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

• DOI: 10.1038/s41467-017-02674-y
• Publication Date: 2018-02-05T12:45:27Z
• Authors: Melanie Werner-Klein; Sebastian Scheitler; Martin Hoffmann; Isabelle Hodak; Klaus Dietz; Petra Lehnert; Veronika Naimer; Bernhard Polzer; Steffi Treitschke; Christian Werno; Aleksandra Markie...; Kathrin Weidele; Zbigniew Czyz; Ulrich Hohenleutner; Christian Hafner; Sebastian Haferkamp; Mark Berneburg; Petra Rümmele; Anja Ulmer; Christoph A. Klein
• Keywords: Male; 0301 basic medicine; Skin Neoplasms; Science; Transplantation, Heterologous; 610 Medizin; Mice, SCID; Article; GTP Phosphohydrolases; Proto-Oncogene Proteins p21(ras); 03 medical and health sciences; Mice, Inbred NOD; Cell Line, Tumor; Animals; Humans; Melanoma; Skin; Mice, Knockout; ddc:610; Comparative Genomic Hybridization; Q; Membrane Proteins; 3. Good health; Lymphatic Metastasis; Mutation; Female; Lymph Nodes

AbstractMouse 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, includingBRAFmutation and gained or lost regions comprising genes likeMETorCDKNA2, 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.