{"id":"https://openalex.org/W7129325472","doi":"https://doi.org/10.21203/rs.3.rs-8907367/v1","title":"A Robust Framework for Predicting Mutation Effects on Transcription Factor Binding: Insights from Mutational Signatures in 560 Breast Cancer Genomes","display_name":"A Robust Framework for Predicting Mutation Effects on Transcription Factor Binding: Insights from Mutational Signatures in 560 Breast Cancer Genomes","publication_year":2026,"publication_date":"2026-02-17","ids":{"openalex":"https://openalex.org/W7129325472","doi":"https://doi.org/10.21203/rs.3.rs-8907367/v1"},"language":"en","primary_location":{"id":"doi:10.21203/rs.3.rs-8907367/v1","doi":"https://doi.org/10.21203/rs.3.rs-8907367/v1","is_oa":true,"landing_page_url":"https://doi.org/10.21203/rs.3.rs-8907367/v1","pdf_url":null,"source":{"id":"https://openalex.org/S4306525896","display_name":"Research Square","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":[],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"Research Square","raw_type":"posted-content"},"volume":null,"type":"preprint","indexed_in":["crossref"],"open_access":{"is_oa":true,"oa_status":"green","oa_url":"https://doi.org/10.21203/rs.3.rs-8907367/v1","any_repository_has_fulltext":true},"authorships":[{"author_position":"first","author":{"id":"https://openalex.org/A5093735875","display_name":"H\u00fcseyin Hilmi K\u0131l\u0131n\u00e7","orcid":"https://orcid.org/0000-0002-1087-0822","observed_orcids":["https://orcid.org/0000-0002-1087-0822"]},"institutions":[{"id":"https://openalex.org/I201799495","display_name":"Middle East Technical University","ror":"https://ror.org/014weej12","country_code":"TR","type":"education","lineage":["https://openalex.org/I201799495"]}],"countries":["TR"],"is_corresponding":false,"raw_author_name":"H\u00fcseyin Hilmi K\u0131l\u0131n\u00e7","raw_affiliation_strings":["Middle East Technical University"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Middle East Technical University","institution_ids":["https://openalex.org/I201799495"]}]},{"author_position":"last","author":{"id":"https://openalex.org/A5038578938","display_name":"Bur\u00e7ak Otlu","orcid":"https://orcid.org/0000-0002-4931-7979","observed_orcids":["https://orcid.org/0000-0002-4931-7979"]},"institutions":[{"id":"https://openalex.org/I201799495","display_name":"Middle East Technical University","ror":"https://ror.org/014weej12","country_code":"TR","type":"education","lineage":["https://openalex.org/I201799495"]}],"countries":["TR"],"is_corresponding":false,"raw_author_name":"Bur\u00e7ak Otlu","raw_affiliation_strings":["Middle East Technical University"],"raw_orcid":null,"affiliations":[{"raw_affiliation_string":"Middle East Technical University","institution_ids":["https://openalex.org/I201799495"]}]}],"institutions":[],"countries_distinct_count":1,"institutions_distinct_count":1,"corresponding_author_ids":[],"corresponding_institution_ids":["https://openalex.org/I201799495"],"apc_list":null,"apc_paid":null,"fwci":null,"has_fulltext":false,"cited_by_count":0,"citation_normalized_percentile":null,"cited_by_percentile_year":null,"biblio":{"volume":null,"issue":null,"first_page":null,"last_page":null},"is_retracted":false,"is_paratext":false,"is_xpac":false,"primary_topic":{"id":"https://openalex.org/T11287","display_name":"Cancer Genomics and Diagnostics","score":0.7573000192642212,"subfield":{"id":"https://openalex.org/subfields/1306","display_name":"Cancer Research"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},"topics":[{"id":"https://openalex.org/T11287","display_name":"Cancer Genomics and Diagnostics","score":0.7573000192642212,"subfield":{"id":"https://openalex.org/subfields/1306","display_name":"Cancer Research"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T12820","display_name":"Chromatin Remodeling and Cancer","score":0.10599999874830246,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}},{"id":"https://openalex.org/T10222","display_name":"Genomics and Chromatin Dynamics","score":0.07370000332593918,"subfield":{"id":"https://openalex.org/subfields/1312","display_name":"Molecular Biology"},"field":{"id":"https://openalex.org/fields/13","display_name":"Biochemistry, Genetics and Molecular Biology"},"domain":{"id":"https://openalex.org/domains/1","display_name":"Life Sciences"}}],"keywords":[{"id":"https://openalex.org/keywords/transcription-factor-binding-affinity","display_name":"transcription factor binding affinity","score":0.8180000185966492},{"id":"https://openalex.org/keywords/somatic-mutations","display_name":"somatic mutations","score":0.9240000247955322},{"id":"https://openalex.org/keywords/mutational-signatures","display_name":"mutational signatures","score":0.9570000171661377},{"id":"https://openalex.org/keywords/breast-cancer","display_name":"breast cancer","score":0.9779999852180481},{"id":"https://openalex.org/keywords/gene-regulatory-networks","display_name":"gene regulatory networks","score":0.5979999899864197},{"id":"https://openalex.org/keywords/enhancers","display_name":"enhancers","score":0.6269999742507935},{"id":"https://openalex.org/keywords/apobec-mutational-signature","display_name":"APOBEC mutational signature","score":0.8040000200271606},{"id":"https://openalex.org/keywords/foxa1","display_name":"FOXA1","score":0.7699999809265137},{"id":"https://openalex.org/keywords/c-myc","display_name":"c-Myc","score":0.7590000033378601},{"id":"https://openalex.org/keywords/brca1-2","display_name":"BRCA1/2","score":0.8009999990463257},{"id":"https://openalex.org/keywords/ets-family","display_name":"ETS family","score":0.9020000100135803},{"id":"https://openalex.org/keywords/transcriptional-dysregulation","display_name":"transcriptional dysregulation","score":0.6890000104904175},{"id":"https://openalex.org/keywords/non-coding-variants","display_name":"non-coding variants","score":0.7049999833106995}],"concepts":[{"id":"https://openalex.org/C86803240","wikidata":"https://www.wikidata.org/wiki/Q420","display_name":"Biology","level":0,"score":0.7386000156402588},{"id":"https://openalex.org/C86339819","wikidata":"https://www.wikidata.org/wiki/Q407384","display_name":"Transcription factor","level":3,"score":0.6140000224113464},{"id":"https://openalex.org/C54355233","wikidata":"https://www.wikidata.org/wiki/Q7162","display_name":"Genetics","level":1,"score":0.6011999845504761},{"id":"https://openalex.org/C70721500","wikidata":"https://www.wikidata.org/wiki/Q177005","display_name":"Computational biology","level":1,"score":0.5781000256538391},{"id":"https://openalex.org/C111936080","wikidata":"https://www.wikidata.org/wiki/Q913367","display_name":"Enhancer","level":4,"score":0.5665000081062317},{"id":"https://openalex.org/C104317684","wikidata":"https://www.wikidata.org/wiki/Q7187","display_name":"Gene","level":2,"score":0.5394999980926514},{"id":"https://openalex.org/C530470458","wikidata":"https://www.wikidata.org/wiki/Q128581","display_name":"Breast cancer","level":3,"score":0.5364000201225281},{"id":"https://openalex.org/C141231307","wikidata":"https://www.wikidata.org/wiki/Q7020","display_name":"Genome","level":3,"score":0.510200023651123},{"id":"https://openalex.org/C501734568","wikidata":"https://www.wikidata.org/wiki/Q42918","display_name":"Mutation","level":3,"score":0.4018000066280365},{"id":"https://openalex.org/C134305767","wikidata":"https://www.wikidata.org/wiki/Q725508","display_name":"Somatic cell","level":3,"score":0.34049999713897705},{"id":"https://openalex.org/C2775905019","wikidata":"https://www.wikidata.org/wiki/Q192572","display_name":"In silico","level":3,"score":0.3314000070095062},{"id":"https://openalex.org/C2779733811","wikidata":"https://www.wikidata.org/wiki/Q5531562","display_name":"Gene signature","level":4,"score":0.3167000114917755},{"id":"https://openalex.org/C121608353","wikidata":"https://www.wikidata.org/wiki/Q12078","display_name":"Cancer","level":2,"score":0.30660000443458557},{"id":"https://openalex.org/C179185449","wikidata":"https://www.wikidata.org/wiki/Q219699","display_name":"Suppressor","level":3,"score":0.3034999966621399},{"id":"https://openalex.org/C165864922","wikidata":"https://www.wikidata.org/wiki/Q411391","display_name":"Regulation of gene expression","level":3,"score":0.3028999865055084},{"id":"https://openalex.org/C13514818","wikidata":"https://www.wikidata.org/wiki/Q5552256","display_name":"Germline mutation","level":4,"score":0.30079999566078186},{"id":"https://openalex.org/C3662595","wikidata":"https://www.wikidata.org/wiki/Q5205743","display_name":"DNA binding site","level":5,"score":0.289000004529953},{"id":"https://openalex.org/C67339327","wikidata":"https://www.wikidata.org/wiki/Q1502576","display_name":"Gene regulatory network","level":4,"score":0.27959999442100525}],"mesh":[],"locations_count":2,"locations":[{"id":"doi:10.21203/rs.3.rs-8907367/v1","doi":"https://doi.org/10.21203/rs.3.rs-8907367/v1","is_oa":true,"landing_page_url":"https://doi.org/10.21203/rs.3.rs-8907367/v1","pdf_url":null,"source":{"id":"https://openalex.org/S4306525896","display_name":"Research Square","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":[],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"Research Square","raw_type":"posted-content"},{"id":"doi:10.64898/2026.02.14.705876","doi":"https://doi.org/10.64898/2026.02.14.705876","is_oa":true,"landing_page_url":"https://doi.org/10.64898/2026.02.14.705876","pdf_url":null,"source":{"id":"https://openalex.org/S4306402567","display_name":"bioRxiv (Cold Spring Harbor Laboratory)","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":"https://openalex.org/I2750212522","host_organization_name":"Cold Spring Harbor Laboratory","host_organization_lineage":["https://openalex.org/I2750212522"],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"bioRxiv","raw_type":"posted-content"}],"best_oa_location":{"id":"doi:10.21203/rs.3.rs-8907367/v1","doi":"https://doi.org/10.21203/rs.3.rs-8907367/v1","is_oa":true,"landing_page_url":"https://doi.org/10.21203/rs.3.rs-8907367/v1","pdf_url":null,"source":{"id":"https://openalex.org/S4306525896","display_name":"Research Square","issn_l":null,"issn":null,"is_oa":false,"is_in_doaj":false,"is_core":false,"listed_in":[],"host_organization":null,"host_organization_name":null,"host_organization_lineage":[],"host_organization_lineage_names":[],"type":"repository"},"license":"cc-by","license_id":"https://openalex.org/licenses/cc-by","version":"acceptedVersion","is_accepted":true,"is_published":false,"raw_source_name":"Research Square","raw_type":"posted-content"},"sustainable_development_goals":[{"id":"https://metadata.un.org/sdg/3","display_name":"Good health and well-being","score":0.8560000061988831}],"study_designs":[],"awards":[],"funders":[],"has_content":{"pdf":false,"grobid_xml":false},"content_urls":null,"referenced_works_count":46,"referenced_works":["https://openalex.org/W1019830208","https://openalex.org/W1493586912","https://openalex.org/W1994122295","https://openalex.org/W2026690931","https://openalex.org/W2033169664","https://openalex.org/W2046740230","https://openalex.org/W2064444082","https://openalex.org/W2078059415","https://openalex.org/W2116467413","https://openalex.org/W2129795133","https://openalex.org/W2142410561","https://openalex.org/W2146393977","https://openalex.org/W2152061559","https://openalex.org/W2259938310","https://openalex.org/W2270152626","https://openalex.org/W2344657883","https://openalex.org/W2593992741","https://openalex.org/W2606776638","https://openalex.org/W2614443510","https://openalex.org/W2895396628","https://openalex.org/W2945144872","https://openalex.org/W2950760001","https://openalex.org/W2951410692","https://openalex.org/W3026538346","https://openalex.org/W3047825284","https://openalex.org/W3091969318","https://openalex.org/W3097629227","https://openalex.org/W3128498209","https://openalex.org/W3151678771","https://openalex.org/W3205421900","https://openalex.org/W3212111676","https://openalex.org/W4200483382","https://openalex.org/W4282932378","https://openalex.org/W4296819410","https://openalex.org/W4308147347","https://openalex.org/W4388420077","https://openalex.org/W4390621251","https://openalex.org/W4390876255","https://openalex.org/W4396601271","https://openalex.org/W4399728237","https://openalex.org/W4400806940","https://openalex.org/W4405529257","https://openalex.org/W4411097961","https://openalex.org/W4413244175","https://openalex.org/W4413662401","https://openalex.org/W4413946439"],"related_works":["https://openalex.org/W7110676756","https://openalex.org/W3128498209","https://openalex.org/W3000043122","https://openalex.org/W2950760001","https://openalex.org/W3093471060","https://openalex.org/W7223016192","https://openalex.org/W2056643175","https://openalex.org/W2487434787","https://openalex.org/W2945144872","https://openalex.org/W2606776638"],"abstract_inverted_index":{"Abstract":[0],"Background:":[1],"A":[2],"vast":[3],"majority":[4],"of":[5,38,58,275,280],"somatic":[6,109,276],"mutations":[7,110,277],"in":[8,11,50,74,176,192,278,295,305],"cancer":[9,114,225],"reside":[10],"noncoding":[12],"regions,":[13],"yet":[14],"systematically":[15,289],"predicting":[16],"their":[17,31,146],"functional":[18,273],"impact":[19],"on":[20,78,96,160,241,255],"gene":[21,59,135,244,292],"regulation":[22],"remains":[23],"a":[24,46,63,72,263,296],"significant":[25],"challenge.":[26],"These":[27,125],"variants":[28,144],"often":[29],"enforce":[30],"effects":[32,159],"by":[33],"altering":[34],"the":[35,56,177,183,193,227,237,251,272,291],"binding":[36,86,123],"affinity":[37],"transcription":[39],"factors":[40],"(TFs)":[41],"to":[42,55,83,106,117,142,145,206],"cis-regulatory":[43],"elements.":[44],"However,":[45],"critical":[47],"gap":[48],"exists":[49],"linking":[51],"specific":[52,161,286],"mutational":[53,130,154,287],"processes":[54,155,288],"disruption":[57],"regulatory":[60,293],"networks":[61],"at":[62,200],"systems":[64],"level.":[65],"Results:":[66],"In":[67,223],"this":[68,104],"study,":[69],"we":[70],"present":[71],"comprehensive":[73],"silico":[75],"pipeline":[76,105],"centered":[77],"k-mer-based":[79],"linear":[80],"regression":[81],"models":[82,94],"quantify":[84],"TF":[85,93,162,281],"affinity.":[87],"Our":[88,149,260],"framework":[89,261],"produced":[90],"403":[91],"high-confidence":[92],"trained":[95],"high-throughput":[97],"ChIP-seq":[98],"and":[99,133,168,179,209,215,220,265,270],"PBM":[100],"datasets.":[101],"We":[102,283],"applied":[103],"3.5":[107],"million":[108],"from":[111],"560":[112],"breast":[113,224,306],"whole":[115],"genomes":[116],"predict":[118],"gain-":[119],"or":[120],"loss-of-function":[121],"(GOF/LOF)":[122],"perturbations.":[124,282],"predictions":[126],"were":[127,170,203],"integrated":[128],"with":[129,213],"signature":[131,185],"analysis":[132,150],"curated":[134],"sets,":[136],"utilizing":[137],"Activity-by-Contact":[138],"model-based":[139],"enhancer-gene":[140],"maps":[141],"link":[143],"target":[147,243],"genes.":[148],"revealed":[151],"that":[152,232,285],"distinct":[153],"exert":[156],"non-random,":[157],"directional":[158],"families.":[163],"The":[164],"APOBEC-associated":[165],"signatures":[166],"(SBS2":[167],"SBS13)":[169],"strongly":[171],"enriched":[172,188],"for":[173,189,236,250,268,302],"GOF":[174,214,234],"events":[175,191,217,249],"Myb/SANT":[178],"FOX":[180],"families,":[181],"while":[182,246],"aging-associated":[184],"SBS1":[186],"was":[187],"LOF":[190,216,248],"Ets":[194],"family":[195,239,253],"members.":[196],"Furthermore,":[197],"predicted":[198],"perturbations":[199],"putative":[201],"enhancers":[202],"significantly":[204],"linked":[205],"key":[207],"oncogenes":[208],"tumor":[210],"suppressor":[211],"genes,":[212],"(e.g.,":[218],"FOXA1":[219],"BRCA1/2,":[221],"respectively).":[222],"samples,":[226],"basal-like":[228],"TNBC":[229],"subtype":[230],"exhibited":[231],"SBS3-driven":[233],"enrichments":[235],"CXXC":[238],"converged":[240,254],"MYC":[242],"programs,":[245],"SBS39-driven":[247],"same":[252],"DNA":[256],"Repair":[257],"pathways.":[258],"Conclusions:":[259],"provides":[262],"robust":[264],"scalable":[266],"approach":[267],"prioritizing":[269],"interpreting":[271],"consequences":[274],"terms":[279],"demonstrate":[284],"rewire":[290],"landscape":[294],"subtype-specific":[297],"manner,":[298],"offering":[299],"novel":[300],"mechanisms":[301],"transcriptional":[303],"deregulation":[304],"cancer.":[307]},"counts_by_year":[],"updated_date":"2026-11-01T11:40:01.658920","created_date":"2026-02-18T00:00:00"}