Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling
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Published:2021-03-04
Issue:1
Volume:12
Page:
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ISSN:2041-1723
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Container-title:Nature Communications
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language:en
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Short-container-title:Nat Commun
Author:
Vergara Ismael A.ORCID, Mintoff Christopher P., Sandhu Shahneen, McIntosh Lachlan, Young Richard J., Wong Stephen Q., Colebatch Andrew, Cameron Daniel L.ORCID, Kwon Julia Lai, Wolfe RoryORCID, Peng Angela, Ellul JasonORCID, Dou Xuelin, Fedele Clare, Boyle Samantha, Arnau Gisela MirORCID, Raleigh Jeanette, Hatzimihalis AthenaORCID, Szeto PacmanORCID, Mooi Jennifer, Widmer Daniel S., Cheng Phil F.ORCID, Amann Valerie, Dummer ReinhardORCID, Hayward NicholasORCID, Wilmott JamesORCID, Scolyer Richard A.ORCID, Cho Raymond J., Bowtell David, Thorne Heather, Alsop Kathryn, Cordner Stephen, Woodford Noel, Leditschke Jodie, O’Brien Patricia, Dawson Sarah-JaneORCID, McArthur Grant A., Mann Graham J.ORCID, Levesque Mitchell P., Papenfuss Anthony T.ORCID, Shackleton MarkORCID
Abstract
AbstractAlthough 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.
Funder
Department of Health | National Health and Medical Research Council Lorenzo and Pamela Galli Charitable Trust
Publisher
Springer Science and Business Media LLC
Subject
General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry
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