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We developed ORION-FISH, which integrates high-plex tissue imaging with a morphology-preserving DNA fluorescence in situ hybridization (DNA-FISH) workflow and single-cell registration, yielding measurements concordant with clinical FISH. In high-grade serous ovarian carcinoma (HGSOC), ORION-FISH recapitulated known chromosomal changes while revealing subclonal heterogeneity missed by targeted sequencing. Applied to serous tubal intraepithelial carcinomas, precursors of HGSOC, ORION-FISH identified intermixed epithelial cells with MYC or CCNE1 copy-number gains, as well as concurrent alterations associated with distinct immune microenvironments. In addition, epithelial cells with MYC and CCNE1 copy-number gains were detected in morphologically normal fallopian tube epithelium, along with rare MDM4 increases across epithelial lineages. Together, ORION-FISH provides a framework linking chromosomal copy-number states to protein-defined phenotypes within preserved tissue architecture, enabling context-aware interrogation of early copy-number diversification at single-cell resolution.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Significance:<\/jats:title>\n                    <jats:p>We introduce ORION-FISH, a spatially resolved workflow integrating multiplexed protein imaging with DNA-FISH to map genomic alterations within intact tissues. Applying this approach to ovarian cancer precursors reveals early copy-number diversification and associations with the local immune context, providing a foundation for studying how genomic and microenvironmental states coevolve during tumor initiation.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1158\/2159-8290.cd-26-0171","type":"journal-article","created":{"date-parts":[[2026,4,18]],"date-time":"2026-04-18T19:31:13Z","timestamp":1776540673000},"page":"1750-1764","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Spatial Integration of Protein and Chromosomal States Reveals Early Copy-Number Changes and Genotype-Associated Immune Neighborhoods in Serous Ovarian Cancer Evolution"],"prefix":"10.1158","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1463-7593","authenticated-orcid":false,"given":"Tanjina","family":"Kader","sequence":"first","affiliation":[{"name":"1Laboratory of Systems 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