The genomic architecture of melanoma

NK Hayward1,2, JS Wilmott2, N Waddell1, PA Johansson1, JV Pearson1, JF Thompson2, RA Scolyer2 and GJ Mann2

  1. QIMR Berghofer Medical Research Institute, Brisbane, QLD
  2. Melanoma Institute Australia, The University of Sydney, NSW

Australia has the highest incidence of cutaneous melanoma worldwide, where it is the fourth most common cancer and a leading cause of cancer death in young adults. Late stage metastatic melanoma was until very recently usually rapidly fatal. However, inhibitors of the MAP kinase pathway and of immune checkpoint mechanisms have dramatically extended patient survival, highlighting the importance of identification of therapeutic targets in cancer through molecular characterization. To comprehensively extend the molecular characterization of melanoma, the Australian Melanoma Genome Project (AMGP) was launched in August 2012 with the support of Melanoma Institute Australia, the Australian Government via Bioplatforms Australia, NSW Health and the Cancer Council NSW. The AMGP aims to analyse whole genomes from 500 primary and metastatic melanomas. To date, whole genome sequencing (WGS) has been completed on matched tumour and blood DNA from 183 patients with cutaneous, acral or mucosal subtypes of melanoma. The landscape of coding and non-coding mutations in cutaneous melanoma showed signatures of ultraviolet radiation induced mutagenesis. In contrast, acral and mucosal melanomas had mutation signatures of unknown aetiology and were dominated by structural changes. TERT promoter mutations were the most frequent, however neither they nor ATRX mutations, associated with alternative lengthening of telomeres, were correlated with greater telomere length. Almost all melanomas had potentially actionable mutations, and most of these were in components of the mitogen-activated protein kinase and phosphoinositol kinase pathways.