Journal article

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 Show all



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 t..

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Awarded by Australian National Health and Medical Research Council (NHMRC)

Awarded by EU Horizon 2020 PHC grant

Funding Acknowledgements

A.T.P. was supported by an Australian National Health and Medical Research Council (NHMRC) Program Grant (1054618) and Senior Research Fellowship (1116955), and by the Lorenzo and Pamela Galli Charitable Trust. M.S. was supported by fellowships from Pfizer Australia, NHMRC, veski and the Victorian Cancer Agency. P.F.C. was supported by EU Horizon 2020 PHC grant No. 633974 (SOUND - Statistical multi-Omics UNDerstanding of Patient Samples). R.A.S. and N.K.H. were supported by the Australian National Health and Medical Research Council (NHMRC). This research was supported by the Victorian Institute of Forensic Medicine, Tobin Brothers Funerals, the Peter MacCallum Cancer Foundation, Bioplatforms Australia, the Melanoma Institute of Australia, the Cancer Council of Victoria, the Victorian Cancer Biobank, the Melbourne Melanoma Project, the Victorian State Government Operational Infrastructure Support scheme and the Australian Government NHMRC Independent Research Institute Infrastructure Support scheme. We acknowledge the CASCADE Management Committee, staff who cared for CASCADE participants, staff at Tobin Brothers Funerals and the Victorian Institute of Forensic Medicine, and the patients and their families. We thank Jocelyn Sietsma Penington and Maria Macheda for support publishing the CASCADE data.