SHORT COMMUNICATION / POSITION PAPER
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Advances in dermatology and venereology Acta Dermato-Venereologica
GNA11-mutated and BAP1-negative Melanomas Ex Blue Naevi : A Particularly Aggressive Entity
Arnaud UGUEN 1 – 3 , Briac GUIBOURG 2 , Sebastian COSTA 2 and Pascale MARCORELLES 2 , 3
1
Inserm , U1078 , Brest , 2 Department of Pathology , University Hospital Morvan , 5 , Avenue Foch , FR-29609 Brest , and 3 European University of Brittany , Brest , France . E-mail : arnaud . uguen @ chu-brest . fr Accepted Dec 8 , 2016 ; Epub ahead of print Dec 8 , 2016
The molecular mechanisms involved in the development and progression of various subtypes of melanoma have been studied widely . In melanomas that lack BRAF- , NRAS- or c-KIT- activating mutations , found in common subtypes of skin melanoma , driver mutations were identified in GNAQ and GNA11 genes coding G proteins in uveal melanomas and in the rare skin melanomas associated with blue naevi or mimicking cellular blue naevi , so-called “ melanoma ex blue naevi ” ( MEBN ) ( 1 – 6 ). Whereas the loss of p16 protein ( coded by the CDKN2A gene ) tumour suppressor function is a major molecular event in the progression of most skin melanomas , the loss of function of another tumour suppressor BAP1 protein is a key molecular event in the progression of uveal melanomas and in their metastatic evolution ( 3 , 7 ). BAP1 loss was further shown to be implicated in many tumour subtypes in cases of sporadic tumours , but also in the novel field of an inherited BAP1 germline mutation cancer predisposition syndrome including , notably , uveal and cutaneous melanomas and epithelioid atypical Spitz tumours ( 8 ). In addition , BAP1 loss has recently been reported to be a frequent molecular event in the progression of MEBN , emphasizing that uveal melanomas and MEBN share some molecular features ( 2 ).
The aim of this paper is to highlight the particular aggressive behaviour of GNA11-mutated MEBN , with a BAP1 loss of expression and / or deletion . This particular profile could be a key factor in determining the risk of metastatic evolution of these rare melanomas .
GNAQ / GNA11 MUTATIONS , CHROMOSOMAL ABERRATIONS AND LOSS OF BAP1
Chan et al . ( 1 ) searched for chromosomal copy number variations and GNAQ / GNA11 mutations in the spectrum of cellular blue naevi , atypical cellular blue naevi and MEBN . They found that the more atypical / malignant the tumours were , the more chromosomal aberrations were present . Notably , they reported 2 / 8 melanomas having the specific GNA11Q209L mutation and losses of chromosomes 3 including the BAP1 locus ( with no loss in the 2 GNAQ-mutated melanomas ), but they did not study BAP1 expression .
The loss of BAP1 has recently emerged as a key molecular mechanism in the progression of MEBN . Costa et al . ( 2 ) reported a file of 11 MEBN . Eight cases were GNA11Q209L-mutated , with 5 cases presenting a loss of
BAP1 expression in the melanoma cells . In 4 of these 5 cases , an adjacent benign blue naevus counterpart was seen with preserved BAP1 expression . Loss of BAP1 has also been reported by Shain et al . ( 3 ) to be involved in the progression of a GNA11Q209L-mutated blue naevus to melanoma . The loss of BAP1 was linked to a homozygous deletion of the 3p21.1 locus in the melanoma counterpart . This chromosomal loss was also observed in 2 cases of GNA11-mutated and BAP1-negative MEBN reported by Costa et al . ( 1 ) ( chromosome 3 deletion , 1 3p deletion ) and in 2 GNA11- and GNAQ-wild type tumours lacking BAP1 expression ( 2 ). Dai et al . ( 9 ) also reported a case of a GNA11-mutated and BAP1-negative MEBN . Other authors reported some MEBN with GNA11 mutations without data about BAP1 expression and a case of BAP1-negative MEBN of the scalp with no data about GNAQ / GNA11 ( 4 , 10 , 11 ). The loss of BAP1 expression in the progression to MEBN emphasizes the reported tumour suppressor function of BAP1 ( 12 ).
ASSOCIATION WITH SCALP AND UVEAL LOCATIONS
From a clinical viewpoint , many of the GNA11-mutated MEBN with loss of expression and / or deletion of BAP1 arose in the scalp ( 2 / 2 cases in Chan et al . ( 1 ), 4 / 5 cases in Costa et al . ( 2 ), 1 / 1 case in Dai et al . ( 9 )). The 3 cases of GNA11-mutated melanomas reported by Yilmaz et al . ( 4 ) and Patel et al . ( 10 ) also arose in the scalp with no data about BAP1 . Besides GNA11 , its paralogue GNAQ is mutated more frequently in benign blue naevi ( approximately 55 % of blue naevi are GNAQ-mutated vs 7 % GNA11-mutated ) than in MEBN and less associated with BAP1 loss ( 1 / 11 cases in Costa et al . without BAP1 loss , 2 / 8 cases in Chan et al . without chromosome 3 deletion , 2 / 10 tumours in Yilmaz et al .) ( 1 , 2 , 4 , 13 ). Moreover , the predilection for the scalp is less evident for GNAQ-mutated MEBN ( 2 of the 5 tumours ) ( 1 , 2 , 4 ). GNA11-mutated melanomas are also classically described in uveal melanomas and reported in the melanomas and melanocytomas of the central nervous system ( 5 , 6 , 13 ). In the uvea , the spatial distribution of GNAQ- and GNA11-mutated melanomas also varies , with a predominance of GNA11-mutated tumours in the cilio-choroidal region compared with the choroid area ( 6 ). Predilection sites of GNA11-mutated melanomas ask for a potential link with the embryological origin of the cells involved in these rare tumours .
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2017 Acta Dermato-Venereologica . doi : 10.2340 / 00015555-2594 Acta Derm Venereol 2017 ; 97 : 743 – 744