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.,Metastatic melanoma is associated with a poor prognosis and understanding the genetic features of metastases may enable better treatment strategies.,Here, the authors analyse multiple metastases from individual patients finding high levels of heterogeneity in metastases from different organs.
New therapeutic modalities for melanoma promise benefit in selected individuals.,Efficacy appears greater in patients with lower tumor burden, suggesting an important role for risk‐stratified surveillance.,Robust predictive markers might permit optimization of agent to patient, while low‐risk prognostic markers might guide more conservative management.,This review evaluates protein, gene, and multiplexed marker panels that may contribute to better risk assessment and improved management of patients with cutaneous melanoma.