{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:19:25Z","timestamp":1792790365076,"version":"4.5.0"},"posted":{"date-parts":[[2026,9,29]]},"group-title":"Genomics","reference-count":70,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/02q83sc19","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Cluster of Excellence iFIT (EXC 2180) \u201cImage-Guided and Functionally Instructed Tumor Therapies\u201d,"},{"name":"Deutsche Forschungsgemeinschaft","id":[{"id":"https:\/\/ror.org\/018mejw64","id-type":"ROR","asserted-by":"crossref"}]},{"name":"National Institutes of Health"},{"name":"Melanoma Research Alliance","id":[{"id":"https:\/\/ror.org\/025ck6r46","id-type":"ROR","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,29]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Genomic events and their timing that grant a primary tumour the competence to disseminate remain poorly defined. We performed sequencing of 247 stage I\/II primary cutaneous melanomas (CMs) and 60 matched metastases without intervening therapy from a prospectively followed registry cohort with a median followup of 92 months, integrating copy-number, mutational, protein and spatial-transcriptomic analyses. Relapse was not distinguished by oncogenic point mutations, which were largely shared between primaries and metastases, but by somatic copy-number alterations (SCNAs) and global chromosomal instability. We defined OncoCycle, a six-gene copy-number signature (amplification of\n                  <jats:italic>CDK4<\/jats:italic>\n                  ,\n                  <jats:italic>MCL1<\/jats:italic>\n                  and\n                  <jats:italic>CD276<\/jats:italic>\n                  ; biallelic loss of\n                  <jats:italic>CDKN2A<\/jats:italic>\n                  ,\n                  <jats:italic>CDKN2B<\/jats:italic>\n                  and\n                  <jats:italic>TP53BP1<\/jats:italic>\n                  ) that predicted relapse independently of established clinicopathological features in melanoma, and a pan-cancer analysis. In matched pairs, metastatic progression was driven by continued copy-number evolution and reduction in intra-tumoural heterogeneity, rather than by acquired point mutations, and OncoCycle alterations from primary tumours were preserved in metastasis seeding clones. Clonal reconstruction revealed both monoclonal and polyclonal metastasis seeding, and spatial transcriptomics resolved copy-number-defined metastatic subclones occupying and programming distinct immune and stromal niches. Thus, metastatic competence was primed early by focal SCNAs on a background of chromosomal instability, elaborated by continued copy-number evolution during dissemination and spatio-temporal interactions with the tumour-microenvironment.\n                <\/jats:p>","DOI":"10.64898\/2026.09.23.753695","type":"posted-content","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T16:35:19Z","timestamp":1790699719000},"source":"Crossref","is-referenced-by-count":0,"title":["Genomic correlates of metastatic competence and progression in human melanoma"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7843-7160","authenticated-orcid":false,"given":"Eftychia","family":"Chatziioannou","sequence":"first","affiliation":[{"name":"Department of Dermatology, University Hospital T\u00fcbingen, Eberhard Karls University T\u00fcbingen, T\u00fcbingen, Germany"},{"name":"1st Department of Dermatology and Venereology, \u201cAndreas Sygros\u201d Hospital for Skin Diseases, National & Kapodistrian University of Athens Medical School, Athens, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karan","family":"Luthria","sequence":"additional","affiliation":[{"name":"Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Parin","family":"Shah","sequence":"additional","affiliation":[{"name":"Vagelos College of Physicians and Surgeons, Herbert Irving Comprehensive Cancer Center, Columbia University, New York, New York"},{"name":"Division of Hematology\/Oncology, Department of Medicine, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, New 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