{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T16:17:21Z","timestamp":1785428241475,"version":"3.56.0"},"posted":{"date-parts":[[2026,4,28]]},"group-title":"Cancer Biology","reference-count":75,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006058","name":"St. Baldrick's Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100006058","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Ludwig Cancer Research"},{"id":[{"id":"https:\/\/ror.org\/01gd7b947","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012116","name":"European Bioinformatics Institute","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100012116","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,4]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Osteosarcoma (OS) genomes are characterized by complex genomic rearrangements (CGRs) that drive genomic instability and clonal diversification early in tumor evolution. As a result, OS tumors display high inter-patient variability, which has hindered molecular stratification and targeted therapeutic development. To study genomic complexity in OS and credential a genetically engineered mouse model of the disease (\n                  <jats:italic>Sp7-Cre Trp53<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>fl<\/jats:italic>\n                  <\/jats:sup>\n                  Rb1\n                  <jats:sup>fl<\/jats:sup>\n                  ), we performed high-depth and multi-region whole genome sequencing (WGS) of 35 tumor samples from 24 mice. Similar to human OS, the murine OS tumors (mOS) had a high number of somatic structural variants (158 per tumor) with low tumor mutational burden of single nucleotide variants (0.87 mutations\/MB). CGRs were identified in 63% (15\/24) of mOS cases, most frequently affecting chromosome 15 (33%, 8\/24 mice) and resulting in\n                  <jats:italic>Myc<\/jats:italic>\n                  amplification in 6 mice, ranging from 5 to 104 copies.\n                  <jats:italic>Myc<\/jats:italic>\n                  amplification was verified with DNA FISH, long-read sequencing and gene expression data, which revealed examples of\n                  <jats:italic>Myc<\/jats:italic>\n                  amplification in both extrachromosomal circular DNA (ecDNA) and in derivative chromosomes generated by CGRs.\n                  <jats:italic>PTEN<\/jats:italic>\n                  loss occurred frequently (59% 12\/22 mice), and contributed to osteosarcomagenesis, as demonstrated by tumor initiation with\n                  <jats:italic>in vivo<\/jats:italic>\n                  CRISPR\/Cas9-mediated deletion experiments (2 mice). Together, these results demonstrate that a preclinical model of osteosarcoma can generate the genomic heterogeneity and complexity of the human disease, thereby facilitating research into mechanisms of tumor initiation and drivers of progression and relapse.\n                <\/jats:p>","DOI":"10.64898\/2026.04.27.721100","type":"posted-content","created":{"date-parts":[[2026,4,29]],"date-time":"2026-04-29T08:00:24Z","timestamp":1777449624000},"source":"Crossref","is-referenced-by-count":1,"title":["Murine osteosarcoma recapitulates the driver landscape and genomic complexity of osteosarcoma evolution in humans"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1638-4219","authenticated-orcid":false,"given":"Geoffrey A.","family":"Smith","sequence":"first","affiliation":[{"name":"Dana-Farber\/Boston Children\u2019s Cancer and Blood Disorders Center; Harvard Medical School, Boston, MA, USA"},{"name":"Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2377-3586","authenticated-orcid":false,"given":"Ianthe A.E.M","family":"van Belzen","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8171-9476","authenticated-orcid":false,"given":"Mathieu","family":"Epinette","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0009-8848-7362","authenticated-orcid":false,"given":"Emilia","family":"Herdes","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8525-483X","authenticated-orcid":false,"given":"Kim L.","family":"Mercer","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9416-6057","authenticated-orcid":false,"given":"Charlotte G.","family":"Butterworth","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7287-192X","authenticated-orcid":false,"given":"Alistair G.","family":"Rust","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SA, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2832-1303","authenticated-orcid":false,"given":"Adrienne M.","family":"Flanagan","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SA, UK"},{"name":"Research Department of Pathology, University College London Cancer Institute, London WC1E 6DD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew G.","family":"Jones","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2036-494X","authenticated-orcid":false,"given":"Isidro","family":"Cortes-Ciriano","sequence":"additional","affiliation":[{"name":"European Molecular Biology Laboratory, European Bioinformatics Institute, Hinxton CB10 1SA, UK"},{"name":"Somatic Genomics Programme, Wellcome Sanger Institute, Hinxton, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5785-8911","authenticated-orcid":false,"given":"Tyler","family":"Jacks","sequence":"additional","affiliation":[{"name":"Koch Institute for Integrative Cancer Research and Department of Biology, Massachusetts Institute of Technology, Cambridge, MA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060809152049000_2026.04.27.721100v2.1","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1038\/s41572-022-00409-y","article-title":"Osteosarcoma","volume":"8","year":"2022","journal-title":"Nat. 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