{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:09:56Z","timestamp":1791230996740,"version":"4.1.0"},"reference-count":37,"publisher":"Public Library of Science (PLoS)","issue":"7","license":[{"start":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T00:00:00Z","timestamp":1658448000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>\n                    Cancer genomic heterogeneity presents significant challenges for understanding oncogenic processes and for cancer\u2019s clinical management. Variation in driver mutation frequency between patients with the same tumor type as well as within an individual patients\u2019 cancer can shape the use of mutations as diagnostic, prognostic, and predictive biomarkers. We have characterized genomic heterogeneity between and within canine splenic hemangiosarcoma (HSA), a common naturally occurring cancer in pet dogs that is similar to human angiosarcoma (AS). HSA is a clinically, physiologically, and genomically complex canine cancer that may serve as a valuable model for understanding the origin and clinical impact of cancer heterogeneity. We conducted a prospective collection of 52 splenic masses from 43 dogs (27 HSA, 15 benign masses, and 1 stromal sarcoma) presenting for emergency care with hemoperitoneum secondary to a ruptured splenic mass. Multi-platform genomic analysis included matched tumor\/normal targeted sequencing panel and exome sequencing. We found candidate somatic cancer driver mutations in 14\/27 (52%) HSAs. Among recurrent candidate driver mutations,\n                    <jats:italic>TP53<\/jats:italic>\n                    was most commonly mutated (30%) followed by\n                    <jats:italic>PIK3CA<\/jats:italic>\n                    (15%),\n                    <jats:italic>AKT1<\/jats:italic>\n                    (11%), and\n                    <jats:italic>CDKN2AIP<\/jats:italic>\n                    (11%). We also identified significant intratumoral genomic heterogeneity, consistent with a branched evolution model, through multi-region exome sequencing of three distinct tumor regions from selected primary splenic tumors. These data provide new perspectives on the genomic landscape of this veterinary cancer and suggest a cross-species value for using HSA in pet dogs as a naturally occurring model of intratumoral heterogeneity.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0264986","type":"journal-article","created":{"date-parts":[[2022,7,22]],"date-time":"2022-07-22T16:05:12Z","timestamp":1658505912000},"page":"e0264986","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":24,"title":["Genomic landscapes of canine splenic angiosarcoma (hemangiosarcoma) contain extensive heterogeneity within and between patients"],"prefix":"10.1371","volume":"17","author":[{"given":"Shukmei","family":"Wong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"E. J.","family":"Ehrhart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1148-2589","authenticated-orcid":true,"given":"Samuel","family":"Stewart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victoria","family":"Zismann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2993-5179","authenticated-orcid":true,"given":"Jacob","family":"Cawley","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebecca","family":"Halperin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Natalia","family":"Briones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith","family":"Richter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karthigayini","family":"Sivaprakasam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nieves","family":"Perdigones","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Contente-Cuomo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Salvatore","family":"Facista","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey M.","family":"Trent","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammed","family":"Murtaza","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chand","family":"Khanna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7192-8699","authenticated-orcid":true,"given":"William P. D.","family":"Hendricks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2022,7,22]]},"reference":[{"issue":"8","key":"pone.0264986.ref001","doi-asserted-by":"crossref","first-page":"686","DOI":"10.1038\/embor.2013.92","article-title":"Cancer heterogeneity\u2014a multifaceted view","volume":"14","author":"EMF De Sousa","year":"2013","journal-title":"EMBO Rep"},{"issue":"2","key":"pone.0264986.ref002","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1038\/nrclinonc.2017.166","article-title":"Tumour heterogeneity and resistance to cancer therapies","volume":"15","author":"I Dagogo-Jack","year":"2018","journal-title":"Nat Rev Clin Oncol"},{"issue":"6","key":"pone.0264986.ref003","doi-asserted-by":"crossref","first-page":"1485","DOI":"10.1002\/cam4.293","article-title":"The impact of genetic heterogeneity on biomarker development in kidney cancer assessed by multiregional sampling","volume":"3","author":"A Sankin","year":"2014","journal-title":"Cancer Med"},{"issue":"9","key":"pone.0264986.ref004","doi-asserted-by":"crossref","first-page":"10051","DOI":"10.18632\/oncotarget.7067","article-title":"Pan-cancer analysis of intratumor heterogeneity as a prognostic determinant of survival.","volume":"7","author":"LG Morris","year":"2016","journal-title":"Oncotarget"},{"key":"pone.0264986.ref005","first-page":"842","author":"DM Vail","year":"2020","edition":"6"},{"issue":"8","key":"pone.0264986.ref006","doi-asserted-by":"crossref","first-page":"781","DOI":"10.3109\/07357900009012210","article-title":"Spontaneously occurring tumors of companion animals as models for human cancer","volume":"18","author":"DM Vail","year":"2000","journal-title":"Cancer Invest"},{"issue":"4","key":"pone.0264986.ref007","doi-asserted-by":"crossref","first-page":"376","DOI":"10.1038\/ng.2921","article-title":"Recurrent PTPRB and PLCG1 mutations in angiosarcoma","volume":"46","author":"S Behjati","year":"2014","journal-title":"Nat Genet"},{"issue":"5","key":"pone.0264986.ref008","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1354\/vp.42-5-618","article-title":"Mutations of phosphatase and tensin homolog deleted from chromosome 10 in canine hemangiosarcoma","volume":"42","author":"EB Dickerson","year":"2005","journal-title":"Vet Pathol"},{"issue":"4","key":"pone.0264986.ref009","doi-asserted-by":"crossref","first-page":"985","DOI":"10.1016\/j.ajpath.2013.12.025","article-title":"Identification of three molecular and functional subtypes in canine hemangiosarcoma through gene expression profiling and progenitor cell characterization","volume":"184","author":"BH Gorden","year":"2014","journal-title":"Am J Pathol"},{"issue":"12","key":"pone.0264986.ref010","doi-asserted-by":"crossref","first-page":"2410","DOI":"10.1158\/1541-7786.MCR-19-0221","article-title":"Comparative Genomics Reveals Shared Mutational Landscape in Canine Hemangiosarcoma and Human Angiosarcoma","volume":"17","author":"K Megquier","year":"2019","journal-title":"Mol Cancer Res"},{"key":"pone.0264986.ref011","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1186\/1471-2407-10-619","article-title":"Gene expression profiling identifies inflammation and angiogenesis as distinguishing features of canine hemangiosarcoma","volume":"10","author":"BA Tamburini","year":"2010","journal-title":"BMC Cancer"},{"issue":"3","key":"pone.0264986.ref012","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1007\/s10577-014-9406-z","article-title":"Genomic profiling reveals extensive heterogeneity in somatic DNA copy number aberrations of canine hemangiosarcoma","volume":"22","author":"R Thomas","year":"2014","journal-title":"Chromosome Res"},{"issue":"3","key":"pone.0264986.ref013","doi-asserted-by":"crossref","first-page":"e0229728","DOI":"10.1371\/journal.pone.0229728","article-title":"Molecular subtypes in canine hemangiosarcoma reveal similarities with human angiosarcoma","volume":"15","author":"G Wang","year":"2020","journal-title":"PLoS One"},{"issue":"5","key":"pone.0264986.ref014","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1158\/1541-7786.MCR-20-0937","article-title":"Genomically Complex Human Angiosarcoma and Canine Hemangiosarcoma Establish Convergent Angiogenic Transcriptional Programs Driven by Novel Gene Fusions","volume":"19","author":"JH Kim","year":"2021","journal-title":"Mol Cancer Res"},{"key":"pone.0264986.ref015","article-title":"Canine Oncopanel: A capture-based, NGS platform for evaluating the mutational landscape and detecting putative driver mutations in canine cancers.","author":"G Wang","year":"2021","journal-title":"Vet Comp Oncol"},{"issue":"11","key":"pone.0264986.ref016","doi-asserted-by":"crossref","first-page":"e0188667","DOI":"10.1371\/journal.pone.0188667","article-title":"Actionable mutations in canine hemangiosarcoma","volume":"12","author":"G Wang","year":"2017","journal-title":"PLoS One"},{"issue":"4","key":"pone.0264986.ref017","doi-asserted-by":"crossref","first-page":"811","DOI":"10.1111\/vco.12621","article-title":"Prospective observational study of dogs with splenic mass rupture suggests potentially lower risk of malignancy and more favourable perioperative outcomes","volume":"18","author":"SD Stewart","year":"2020","journal-title":"Vet Comp Oncol"},{"key":"pone.0264986.ref018","doi-asserted-by":"crossref","first-page":"8760","DOI":"10.1038\/ncomms9760","article-title":"Multifocal clonal evolution characterized using circulating tumour DNA in a case of metastatic breast cancer","volume":"6","author":"M Murtaza","year":"2015","journal-title":"Nat Commun"},{"key":"pone.0264986.ref019","author":"B. Institute","year":"2019"},{"key":"pone.0264986.ref020","article-title":"ea-utils: \"Command-line tools for processing biological sequencing data","author":"E. Aronesty","year":"2011"},{"key":"pone.0264986.ref021","author":"S. Andrews","year":"2010","journal-title":"FastQC: A Quality Control Tool for High Throughput Sequence Data"},{"issue":"14","key":"pone.0264986.ref022","doi-asserted-by":"crossref","first-page":"1754","DOI":"10.1093\/bioinformatics\/btp324","article-title":"Fast and accurate short read alignment with Burrows-Wheeler transform","volume":"25","author":"H Li","year":"2009","journal-title":"Bioinformatics"},{"issue":"16","key":"pone.0264986.ref023","doi-asserted-by":"crossref","first-page":"2078","DOI":"10.1093\/bioinformatics\/btp352","article-title":"The Sequence Alignment\/Map format and SAMtools","volume":"25","author":"H Li","year":"2009","journal-title":"Bioinformatics"},{"issue":"6452","key":"pone.0264986.ref024","doi-asserted-by":"crossref","DOI":"10.1126\/science.aau9923","article-title":"Somatic evolution and global expansion of an ancient transmissible cancer lineage","volume":"365","author":"A Baez-Ortega","year":"2019","journal-title":"Science"},{"key":"pone.0264986.ref025","doi-asserted-by":"crossref","first-page":"11 0 1","DOI":"10.1002\/0471250953.bi1110s43","article-title":"From FastQ data to high confidence variant calls: the Genome Analysis Toolkit best practices pipeline","volume":"43","author":"GA Van der Auwera","year":"2013","journal-title":"Curr Protoc Bioinformatics"},{"issue":"5","key":"pone.0264986.ref026","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nbt.4096","article-title":"Integrating single-cell transcriptomic data across different conditions, technologies, and species","volume":"36","author":"A Butler","year":"2018","journal-title":"Nat Biotechnol"},{"issue":"14","key":"pone.0264986.ref027","doi-asserted-by":"crossref","first-page":"1811","DOI":"10.1093\/bioinformatics\/bts271","article-title":"Strelka: accurate somatic small-variant calling from sequenced tumor-normal sample pairs","volume":"28","author":"CT Saunders","year":"2012","journal-title":"Bioinformatics"},{"issue":"3","key":"pone.0264986.ref028","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1038\/nbt.2514","article-title":"Sensitive detection of somatic point mutations in impure and heterogeneous cancer samples","volume":"31","author":"K Cibulskis","year":"2013","journal-title":"Nat Biotechnol"},{"key":"pone.0264986.ref029","article-title":"Scaling accurate genetic variant discovery to tens of thousands of samples","author":"R Poplin","year":"2018","journal-title":"bioRxiv"},{"key":"pone.0264986.ref030","author":"E Garrison","year":"2012","journal-title":"Haplotype-based variant detection from short-read sequencing"},{"issue":"21","key":"pone.0264986.ref031","doi-asserted-by":"crossref","first-page":"2987","DOI":"10.1093\/bioinformatics\/btr509","article-title":"A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data","volume":"27","author":"H. Li","year":"2011","journal-title":"Bioinformatics"},{"issue":"2","key":"pone.0264986.ref032","doi-asserted-by":"crossref","first-page":"80","DOI":"10.4161\/fly.19695","article-title":"A program for annotating and predicting the effects of single nucleotide polymorphisms, SnpEff: SNPs in the genome of Drosophila melanogaster strain w1118; iso-2; iso-3","volume":"6","author":"P Cingolani","year":"2012","journal-title":"Fly (Austin)."},{"key":"pone.0264986.ref033","doi-asserted-by":"crossref","first-page":"3401","DOI":"10.2147\/OTT.S196638","article-title":"Assessment of tumor mutation burden calculation from gene panel sequencing data","volume":"12","author":"Z Xu","year":"2019","journal-title":"Onco Targets Ther"},{"issue":"1","key":"pone.0264986.ref034","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1093\/annonc\/mdu479","article-title":"Sequenza: allele-specific copy number and mutation profiles from tumor sequencing data.","volume":"26","author":"F Favero","year":"2015","journal-title":"Ann Oncol"},{"issue":"19","key":"pone.0264986.ref035","doi-asserted-by":"crossref","first-page":"5866","DOI":"10.1158\/1078-0432.CCR-19-1145","article-title":"Identification of Recurrent Activating HER2 Mutations in Primary Canine Pulmonary Adenocarcinoma","volume":"25","author":"G Lorch","year":"2019","journal-title":"Clin Cancer Res"},{"key":"pone.0264986.ref036","article-title":"Genomic analysis reveals shared genes and pathways in human and canine angiosarcoma.","author":"K. Lindblad-Toh","year":"2019","journal-title":"bioRxiv"},{"issue":"7069","key":"pone.0264986.ref037","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/nature04338","article-title":"Genome sequence, comparative analysis and haplotype structure of the domestic dog","volume":"438","author":"K Lindblad-Toh","year":"2005","journal-title":"Nature"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0264986","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,12]],"date-time":"2023-02-12T06:36:21Z","timestamp":1676183781000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0264986"}},"subtitle":[],"editor":[{"given":"Douglas H.","family":"Thamm","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2022,7,22]]},"references-count":37,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2022,7,22]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0264986","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.11.15.380048","asserted-by":"object"}]},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,7,22]]}}}