Conjunctival Melanomas Harbor BRAF and NRAS Mutations and Copy Number Changes Similar to Cutaneous and Mucosal Melanomas

Abstract

Purpose: Conjunctival melanoma is a rare but potentially deadly tumor of the eye. Despite effective local therapies, recurrence and metastasis remain frequent. Once the tumor has metastasized, treatment options are limited and the prognosis is poor. To date, little is known of the genetic alterations in conjunctival melanomas.Experimental Design: We conducted genetic analysis of 78 conjunctival melanomas, to our knowledge the largest cohort reported to date. An oncogene hotspot array was run on 38 samples, screening for a panel of known cancer-relevant mutations. Thirty tumors were analyzed for genome-wide copy number alterations (CNA) using array-based comparative genomic hybridization. Sanger sequencing of selected target mutations was conducted in all samples.Results: BRAF mutations were identified in 23 of 78 (29%) tumors. NRAS mutations, previously not recognized as relevant in conjunctival melanoma, were detected in 14 of 78 (18%) tumors. We found CNAs affecting various chromosomes distributed across the genome in a pattern reminiscent of cutaneous and mucosal melanoma but differing markedly from uveal melanoma.Conclusions: The presence of NRAS or BRAF mutations in a mutually exclusive pattern in roughly half (47%) of conjunctival melanomas and the pattern of CNAs argue for conjunctival melanoma being closely related to cutaneous and mucosal melanoma but entirely distinct from uveal melanoma. Patients with metastatic conjunctival melanoma should be considered for therapeutic modalities available for metastatic cutaneous and mucosal melanoma including clinical trials of novel agents.

Nras in melanoma: Targeting the undruggable target

“…While in some studies NRAS mutated melanomas were reported to be significantly thicker and higher Clark's level than wt tumors [61,62,64,68] other reports could not confirm any association between NRAS mutation and tumor thickness [70,71]. Ulceration was reported to be lower in NRAS-mutated tumors in comparison to BRAF mutated tumors (9.7 versus 22.4%, respectively) [63] but no obvious effect of mutational status on the presence of ulceration was reported by others [68].…”

Conjunctival Melanoma and BRAF Inhibitor Therapy

“…BRAF mutations were significantly rising in tumors located at the caruncle (66% BRAF vs. 0% NRAS and 33% wild-type; P=0.03) as well as tumors originating from melanocytic nevi (65% BRAF vs. 27% NRAS and 9% wild-type; P<0.001) [10]. So a close relationship of conjunctival melanoma was suggested to cutaneous and mucosal melanoma and therefore therapeutic options of metastatic cutaneous and mucosal melanomas should be taken into consideration including clinical trials of novel agents for this patient´cohort [10]. lamina propria, enlarged nuclei, eosinophilic nucleoli and nuclear inclusions.…”

“…In 22-50% of conjunctival melanomas a V599E (V600E sometimes called) BRAF mutation was detected [1,9,10]. Griewank et al identified BRAF mutations in 23 of 78 (29%) conjunctival melanomas, demonstrating the majority of BRAF mutations (n=21; 91%) were V600E (T1799A) mutations [10].…”

“…Griewank et al identified BRAF mutations in 23 of 78 (29%) conjunctival melanomas, demonstrating the majority of BRAF mutations (n=21; 91%) were V600E (T1799A) mutations [10]. BRAF mutations were significantly rising in tumors located at the caruncle (66% BRAF vs. 0% NRAS and 33% wild-type; P=0.03) as well as tumors originating from melanocytic nevi (65% BRAF vs. 27% NRAS and 9% wild-type; P<0.001) [10].…”

“…Griewank et al identified BRAF mutations in 23 of 78 (29%) conjunctival melanomas, demonstrating the majority of BRAF mutations (n=21; 91%) were V600E (T1799A) mutations [10]. BRAF mutations were significantly rising in tumors located at the caruncle (66% BRAF vs. 0% NRAS and 33% wild-type; P=0.03) as well as tumors originating from melanocytic nevi (65% BRAF vs. 27% NRAS and 9% wild-type; P<0.001) [10]. So a close relationship of conjunctival melanoma was suggested to cutaneous and mucosal melanoma and therefore therapeutic options of metastatic cutaneous and mucosal melanomas should be taken into consideration including clinical trials of novel agents for this patient´cohort [10].…”