Multi-site clonality analysis uncovers pervasive heterogeneity across melanoma metastases

Roy Rabbie, Naser Ansari-Pour, Oliver Cast, Doreen Lau, Francis Scott, Sarah J. Welsh, Christine Parkinson, Leila Khoja, Luiza Moore, Mark Tullett, Kim Wong, Ingrid Ferreira, Julia M. Martínez Gómez, Mitchell Levesque, Ferdia A. Gallagher, Alejandro Jiménez-Sánchez, Laura Riva, Martin L. Miller, Kieren Allinson, Peter J. Campbell, Pippa Corrie, David C. Wedge () and David J. Adams ()
Additional contact information
Roy Rabbie: Experimental Cancer Genetics, The Wellcome Sanger Institute
Naser Ansari-Pour: University of Oxford
Oliver Cast: University of Cambridge, Li Ka Shing Centre
Doreen Lau: University of Cambridge
Francis Scott: University of Cambridge
Sarah J. Welsh: Cambridge University Hospitals NHS Foundation Trust
Christine Parkinson: Cambridge University Hospitals NHS Foundation Trust
Leila Khoja: University of Birmingham
Luiza Moore: The Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute
Mark Tullett: St Richard’s Hospital, Spitalfield Lane
Kim Wong: Experimental Cancer Genetics, The Wellcome Sanger Institute
Ingrid Ferreira: Experimental Cancer Genetics, The Wellcome Sanger Institute
Julia M. Martínez Gómez: University of Zurich, University of Zurich Hospital
Mitchell Levesque: University of Zurich, University of Zurich Hospital
Ferdia A. Gallagher: University of Cambridge
Alejandro Jiménez-Sánchez: University of Cambridge, Li Ka Shing Centre
Laura Riva: Experimental Cancer Genetics, The Wellcome Sanger Institute
Martin L. Miller: University of Cambridge, Li Ka Shing Centre
Kieren Allinson: Cambridge University Hospitals NHS Foundation Trust
Peter J. Campbell: The Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute
Pippa Corrie: Cambridge University Hospitals NHS Foundation Trust
David C. Wedge: University of Oxford
David J. Adams: Experimental Cancer Genetics, The Wellcome Sanger Institute

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-18060-0

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