Evolution of late-stage metastatic melanoma is dominated by aneuploidy and whole genome doubling
Ismael A. Vergara,Ismael A. Vergara,Christopher P. Mintoff,Shahneen Sandhu,Lachlan McIntosh,Lachlan McIntosh,Richard J. Young,Stephen Q. Wong,Andrew J. Colebatch,Daniel L Cameron,Daniel L Cameron,Julia Lai Kwon,Rory Wolfe,Angela Peng,Angela Peng,Jason Ellul,Xuelin Dou,Clare G Fedele,Samantha E. Boyle,Gisela Mir Arnau,Jeanette Raleigh,Athena Hatzimihalis,Pacman Szeto,Pacman Szeto,Jennifer Mooi,Daniel S. Widmer,Phil F. Cheng,Valerie C Amann,Reinhard Dummer,Nicholas K. Hayward,James S. Wilmott,Richard A. Scolyer,Richard A. Scolyer,Raymond J. Cho,David D.L. Bowtell,David D.L. Bowtell,Heather Thorne,Kathryn Alsop,Stephen Cordner,Noel Woodford,Jodie Leditschke,Patricia C. M. O’Brien,Sarah-Jane Dawson,Sarah-Jane Dawson,Grant A. McArthur,Grant A. McArthur,Graham J. Mann,Mitchell P. Levesque,Anthony T. Papenfuss,Mark Shackleton +49 more
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In this article, the authors analyzed the evolution of human melanoma progressing from early to late disease in 13 patients by sampling their tumours at multiple sites and times, revealing that dysregulation of genomic integrity is a key driver of selective clonal advantage during melanoma progression.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-naive 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.read more
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Molecular characterization of fast-growing melanomas
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Squaring the circle: circRNAs in melanoma.
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Inactivation of the Hippo tumor suppressor pathway promotes melanoma
TL;DR: In this article , the Hippo tumor suppressor pathway has been shown to be a critical barrier to melanoma development by activating mutations in the MAP kinase BRAF, which leads to activation in melanocytes in vitro and in vivo.
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Oncogenic BRAF Induces Whole-Genome Doubling Through Suppression of Cytokinesis
TL;DR: Together these data suggest that common abnormalities of melanomas linked to tumorigenesis - amplified centrosomes and whole-genome doubling events - can be induced by oncogenic BRAF and other mutations that increase RAS/MAPK pathway activity.
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TL;DR: Intratumor heterogeneity can lead to underestimation of the tumor genomics landscape portrayed from single tumor-biopsy samples and may present major challenges to personalized-medicine and biomarker development.
Journal ArticleDOI
Cancer Genome Landscapes
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TL;DR: This work has revealed the genomic landscapes of common forms of human cancer, which consists of a small number of “mountains” (genes altered in a high percentage of tumors) and a much larger number of "hills" (Genes altered infrequently).
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