Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling

Ismael A. Vergara, Christopher P. Mintoff, Shahneen Sandhu, Lachlan McIntosh, Richard J. Young, Stephen Q. Wong, Andrew Colebatch, Daniel L. Cameron, Julia Lai Kwon, Rory Wolfe, Angela Peng, Jason Ellul, Xuelin Dou, Clare Fedele, Samantha Boyle, Gisela Mir Arnau, Jeanette Raleigh, Athena Hatzimihalis, Pacman Szeto, Jennifer MooiDaniel S. Widmer, Phil F. Cheng, Valerie Amann, Reinhard Dummer, Nicholas Hayward, James Wilmott, Richard A. Scolyer, Raymond J. Cho, David Bowtell, Heather Thorne, Kathryn Alsop, Stephen Cordner, Noel Woodford, Jodie Leditschke, Patricia O’Brien, Sarah-Jane Dawson, Grant A. McArthur, Graham J. Mann, Mitchell P. Levesque, Anthony T. Papenfuss, Mark Shackleton

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44 Citations (Scopus)


Although melanoma is initiated by acquisition of point mutations and limited focal copy number alterations in melanocytes-of-origin, the nature of genetic changes that characterise lethal metastatic disease is poorly understood. Here, we analyze the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times. Whole exome and genome sequencing data from 88 tumour samples reveals only limited gain of point mutations generally, with net mutational loss in some metastases. In contrast, melanoma evolution is dominated by whole genome doubling and large-scale aneuploidy, in which widespread loss of heterozygosity sculpts the burden of point mutations, neoantigens and structural variants even in treatment-naïve and primary cutaneous melanomas in some patients. These results imply that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.

Original languageEnglish
Article number1434
Number of pages15
JournalNature Communications
Issue number1
Publication statusPublished - 4 Mar 2021

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