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Brief Report
October 24, 2019

Integrative Exome and Transcriptome Analysis of Conjunctival Melanoma and Its Potential Application for Personalized Therapy

Author Affiliations
  • 1Kellogg Eye Center, Department of Ophthalmology and Visual Sciences, University of Michigan, Ann Arbor
  • 2Graduate School of Public Health, Department of Human Genetics, University of Pittsburgh, Pittsburgh, Pennsylvania
  • 3Michigan Center for Translational Pathology, University of Michigan, Ann Arbor
  • 4Department of Pathology, University of Michigan, Ann Arbor
JAMA Ophthalmol. 2019;137(12):1444-1448. doi:10.1001/jamaophthalmol.2019.4237
Key Points

Question  What are the molecular features of conjunctival melanoma?

Findings  In this case series of 8 patients with conjunctival melanoma examined, 1 had BRAF/V600E mutation, 3 had NRAS/Q61R mutation, 3 had NF1 mutations, and 1 had triple-wild type; mutation burden ranged from 1.1 to 15.6 mutations per megabase. A patient with an unresectable tumor and BRAF/V600E mutation was treated with combined systemic BRAF and MEK inhibitors, and after 3 months of therapy, conjunctival melanoma responded and the residual tumor was excised.

Meaning  Conjunctival melanoma appears to show some distinctive molecular features and its mutational profile may be worth evaluating in patients with advanced disease where neoadjuvant/adjuvant therapy may be considered.

Abstract

Importance  Greater understanding of molecular features of conjunctival melanoma (CM) may improve its clinical management.

Objective  To evaluate molecular features of CM and application of this information into clinical care.

Design, Setting, and Participants  In a prospective case series of CM with integrative exome and transcriptome analysis, 8 patients at an academic ocular oncology setting were evaluated. The study was conducted from November 2015 to March 2018.

Interventions/Exposures  Integrative exome and transcriptome analysis of CMs and clinical management of a patient’s care by using this information.

Main Outcomes and Measures  Molecular characterization of CM and its potential clinical application.

Results  In the 8 patients (4 men) included in analysis, 4 subgroups of CM were observed, including the BRAF V600E mutation in 1 tumor, NRAS Q61R mutation in 3 tumors, NF1 mutations (Q1188X, R440X, or M1215K+ S15fs) in 3 tumors, and triple-wild type (triple-WT) in 1 tumor. The triple-WT case had CCND1 amplification and mutation in the CIC gene (Q1508X). Five tumors, including the triple-WT, also harbored mutations in MAPK genes. In addition to the genes linked to mitogen-activated protein kinase and phosphoinositol 3-kinase pathways, those involved in cell cycle and/or survival, ubiquitin-mediated protein degradation, and chromatin remodeling/epigenetic regulation (ATRX being the most frequently mutated: noted in 5 tumors) may play an important role. Other frequently mutated genes included PREX2 (n = 3), APOB (n = 4), and RYR1/2 (n = 4), although their relevance remains to be determined. The mutation burden ranged from 1.1 to 15.6 mutations per megabase (Mut/Mb) and was 3.3 Mut/Mb or less in 3 tumors and more than 10 Mut/Mb in 2 tumors. A patient with a large tumor and BRAF V600E mutation was treated with combined systemic BRAF (dabrafenib) and MEK (trametinib) inhibitors. After 3 months of therapy, her CM responded substantially and the residual tumor was removed by local surgical excision.

Conclusions and Relevance  The NRAS Q61R and NF1 mutations were more common than the BRAF V600E mutation in this series. Although small tumors (where incisional biopsy is not indicated) are treated with surgical excision regardless of mutational profile, in large tumors carrying the BRAF V600E mutation, neoadjuvant therapy with combined systemic BRAF and MEK inhibitors followed by local excision may be used as an alternative to exenteration. Integrative omics analysis of CM may be informative and guide clinical management and treatment in selected cases.

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    1 Comment for this article
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    Comment to Demirci et al.: Conjunctival melanoma, genomics and personalised medicine
    Sarah Coupland, MBBS, PhD | Consultant Histopathologist, Royal Liverpool University Hospital, Liverpool, UK; George Holt Chair of Chair of Pathology, University of Liverpool, Liverpool, UK
    We read with interest the study by Demirci et al. describing the molecular genetic findings in eight conjunctival melanoma (CoM) tumours using integrative exome and transcriptome analysis.(1) Demirci et al, indeed, consolidate the main 3 mutations in CoM (BRAF, Ras and NF1) previously reported by us and others alongside amplifications and deletions of resemblance to cutaneous melanoma (CM). (2-13) It is unfortunate, however, that the authors did not quote the work from our group by Lake et al, which was one of the earliest studies describing BRAF mutations alongside amplifications on 6p and deletions in 10q in primary as well as metastatic CoM using multiplex-ligation-dependant probe amplification, neither the most recent large international collaborative study by Kenawy et al., involving multiple international ocular oncology centres of excellence.(9, 13)

    The authors state in their introduction that molecular features of CoM are not well-defined; however, we believe that there is currently improving knowledge of CoM genetics than previously, which Demirci et al might have missed by the oversight of our multicentre-collaborative study that examined 59 CoM samples. We detailed copy number alterations (CNAs), and unprecedentedly their frequencies, using Single Nucleotide Polymorphism array. (13) We also reported the novel finding of chromosome 10 deletions, inclusive of tumour suppressor genes those well-recognised in CM, their significant metastatic potential and possible prognostic role in CoM. Indeed, our study provided an unparalleled comprehensive reference database of CoM-specific genetic aberrations and similarity to its cutaneous counterpart.

    With regards to the treatment of advanced local CoM, we do not believe that primary management of the local tumour with systemic therapy is advantageous; we rather advocate prompt treatment of the primary tumour, even exenteration, as key to preventing metastasis. (14, 15) We agree with Demirci et al, that there are regional and multi‐gene involvement in CoM pathogenesis, however, yet to be studied whether such multi-alterations are maintained within metastatic seeds, then, ideally, concomitant systemic therapies are recommended. (13)

    In summary, we are pleased that the report by Demirci et al. complements the work by our group and others in enhancing the understanding of CoM genetics. Future collaborative projects into the genetics of CoM precursors and metastasis should facilitate clinical trials and the discovery of personalised therapeutic models.

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    CONFLICT OF INTEREST: None Reported
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