Genetic alterations driving metastatic colony formation are acquired outside of the primary tumour in melanoma

Melanie Werner-Klein, Sebastian Scheitler, Martin Hoffmann, Isabelle Hodak, Klaus Dietz, Petra Lehnert, Veronika Naimer, Bernhard Polzer, Steffi Treitschke, Christian Werno, Aleksandra Markiewicz, Kathrin Weidele, Zbigniew Czyz, Ulrich Hohenleutner, Christian Hafner, Sebastian Haferkamp, Mark Berneburg, Petra Rümmele, Anja Ulmer and Christoph A. Klein ()
Additional contact information
Melanie Werner-Klein: University of Regensburg
Sebastian Scheitler: University of Regensburg
Martin Hoffmann: Fraunhofer-Institute for Toxicology and Experimental Medicine
Isabelle Hodak: University of Regensburg
Klaus Dietz: University of Tübingen
Petra Lehnert: University of Tübingen
Veronika Naimer: University of Regensburg
Bernhard Polzer: Fraunhofer-Institute for Toxicology and Experimental Medicine
Steffi Treitschke: Fraunhofer-Institute for Toxicology and Experimental Medicine
Christian Werno: Fraunhofer-Institute for Toxicology and Experimental Medicine
Aleksandra Markiewicz: University of Regensburg
Kathrin Weidele: Fraunhofer-Institute for Toxicology and Experimental Medicine
Zbigniew Czyz: Fraunhofer-Institute for Toxicology and Experimental Medicine
Ulrich Hohenleutner: University of Regensburg
Christian Hafner: University of Regensburg
Sebastian Haferkamp: University of Regensburg
Mark Berneburg: University of Regensburg
Petra Rümmele: University of Regensburg
Anja Ulmer: University of Tübingen
Christoph A. Klein: University of Regensburg

Nature Communications, 2018, vol. 9, issue 1, 1-17

Abstract: Abstract Mouse models indicate that metastatic dissemination occurs extremely early; however, the timing in human cancers is unknown. We therefore determined the time point of metastatic seeding relative to tumour thickness and genomic alterations in melanoma. Here, we find that lymphatic dissemination occurs shortly after dermal invasion of the primary lesion at a median thickness of ~0.5 mm and that typical driver changes, including BRAF mutation and gained or lost regions comprising genes like MET or CDKNA2, are acquired within the lymph node at the time of colony formation. These changes define a colonisation signature that was linked to xenograft formation in immunodeficient mice and death from melanoma. Thus, melanoma cells leave primary tumours early and evolve at different sites in parallel. We propose a model of metastatic melanoma dormancy, evolution and colonisation that will inform direct monitoring of adjuvant therapy targets.

Date: 2018
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DOI: 10.1038/s41467-017-02674-y

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