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We analyzed single-cell RNA sequencing data from 14 HER2-positive breast cancer patients and spatial transcriptomics from 8 patients. CNVs were inferred to evaluate genomic alterations and reconstruct tumor subclone evolutionary trajectories. Survival analyses were performed on CNV-correlated transcripts. We identified 68,064 cells and 4,764 spatial transcriptomic spots, and observed early and pervasive CNV events in DCIS. IDC exhibiting a higher CNV burden supported the hypothesis of progressive genomic instability during tumor evolution. Shared CNV regions across DCIS and IDC suggested the common clonal origin, favoring a multi-threaded evolutionary model. Amplifications in chromosome 17q12-21 were associated with poor prognosis. CNV-driven clonal evolution probably originates at early stages of HER2-positive breast cancer and persists through disease progression. Early CNV events may serve as predictive biomarkers and potential intervention targets to prevent disease advancement.<\/jats:p>","DOI":"10.1038\/s41598-026-44476-7","type":"journal-article","created":{"date-parts":[[2026,3,16]],"date-time":"2026-03-16T16:50:02Z","timestamp":1773679802000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Decoding clone evolution in HER2 amplified breast cancer through single-cell and spatial transcriptomics analysis of copy number variations"],"prefix":"10.1038","volume":"16","author":[{"given":"Jiao","family":"Yang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yong","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Suxia","family":"Luo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuanqiang","family":"Duan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,3,16]]},"reference":[{"issue":"7922","key":"44476_CR1","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1038\/s41586-022-05023-2","volume":"608","author":"A Erickson","year":"2022","unstructured":"Erickson, A. et al. 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