Genomic correlates of metastatic competence and progression in human melanoma
Year: 2026
Type: preprint
Study design: Observational Study
Abstract: 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 CDK4 , MCL1 and CD276 ; biallelic loss of CDKN2A , CDKN2B and TP53BP1 ) 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.
Authors: Eftychia Chatziioannou, Karan Luthria, Parin Shah, Sorin Armeanu-Ebinger, Jakob Admard, Christopher Schroeder, Stephan Forchhammer, Frederik Stihler, Xingpei Zhang, Synaida Maiche, Zeynep Cakmak, Anette Barbara Mankel, Josua Stadelmaier, Teresa Amaral, Ulrike Leiter, Evelyn Maczey, Sven Mattern, Irina Bonzheim, Falko Fend, Claus Garbe, Yvonne Heneka, Marie Krauss, Oltin Tiberiu Pop, Laura Schreieder, Sebastian Haferkamp, Alexander J. Stratigos, Christian M. Schürch, Stephan Ossowski, Peter Martus, Sven Nahnsen, Tobias Sinnberg, Lukas Flatz, Olaf Riess, Benjamin Izar, Martin Röcken
Institutions: National and Kapodistrian University of Athens, Universitätsklinikum Tübingen, Andreas Sygros Hospital, University of Tübingen, Herbert Irving Comprehensive Cancer Center, Columbia University, Columbia University Irving Medical Center, University of Cologne, University Hospital Cologne, Quantitative Biology Center, German Cancer Research Center, Deutsches Konsortium für Translationale Krebsforschung, Kantonsspital St. Gallen, University Hospital Regensburg, Charité – Universitätsmedizin Berlin
Language: English
Subfield: Cancer Research
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W7214806430