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How renal epithelial cells tolerate this deleterious aneuploidy during early tumorigenesis remains unclear. Analysis of 949 ccRCC genomes reveals two major classes of chromosome 3p alterations: simple deletions and complex rearrangements surrounding a terminal breakpoint \u2013 a pattern we term breakpoint-confined chromothripsis. We modeled both alterations in non-transformed human renal proximal tubule epithelial cells by introducing a single DNA double-strand break on chromosome 3p. Despite an initial fitness disadvantage, chromosome 3p loss drives adaptive genomic evolution that recapitulates recurrent ccRCC-associated aneuploidies, including 5q gain and 14q loss. These alterations alleviate the fitness constraints of 3p loss and promote metabolic reprogramming, clonal expansion, and malignant transformation, producing tumors with features of ccRCC. Thus, a single chromosome break initiates the evolutionary trajectory of ccRCC by creating a fitness bottleneck that selects for recurrent aneuploidies.<\/jats:p>","DOI":"10.64898\/2026.07.10.737056","type":"posted-content","created":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T23:05:22Z","timestamp":1783724722000},"source":"Crossref","is-referenced-by-count":0,"title":["A single chromosome 3p break initiates clear cell renal cell carcinoma evolution"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7985-0862","authenticated-orcid":false,"given":"Rashmi","family":"Dahiya","sequence":"first","affiliation":[{"name":"Children\u2019s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, 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, Cambridge, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9073-3835","authenticated-orcid":false,"given":"Chengheng","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9535-3620","authenticated-orcid":false,"given":"Angad","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2755-9317","authenticated-orcid":false,"given":"Yu-Fen","family":"Lin","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahyeon","family":"Ko","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amanda K.","family":"Mennie","sequence":"additional","affiliation":[{"name":"Children\u2019s Medical Center Research Institute, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6698-2893","authenticated-orcid":false,"given":"Emilija","family":"Aleksandrovic","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2016-3494","authenticated-orcid":false,"given":"Justin L.","family":"Engel","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey","family":"Miyata","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA"},{"name":"Kidney Cancer Program, Harold C. 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