Dataset Information

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

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).

SUBMITTER: Johansson PA

PROVIDER: S-EPMC7229209 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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

Johansson Peter A PA Brooks Kelly K Newell Felicity F Palmer Jane M JM Wilmott James S JS Pritchard Antonia L AL Broit Natasa N Wood Scott S Carlino Matteo S MS Leonard Conrad C Koufariotis Lambros T LT Nathan Vaishnavi V Beasley Aaron B AB Howlie Madeleine M Dawson Rebecca R Rizos Helen H Schmidt Chris W CW Long Georgina V GV Hamilton Hayley H Kiilgaard Jens F JF Isaacs Timothy T Gray Elin S ES Rolfe Olivia J OJ Park John J JJ Stark Andrew A Mann Graham J GJ Scolyer Richard A RA Pearson John V JV van Baren Nicolas N Waddell Nicola N Wadt Karin W KW McGrath Lindsay A LA Warrier Sunil K SK Glasson William W Hayward Nicholas K NK

Nature communications 20200515 1

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 g ...[more]

PMID: 32415113

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Project description:Background: Uveal melanoma (UM) is the most common primary intraocular cancer in adults. Genomic studies have provided insights into molecular subgroups and oncogenic drivers of UM that may lead to novel therapeutic strategies. Methods: Dataset TCGA-UVM, download from TCGA portal, were taken as the training cohort, and dataset GSE22138, obtained from GEO database, was set as the validation cohort. In training cohort, Kaplan-Meier analysis and univariate Cox regression model were applied to preliminary screen prognostic genes. Besides, the Cox regression model with LASSO was implemented to build a multi-gene signature, which was then validated in the validation cohorts through Kaplan-Meier, Cox, and ROC analyses. In addition, the correlation between copy number aberrations and risk score was evaluated by Spearman test. GSEA and immune infiltrating analyses were conducted for understanding function annotation and the role of the signature in the tumor microenvironment. Results: A ten-gene signature was built, and it was examined by Kaplan-Meier analysis revealing that significantly overall survival, progression-free survival, and metastasis-free survival difference was seen. The ten-gene signature was further proven to be an independent risk factor compared to other clinic-pathological parameters via the Cox regression analysis. Moreover, the receiver operating characteristic curve (ROC) analysis results demonstrated a better predictive power of the UM prognosis that our signature owned. The ten-gene signature was significantly correlated with copy numbers of chromosome 3, 8q, 6q, and 6p. Furthermore, GSEA and immune infiltrating analyses showed that the signature had close interactions with immune-related pathways and the tumor environment. Conclusions: Identifying the ten-gene signature (SIRT3, HMCES, SLC44A3, TCTN1, STPG1, POMGNT2, RNF208, ANXA2P2, ULBP1, and CA12) could accurately identify patients' prognosis and had close interactions with the immunodominant tumor environment, which may provide UM patients with personalized prognosis prediction and new treatment insights.

Dataset Information

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

Publications

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

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