Dataset Information

Molecular Characteristics of Conjunctival Melanoma Using Whole-Exome Sequencing.

ABSTRACT: Importance:Conjunctival melanoma (CM) is a highly aggressive ocular cancer for which treatment options are limited; the molecular pathogenesis is poorly understood. Objective:To identify the molecular characteristics of CM using next-generation whole-exome sequencing (WES). Design, Setting, and Participants:Whole-exome sequencing was performed on tumor DNA extracted from the archived specimens of 5 patients with CM who had been treated with surgical excision between 2006 and 2011. These samples were analyzed at a tertiary academic ocular oncology referral center using a customized bioinformatic pipeline. Main Outcomes and Measures:Sample analyses were designed to detect driver mutations, chromosome copy number aberrations, and mutation signatures. Results:The study’s 5 patients ranged in age from 51 to 77 years. Four of the 5 were female, and all were white. Mutations were detected in known oncogenes, including BRAF, NRAS, NF1, EGFR, ALK, TERT, and APC. None of the mutations associated with uveal melanoma were found. All samples demonstrated a C?T mutation signature typical of UV-induced DNA damage. The most common CNA was a gain in chromosome 6p. Conclusions and Relevance:In these 5 patients, WES allowed identification of mutations that can be targeted with therapy and supported the role of UV light in CM pathogenesis. These findings indicate a need for larger studies to evaluate the diagnostic, prognostic, and therapeutic value of WES for CM.

SUBMITTER: Swaminathan SS

PROVIDER: S-EPMC5782797 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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Molecular Characteristics of Conjunctival Melanoma Using Whole-Exome Sequencing.

Swaminathan Swarup S SS Field Matthew G MG Sant David D Wang Gaofeng G Galor Anat A Dubovy Sander R SR Harbour J William JW Karp Carol L CL

JAMA ophthalmology 20171201 12

<h4>Importance</h4>Conjunctival melanoma (CM) is a highly aggressive ocular cancer for which treatment options are limited; the molecular pathogenesis is poorly understood.<h4>Objective</h4>To identify the molecular characteristics of CM using next-generation whole-exome sequencing (WES).<h4>Design, setting, and participants</h4>Whole-exome sequencing was performed on tumor DNA extracted from the archived specimens of 5 patients with CM who had been treated with surgical excision between 2006 an ...[more]

PMID: 29121185

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Project description:Background:Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we performed an exome-wide, gene-based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM). Methods:Using 11?990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by large-scale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Four models were used to estimate the association among different types of variants. In vitro functional validation was performed using three human melanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of human melanoma A375 melanoma cells in nude mice (eight mice per group). All statistical tests were two-sided. Results:Strong signals were detected for CDKN2A (Pmin = 6.16?×?10-8) in the CM cohort (n?=?273) and BAP1 (Pmin = 3.83?×?10-6) in the OM (n?=?99) cohort. Eleven genes that exhibited borderline association (P < 10-4) were independently validated using The Cancer Genome Atlas melanoma cohort (379?CM, 47 OM) and a matched set of 3563 European controls with CDKN2A (P = .009), BAP1 (P = .03), and EBF3 (P = 4.75?×?10-4), a candidate risk locus, all showing evidence of replication. EBF3 was then evaluated using germline data from a set of 132 familial melanoma cases and 4769 controls of UK origin (joint P = 1.37?×?10-5). Somatically, loss of EBF3 expression correlated with progression, poorer outcome, and high MITF tumors. Functionally, induction of EBF3 in melanoma cells reduced cell growth in vitro, retarded tumor formation in vivo, and reduced MITF levels. Conclusions:The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene.

Dataset Information

Molecular Characteristics of Conjunctival Melanoma Using Whole-Exome Sequencing.

Publications

Molecular Characteristics of Conjunctival Melanoma Using Whole-Exome Sequencing.

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