematology & Immunology, Heidelberg University Hospital , 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David T W","family":"Jones","sequence":"additional","affiliation":[{"name":"Hopp Children\u2019s Cancer Center Heidelberg (KiTZ) , 69120 Heidelberg, Germany"},{"name":"Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK) , 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1945-497X","authenticated-orcid":false,"given":"David","family":"Capper","sequence":"additional","affiliation":[{"name":"Department of Neuropathology, Charit\u00e9 \u2013 Universit\u00e4tsmedizin Berlin, Corporate Member of Freie Universit\u00e4t Berlin and Humboldt-Universit\u00e4t zu Berlin , 10117 Berlin, Germany"},{"name":"German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ) , 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8287-5967","authenticated-orcid":false,"given":"Marc","family":"Zapatka","sequence":"additional","affiliation":[{"name":"Division of Molecular Genetics, German Cancer Research Center (DKFZ) , 69120 Heidelberg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3480-6649","authenticated-orcid":false,"given":"Volker","family":"Hovestadt","sequence":"additional","affiliation":[{"name":"Department of Pediatric Oncology, Dana-Farber Cancer Institute , Boston, MA 02115, United States"},{"name":"Broad Institute of MIT and Harvard , Cambridge, MA 02142, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2024,1,19]]},"reference":[{"key":"2024020317044942900_btae029-B1","doi-asserted-by":"crossref","first-page":"1363","DOI":"10.1093\/bioinformatics\/btu049","article-title":"Minfi: a flexible and comprehensive bioconductor package for the analysis of infinium DNA methylation microarrays","volume":"30","author":"Aryee","year":"2014","journal-title":"Bioinformatics"},{"key":"2024020317044942900_btae029-B2","doi-asserted-by":"crossref","first-page":"899","DOI":"10.1038\/nature08822","article-title":"The landscape of somatic copy-number alteration across human cancers","volume":"463","author":"Beroukhim","year":"2010","journal-title":"Nature"},{"key":"2024020317044942900_btae029-B3","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1016\/j.ygeno.2011.07.007","article-title":"High density DNA methylation array with single CpG site resolution","volume":"98","author":"Bibikova","year":"2011","journal-title":"Genomics"},{"key":"2024020317044942900_btae029-B4","doi-asserted-by":"crossref","first-page":"bbac161","DOI":"10.1093\/bib\/bbac161","article-title":"Refinement of computational identification of somatic copy number alterations using DNA methylation microarrays illustrated in cancers of unknown primary","volume":"23","author":"Blecua","year":"2022","journal-title":"Brief Bioinform"},{"key":"2024020317044942900_btae029-B5","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1868-7083-4-22","article-title":"A systematic evaluation of whole genome amplification of bisulfite-modified DNA","volume":"4","author":"Bundo","year":"2012","journal-title":"Clin Epigenet"},{"key":"2024020317044942900_btae029-B6","doi-asserted-by":"crossref","first-page":"2481","DOI":"10.1056\/NEJMoa1402121","article-title":"Comprehensive, integrative genomic analysis of diffuse Lower-Grade gliomas","volume":"372","author":"Brat","year":"2015","journal-title":"N Engl J Med"},{"key":"2024020317044942900_btae029-B7","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1038\/nature11404","article-title":"Comprehensive genomic characterization of squamous cell lung cancers","volume":"489","author":"Cancer Genome Atlas Research Network","year":"2012","journal-title":"Nature"},{"key":"2024020317044942900_btae029-B8","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1038\/nature26000","article-title":"DNA methylation-based classification of Central nervous system tumours","volume":"555","author":"Capper","year":"2018","journal-title":"Nature"},{"key":"2024020317044942900_btae029-B9","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1089\/cmb.2018.0143","article-title":"Measuring DNA copy number variation using high-density methylation microarrays","volume":"26","author":"Cho","year":"2019","journal-title":"J Comput Biol"},{"key":"2024020317044942900_btae029-B10","doi-asserted-by":"crossref","first-page":"1160","DOI":"10.1056\/NEJMra0707704","article-title":"EGFR antagonists in cancer treatment","volume":"358","author":"Ciardiello","year":"2008","journal-title":"N Engl J Med"},{"key":"2024020317044942900_btae029-B11","doi-asserted-by":"crossref","first-page":"e71","DOI":"10.1093\/nar\/gkv1507","article-title":"TCGAbiolinks: an R\/bioconductor package for integrative analysis of TCGA data","volume":"44","author":"Colaprico","year":"2015","journal-title":"Nucleic Acids Res"},{"key":"2024020317044942900_btae029-B12","doi-asserted-by":"crossref","first-page":"37","DOI":"10.3233\/JAD-160469","article-title":"Copy number variants in Alzheimer\u2019s disease","volume":"55","author":"Cuccaro","year":"2017","journal-title":"J Alzheimers Dis"},{"key":"2024020317044942900_btae029-B13","doi-asserted-by":"crossref","first-page":"R30","DOI":"10.1186\/gb-2014-15-2-r30","article-title":"Using high-density DNA methylation arrays to profile copy number alterations","volume":"15","author":"Feber","year":"2014","journal-title":"Genome Biol"},{"key":"2024020317044942900_btae029-B14","doi-asserted-by":"crossref","first-page":"4677","DOI":"10.1093\/bioinformatics\/btac586","article-title":"Tangent normalization for somatic copy-number inference in cancer genome analysis","volume":"38","author":"Gao","year":"2022","journal-title":"Bioinformatics"},{"key":"2024020317044942900_btae029-B15","doi-asserted-by":"crossref","first-page":"747","DOI":"10.1101\/gr.269233.120","article-title":"DNA methylation epitypes highlight underlying developmental and disease pathways in acute myeloid leukemia","volume":"31","author":"Giacopelli","year":"2021","journal-title":"Genome Res"},{"key":"2024020317044942900_btae029-B16","doi-asserted-by":"crossref","first-page":"551","DOI":"10.1038\/nrg2593","article-title":"Mechanisms of change in gene copy number","volume":"10","author":"Hastings","year":"2009","journal-title":"Nat Rev Genet"},{"key":"2024020317044942900_btae029-B17","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1007\/s00401-013-1126-5","article-title":"Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays","volume":"125","author":"Hovestadt","year":"2013","journal-title":"Acta Neuropathol"},{"key":"2024020317044942900_btae029-B18","author":"Hovestadt","year":"2015"},{"key":"2024020317044942900_btae029-B19","doi-asserted-by":"crossref","first-page":"683","DOI":"10.1016\/j.cell.2007.01.029","article-title":"The epigenomics of cancer","volume":"128","author":"Jones","year":"2007","journal-title":"Cell"},{"key":"2024020317044942900_btae029-B20","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1002\/gepi.22269","article-title":"Critical evaluation of copy number variant calling methods using DNA methylation","volume":"44","author":"Kilaru","year":"2020","journal-title":"Genet Epidemiol"},{"key":"2024020317044942900_btae029-B21","doi-asserted-by":"crossref","first-page":"2266","DOI":"10.1093\/bioinformatics\/btx156","article-title":"cnAnalysis450k: an R package for comparative analysis of 450k\/EPIC illumina methylation array derived copy number data","volume":"33","author":"Knoll","year":"2017","journal-title":"Bioinformatics"},{"key":"2024020317044942900_btae029-B22","volume-title":"Nat Commun","author":"K\u00f6lsche"},{"key":"2024020317044942900_btae029-B23","doi-asserted-by":"crossref","first-page":"a003236","DOI":"10.1101\/cshperspect.a003236","article-title":"Oncogenes and tumor suppressor genes","volume":"2","author":"Lee","year":"2010","journal-title":"Cold Spring Harb Perspect Biol"},{"key":"2024020317044942900_btae029-B24","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1016\/j.neuron.2011.05.015","article-title":"Rare de novo and transmitted copy-number variation in autistic spectrum disorders","volume":"70","author":"Levy","year":"2011","journal-title":"Neuron"},{"key":"2024020317044942900_btae029-B25","doi-asserted-by":"crossref","first-page":"D986","DOI":"10.1093\/nar\/gkt958","article-title":"The database of genomic variants: a curated collection of structural variation in the human genome","volume":"42","author":"MacDonald","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"2024020317044942900_btae029-B26","doi-asserted-by":"crossref","first-page":"859828","DOI":"10.3389\/fbinf.2022.859828","article-title":"MethylMasteR: a comparison and customization of methylation-based copy number variation calling software in cancers harboring large scale chromosomal deletions","volume":"2","author":"Mariani","year":"2022","journal-title":"Front Bioinform"},{"key":"2024020317044942900_btae029-B27","doi-asserted-by":"crossref","first-page":"R41","DOI":"10.1186\/gb-2011-12-4-r41","article-title":"GISTIC2.0 facilitates sensitive and confident localization of the targets of focal somatic copy-number alteration in human cancers","volume":"12","author":"Mermel","year":"2011","journal-title":"Genome Biol"},{"key":"2024020317044942900_btae029-B28","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1186\/s13059-019-1664-9","article-title":"RnBeads 2.0: comprehensive analysis of DNA methylation data","volume":"20","author":"M\u00fcller","year":"2019","journal-title":"Genome Biol"},{"key":"2024020317044942900_btae029-B29","doi-asserted-by":"crossref","first-page":"btad190","DOI":"10.1093\/bioinformatics\/btad190","article-title":"bootRanges: flexible generation of null sets of genomic ranges for hypothesis testing","volume":"39","author":"Mu","year":"2023","journal-title":"Bioinformatics"},{"key":"2024020317044942900_btae029-B30","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/nature22973","article-title":"The whole-genome landscape of medulloblastoma subtypes","volume":"547","author":"Northcott","year":"2017","journal-title":"Nature"},{"key":"2024020317044942900_btae029-B31","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1093\/biostatistics\/kxh008","article-title":"Circular binary segmentation for the analysis of array-based DNA copy number data","volume":"5","author":"Olshen","year":"2004","journal-title":"Biostatistics"},{"key":"2024020317044942900_btae029-B32","doi-asserted-by":"crossref","first-page":"500","DOI":"10.1038\/ng0506-500","article-title":"GenePattern 2.0","volume":"38","author":"Reich","year":"2006","journal-title":"Nat Genet"},{"key":"2024020317044942900_btae029-B33","author":"Seshan","year":"2022"},{"key":"2024020317044942900_btae029-B34","doi-asserted-by":"crossref","DOI":"10.1201\/9780429447273","volume-title":"Interactive Web-Based Data Visualization with R, Plotly, and Shiny","author":"Sievert","year":"2020"},{"key":"2024020317044942900_btae029-B35","doi-asserted-by":"crossref","first-page":"264","DOI":"10.12688\/f1000research.2-264.v1","article-title":"illuminaio: an open source IDAT parsing tool for illumina microarrays","volume":"2","author":"Smith","year":"2013","journal-title":"F1000Res"},{"key":"2024020317044942900_btae029-B36","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1038\/s41586-022-04738-6","article-title":"Signatures of copy number alterations in human cancer","volume":"606","author":"Steele","year":"2022","journal-title":"Nature"},{"key":"2024020317044942900_btae029-B37","doi-asserted-by":"crossref","first-page":"917","DOI":"10.1038\/s41591-023-02255-1","article-title":"Multiomic neuropathology improves diagnostic accuracy in pediatric neuro-oncology","volume":"29","author":"Sturm","year":"2023","journal-title":"Nat Med"},{"key":"2024020317044942900_btae029-B38","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2016.01.015","article-title":"New brain tumor entities emerge from molecular classification of CNS-PNETs","volume":"164","author":"Sturm","year":"2016","journal-title":"Cell"},{"key":"2024020317044942900_btae029-B39","doi-asserted-by":"crossref","first-page":"425","DOI":"10.1016\/j.ccr.2012.08.024","article-title":"Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma","volume":"22","author":"Sturm","year":"2012","journal-title":"Cancer Cell"},{"key":"2024020317044942900_btae029-B40","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":"2018","journal-title":"Nucleic Acids Res"},{"key":"2024020317044942900_btae029-B41","author":"WHO Classification of Tumours Editorial Board","year":"2021"}],"container-title":["Bioinformatics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/bioinformatics\/advance-article-pdf\/doi\/10.1093\/bioinformatics\/btae029\/56284969\/btae029.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/40\/2\/btae029\/56576661\/btae029.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article-pdf\/40\/2\/btae029\/56576661\/btae029.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,2,3]],"date-time":"2024-02-03T17:05:29Z","timestamp":1706979929000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/bioinformatics\/article\/doi\/10.1093\/bioinformatics\/btae029\/7582283"}},"subtitle":[],"editor":[{"given":"Janet","family":"Kelso","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2024,1,19]]},"references-count":41,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2024,2,1]]}},"URL":"https:\/\/doi.org\/10.1093\/bioinformatics\/btae029","relation":{},"ISSN":["1367-4803","1367-4811"],"issn-type":[{"value":"1367-4803","type":"print"},{"value":"1367-4811","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2024,2,1]]},"published":{"date-parts":[[2024,1,19]]},"article-number":"btae029"}}