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 Mooi, Daniel 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 () and Mark Shackleton ()
Additional contact information
Ismael A. Vergara: Walter and Eliza Hall Institute of Medical Research
Christopher P. Mintoff: Peter MacCallum Cancer Centre
Shahneen Sandhu: Peter MacCallum Cancer Centre
Lachlan McIntosh: Walter and Eliza Hall Institute of Medical Research
Richard J. Young: Peter MacCallum Cancer Centre
Stephen Q. Wong: Peter MacCallum Cancer Centre
Andrew Colebatch: Peter MacCallum Cancer Centre
Daniel L. Cameron: Walter and Eliza Hall Institute of Medical Research
Julia Lai Kwon: Peter MacCallum Cancer Centre
Rory Wolfe: Monash University
Angela Peng: Peter MacCallum Cancer Centre
Jason Ellul: Peter MacCallum Cancer Centre
Xuelin Dou: Peter MacCallum Cancer Centre
Clare Fedele: Peter MacCallum Cancer Centre
Samantha Boyle: Peter MacCallum Cancer Centre
Gisela Mir Arnau: Peter MacCallum Cancer Centre
Jeanette Raleigh: Peter MacCallum Cancer Centre
Athena Hatzimihalis: Peter MacCallum Cancer Centre
Pacman Szeto: Peter MacCallum Cancer Centre
Jennifer Mooi: Peter MacCallum Cancer Centre
Daniel S. Widmer: University of Zürich Hospital
Phil F. Cheng: University of Zürich Hospital
Valerie Amann: University of Zürich Hospital
Reinhard Dummer: University of Zürich Hospital
Nicholas Hayward: Melanoma Institute of Australia
James Wilmott: Melanoma Institute of Australia
Richard A. Scolyer: Melanoma Institute of Australia
Raymond J. Cho: University of California
David Bowtell: Peter MacCallum Cancer Centre
Heather Thorne: Peter MacCallum Cancer Centre
Kathryn Alsop: Peter MacCallum Cancer Centre
Stephen Cordner: The Victorian Institute of Forensic Medicine
Noel Woodford: The Victorian Institute of Forensic Medicine
Jodie Leditschke: The Victorian Institute of Forensic Medicine
Patricia O’Brien: The Victorian Institute of Forensic Medicine
Sarah-Jane Dawson: Peter MacCallum Cancer Centre
Grant A. McArthur: Peter MacCallum Cancer Centre
Graham J. Mann: Melanoma Institute of Australia
Mitchell P. Levesque: University of Zürich Hospital
Anthony T. Papenfuss: Walter and Eliza Hall Institute of Medical Research
Mark Shackleton: Peter MacCallum Cancer Centre

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract 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.

Date: 2021
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DOI: 10.1038/s41467-021-21576-8

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