Molecular Genetics of Conjunctival Melanoma and Prognostic Value of TERT Promoter Mutation Analysis.

Natasha M Van Poppelen,Dion Paridaens,Annelies De Klein,Jolanda Vaarwater,Robert M Verdijk,Jolique A Van Ipenburg,Erwin Brosens,Nicole Naus,Emine Kiliç,Tom Brands,Frank Magielsen,Bert Eussen,Quincy Van Den Bosch,Hendrikus J Dubbink

doi:10.3390/ijms22115784

Abstract

The aim of this study was exploration of the genetic background of conjunctival melanoma (CM) and correlation with recurrent and metastatic disease. Twenty-eight CM from the Rotterdam Ocular Melanoma Study group were collected and DNA was isolated from the formalin-fixed paraffin embedded tissue. Targeted next-generation sequencing was performed using a panel covering GNAQ, GNA11, EIF1AX, BAP1, BRAF, NRAS, c-KIT, PTEN, SF3B1, and TERT genes. Recurrences and metastasis were present in eight (29%) and nine (32%) CM cases, respectively. TERT promoter mutations were most common (54%), but BRAF (46%), NRAS (21%), BAP1 (18%), PTEN (14%), c-KIT (7%), and SF3B1 (4%) mutations were also observed. No mutations in GNAQ, GNA11, and EIF1AX were found. None of the mutations was significantly associated with recurrent disease. Presence of a TERT promoter mutation was associated with metastatic disease (p-value = 0.008). Based on our molecular findings, CM comprises a separate entity within melanoma, although there are overlapping molecular features with uveal melanoma, such as the presence of BAP1 and SF3B1 mutations. This warrants careful interpretation of molecular data, in the light of clinical findings. About three quarter of CM contain drug-targetable mutations, and TERT promoter mutations are correlated to metastatic disease in CM.

Highlights

Conjunctival melanoma (CM) comprises 5–10% of all ocular melanoma [1,2,3]
Pathways involved in the pathogenesis of conjunctival melanoma (CM) included the MAPK/ERK pathway and the PI3K/AKT pathways, and these pathways overlap with the pathways involved in cutaneous melanoma [6]
The mutation that we found most frequent in CM is a TERT promoter mutation, congruent with other studies concerning ocular melanoma [6,13,14] and cancer originating from other sites

Summary

Introduction

Conjunctival melanoma (CM) comprises 5–10% of all ocular melanoma [1,2,3]. The majority derives from primary acquired melanosis with atypia (PAM), but infrequently, CM develops from a pre-existing nevus or de novo [1,3,4,5,6]. CM has an incidence of 0.2–0.8 per million [3,6,7], with an increasing trend [3,8]. The 5- and 10-years cumulative incidence of CM-related mortality is 17–31% and 22–59%, respectively [5,7,9,10,11]. The prognosis of ocular melanoma, including CM and uveal melanoma (UM), depends on clinical and histopathological features, as well as the molecular genetic make-up [3,12,13]. The molecular make-up of UM has been well-characterized, with UM harboring recurrent mutations in guanine-nucleotide-binding protein-Q (GNAQ), guaninenucleotide-binding protein-alpha 11 (GNA11), BRCA-associated protein 1 (BAP1), splicing factor 3 subunit 1 (SF3B1), and eukaryotic translation initiation factor 1A (EIF1AX). BAP1 and SF3B1 mutations are associated with the development of metastasis in UM. After the diagnosis of metastatic disease, patients with UM have a survival between 2–9 months [12]

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