Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling
Vergara, Ismael A., Mintoff, Christopher P., Sandhu, Shahneen, McIntosh, Lachlan, Young, Richard J., Wong, Stephen, Colebatch, Andrew, Cameron, Daniel L., Kwon, Julia Lai, Wolfe, Rory, Peng, Angela, Ellul, Jason, Dou, Xuelin, Fedele, Clare, Boyle, Samantha, Arnau, Gisela Mir, Raleigh, Jeanette, Hatzimihalis, Athena, Szeto, Pacman, Mooi, Jennifer, Widmer, Daniel S., Cheng, Phil F., Amann, Valerie, Dummer, Reinhard, Hayward, Nicholas, Wilmott, James, Scolyer, Richard A., Cho, Raymond J., Bowtell, David, Thorne, Heather, Alsop, Kathryn, Cordner, Stephen, Woodford, Noel, Leditschke, Jodie, O’Brien, Patricia, Dawson, Sarah Jane, McArthur, Grant A., Mann, Graham J., Levesque, Mitchell P., Papenfuss, Anthony T., and Shackleton, Mark (2021) Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling. Nature Communications, 12 (1). 1434.
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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.
| Item ID: | 75272 |
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| Item Type: | Article (Research - C1) |
| ISSN: | 2041-1723 |
| Copyright Information: | Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
| Funders: | National Health and Medical Research Council of Australia (NHMRC) |
| Projects and Grants: | NHMRC 1054618, NHMRC 1116955 |
| Date Deposited: | 17 Aug 2022 00:36 |
| FoR Codes: | 32 BIOMEDICAL AND CLINICAL SCIENCES > 3211 Oncology and carcinogenesis > 321109 Predictive and prognostic markers @ 50% 32 BIOMEDICAL AND CLINICAL SCIENCES > 3211 Oncology and carcinogenesis > 321103 Cancer genetics @ 50% |
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