Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases

Roy Rabbie,David J Adams,Alejandro Jiménez-Sánchez,Kim Wong,Julia M Martínez Gómez,Martin L Miller,Laura Riva,Mark Tullett,Christine Parkinson,Naser Ansari-Pour,Ingrid Ferreira,David C Wedge,Doreen Lau,Leila Khoja,Luiza Moore,Francis Scott,Pippa Corrie,Mitchell P Levesque ,Oliver Cast,Sarah J Welsh,Ferdia A Gallagher,Kieren Allinson,Peter J Campbell

doi:10.1038/s41467-020-18060-0

Abstract

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.

Highlights

Metastatic melanoma carries a poor prognosis despite modern systemic therapies
In this paper we extend the definition of intratumour heterogeneity’ (ITH) to ‘intra-patient tumour heterogeneity’, using it to refer to the observation of variants within a tumour that are non-truncal, including variants that may be clonal within some individual samples
Our index case was a 71-year-old male of European descent with no relevant family history, who initially presented with a 1.2 mm Breslow thickness non-ulcerated, Clark level 3 superficial spreading melanoma which was resected from the anterior chest wall with a wide local excision (Fig. 1a)

Summary

Introduction

Metastatic melanoma carries a poor prognosis despite modern systemic therapies. Understanding the evolution of the disease could help inform patient management. Few studies have explored the temporal and spatial evolution of molecular alterations acquired during disease progression Such findings may inform risk and our understanding of the mode of metastatic spread, with implications for future patient management. By further showing that most somatic alterations (point mutations and copy number changes) were shared, the authors concluded that primary melanomas and melanoma metastases tend to select for the same set of pathogenic mutations. One feature of such studies is that the clonal composition of each sample is determined using the presence or absence of mutations in each sample. Inferring clonality from allelic frequencies requires an integrative approach harnessing the most sensitive sequencing technologies, while considering measures of tumour ploidy and purity

Methods

Results

Conclusion