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Nat Commun. 2018 Feb 9;9(1):595. doi: 10.1038/s41467-017-02674-y.

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

Author information

1
Experimental Medicine and Therapy Research, University of Regensburg, Franz-Josef Strauß Allee 11, 93053, Regensburg, Germany.
2
Regensburg Center for Interventional Immunology (RCI) and University Medical Center of Regensburg, Franz-Josef Strauß Allee 11, 93053, Regensburg, Germany.
3
Division of Personalized Tumor Therapy, Fraunhofer-Institute for Toxicology and Experimental Medicine, Regensburg, Am Biopark 9, 93053, Germany.
4
Department of Medical Biometry, University of Tübingen, Silcherstr. 5, 72076, Tübingen, Germany.
5
Department of Dermatology, University of Tübingen, Liebermeisterstr. 25, 72076, Tübingen, Germany.
6
Department of Dermatology, University of Regensburg, Franz-Josef Strauß Allee 11, 93053, Regensburg, Germany.
7
Department of Pathology, University of Regensburg, Franz-Josef Strauß Allee 11, 93053, Regensburg, Germany.
8
Institute of Pathology, University Hospital, Friedrich-Alexander-University Erlangen-Nürnberg, Krankenhausstr. 8-10, 91054, Erlangen, Germany.
9
Experimental Medicine and Therapy Research, University of Regensburg, Franz-Josef Strauß Allee 11, 93053, Regensburg, Germany. Christoph.klein@ukr.de.
10
Division of Personalized Tumor Therapy, Fraunhofer-Institute for Toxicology and Experimental Medicine, Regensburg, Am Biopark 9, 93053, Germany. Christoph.klein@ukr.de.

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.

PMID:
29426936
PMCID:
PMC5807512
DOI:
10.1038/s41467-017-02674-y
[Indexed for MEDLINE]
Free PMC Article

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