Whole genome landscapes of uveal melanoma show an ultraviolet radiation signature in iris tumours

Peter A. Johansson(QIMR Berghofer Medical Research Institute), Kelly Brooks(QIMR Berghofer Medical Research Institute), Felicity Newell(QIMR Berghofer Medical Research Institute), Jane M. Palmer(QIMR Berghofer Medical Research Institute), James S. Wilmott(The University of Sydney), Antonia L. Pritchard(QIMR Berghofer Medical Research Institute), Natasa Broit(The University of Queensland), Scott Wood(QIMR Berghofer Medical Research Institute), Matteo S. Carlino(The University of Sydney), Conrad Leonard(QIMR Berghofer Medical Research Institute), Lambros T. Koufariotis(QIMR Berghofer Medical Research Institute), Vaishnavi Nathan(The University of Queensland), Aaron B. Beasley(Edith Cowan University), Madeleine Howlie(QIMR Berghofer Medical Research Institute), Rebecca Dawson(QIMR Berghofer Medical Research Institute), Helen Rizos(The University of Sydney), Christopher Schmidt(QIMR Berghofer Medical Research Institute), Georgina V. Long(The University of Sydney), Hayley R. Hamilton(QIMR Berghofer Medical Research Institute), Jens Folke Kiilgaard(University of Copenhagen), Timothy Isaacs(The University of Western Australia), Elin S. Gray(Edith Cowan University), Olivia Rolfe(City Eye Centre), John Park(Macquarie University), Andrew Stark(City Eye Centre), Graham J. Mann(Australian National University), Richard A. Scolyer(The University of Sydney), John V. Pearson(QIMR Berghofer Medical Research Institute), Nicolas van Baren(Ludwig Cancer Research), Nicola Waddell(QIMR Berghofer Medical Research Institute), Karin Wadt(Rigshospitalet), Lindsay A. McGrath(City Eye Centre), Sunil Warrier(City Eye Centre), William Glasson(City Eye Centre), Nicholas K. Hayward(QIMR Berghofer Medical Research Institute)
Nature Communications
May 15, 2020
10.1038/s41467-020-16276-8
Cited by 143Open Access
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Abstract

Uveal melanoma (UM) is the most common intraocular tumour in adults and despite surgical or radiation treatment of primary tumours, ~50% of patients progress to metastatic disease. Therapeutic options for metastatic UM are limited, with clinical trials having little impact. Here we perform whole-genome sequencing (WGS) of 103 UM from all sites of the uveal tract (choroid, ciliary body, iris). While most UM have low tumour mutation burden (TMB), two subsets with high TMB are seen; one driven by germline MBD4 mutation, and another by ultraviolet radiation (UVR) exposure, which is restricted to iris UM. All but one tumour have a known UM driver gene mutation (GNAQ, GNA11, BAP1, PLCB4, CYSLTR2, SF3B1, EIF1AX). We identify three other significantly mutated genes (TP53, RPL5 and CENPE).

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