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Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Through whole-genome sequencing of 13 melanoma metastases sampled at autopsy from a treatment naïve patient and by leveraging the analytical power of multi-sample analyses, we reveal evidence of diversification among metastatic lineages. UV-induced mutations dominate the trunk, whereas APOBEC-associated mutations are found in the branches of the evolutionary tree. Multi-sample analyses from a further seven patients confirmed that lineage diversification was pervasive, representing an important mode of melanoma dissemination. Our analyses demonstrate that joint analysis of cancer cell fraction estimates across multiple metastases can uncover previously unrecognised levels of tumour heterogeneity and highlight the limitations of inferring heterogeneity from a single biopsy.

Original publication

DOI

10.1038/s41467-020-18060-0

Type

Journal article

Journal

Nat Commun

Publication Date

27/08/2020

Volume

11

Keywords

Aged, Biopsy, Clonal Evolution, DNA Mutational Analysis, Genetic Heterogeneity, Humans, Male, Melanoma, Prospective Studies, Skin, Skin Neoplasms, Whole Genome Sequencing