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Vol. 114. Núm. 1.
Páginas 80-82 (enero 2022)
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Vol. 114. Núm. 1.
Páginas 80-82 (enero 2022)
Case and Research Letter
Open Access
Melanocortin-1 Receptor (MC1R) Gene Variants are Not Associated With Vascular Brain Alterations
Las variantes del gen receptor de melanocortina-1 (MC1R) no están asociadas a las enfermedades vasculares cerebrales
E. Candreaa,b,*, S. Podlipnikb,*, L. Oleagad, S. Puigb,c,
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Corresponding authors.
a Dermatology Department, University of Medicine and Pharmacy “I. Hatieganu”, Cluj Napoca, Romania
b Dermatology Department, Melanoma Unit, Hospital Clinic of Barcelona, IDIBAPS, University of Barcelona, Barcelona, Spain
c Biomedical Research Networking Center on Rare Diseases (CIBERER), ISCIII, Spain
d Radiology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain
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E. Candrea, S. Podlipnik, L. Oleaga, S. Puig
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To the Editor,

The melanocortin-1 receptor (MC1R) gene is an important regulator of human skin pigmentation and loss-of-function variants are associated with a higher risk of developing melanoma.1MC1R gene variants have also been associated with Parkinson disease, late-onset Alzheimer's disease and age of onset modulation in Huntington's disease patients.2–4MC1R expression in the brain is found in the vascular endothelium.5 Weak MC1R activity predisposes to vascular endothelial dysfunction.6 Different types of brain vascular lesions can be differentiated on magnetic resonance imaging (MRI): aneurysms, arteriovenous malformations (AVM), developmental venous anomalies (DVA), capillary telangiectasia, and cavernous malformation.7 Brain vascular lesions represent an abnormality in vessel development and a possible error may occur during vasculogenesis or, more likely, during angiogenesis. Brain angiogenesis is diminished after birth but may reactivate as a response to any of several triggers such as sensory enrichment, exercise, stress, hormones or chronic hypoxia. Interestingly, vascular malformations of the brain are not necessarily completely developed at birth, as active growth and de novo formation of CCM and AVM may occur in adulthood.8 The study aimed to analyze the relationship between MC1R status and the presence of brain vascular lesions.

Material and methods

During the study period 1300 consecutive melanoma patients were visited at the Department of Dermatology at Hospital Clínic de Barcelona. Genomic DNA from blood samples was isolated using the Wizard® Genomic DNA Purification Kit (Promega, Madison, WI, USA) and the status of the MC1R gene was determined by PCR amplification and sequencing as previously described.1 In the staging and/or follow-up protocol, brain MRI was requested for intermediate or high-risk melanoma patients. As inclusion criteria, only patients with at least one brain MRI were included. Brain vascular lesions were classified into distinct groups: aneurysms and vascular malformations (AVM, DVA, capillary telangiectasia, and cavernous malformation).


A total of 476 patients were finally included in our study and the baseline characteristics of the cohort are summarized in Table 1. MC1R variants were found in 324 patients (68.1%) and 152 patients (31.89) were wild-type. A total of 44 brain vascular abnormalities were incidentally detected during MRI examinations. Developmental venous abnormalities were present in 23 cases (4.8%), cavernous malformation in 16 cases (3.4%), brain aneurysm in 3 cases (0.6%) and brain arteriovenous malformations in 2 cases (0.4%). We analyzed the possible association between the presence of MC1R variants and vascular alterations detected by MRI. After the data processing, no statistically significant difference in the number or type of brain vascular lesions of the brain was found (P=.986).

Table 1.

Basal Characteristics of the Cohort.

  MC1R variants (N=324)  MC1R wild-type (N=152)  Total (N=476)  p value 
Gender        0.821 
Female  152 (46.9%)  73 (48.0%)  225 (47.3%)   
Male  172 (53.1%)  79 (52.0%)  251 (52.7%)   
Age        0.878 
Median (Q1, Q3)  56.66 (44.98, 68.10)  56.01 (43.47, 69.45)  56.43 (44.62, 68.56)   
Brain vascular malformation        0.986 
Non-vascular malformation  294 (90.7%)  138 (90.8%)  432 (90.8%)   
Vascular malformation  30 (9.3%)  14 (9.2%)  44 (9.2%)   
Radiological diagnosis (detail)        0.110 
Developmental venous anomaly  19 (5.9%)  4 (2.6%)  23 (4.8%)   
Cavernous malformation  7 (2.2%)  9 (5.9%)  16 (3.4%)   
Brain aneurysm  2 (0.6%)  1 (0.7%)  3 (0.6%)   
Brain arteriovenous malformation  2 (0.6%)  0 (0.0%)  2 (0.4%)   
None  294 (90.7%)  138 (90.8%)  432 (90.8%)   
Eye color        0.937 
Brown-black  188 (63.9%)  93 (64.6%)  281 (64.2%)   
Green  55 (18.7%)  25 (17.4%)  80 (18.3%)   
Blue  51 (17.3%)  26 (18.1%)  77 (17.6%)   
Missing values  30  38   
Hair color        0.004 
Brown-black  205 (70.0%)  113 (79.6%)  318 (73.1%)   
Blond  69 (23.5%)  29 (20.4%)  98 (22.5%)   
Red  19 (6.5%)  0 (0.0%)  19 (4.4%)   
Missing values  31  10  41   
Phototype        0.084 
24 (8.1%)  5 (3.5%)  29 (6.6%)   
II  149 (50.0%)  67 (46.5%)  216 (48.9%)   
III  105 (35.2%)  61 (42.4%)  166 (37.6%)   
IV  18 (6.0%)  11 (7.6%)  29 (6.6%)   
2 (0.7%)  0 (0.0%)  2 (0.5%)   
Missing values  26  34   

Many factors affecting brain vascular lesions are yet to be clarified, such as the link between genetic mutations, mutant cell lineage, and clinical expression. It has been hypothesized that a mutation in one copy of a given gene may be followed by a second trigger (such as a somatic mutation) to a second copy of the gene or a mutation in another gene acting in the same cellular pathway causing a vascular brain lesion to appear.8 Somatically mutated endothelial cells clonally expand to initiate cerebral cavernous malformations and subsequently incorporate wild-type endothelial cells and so increase the size of a cerebral cavernous malformation.9 Taking into consideration the disturbing neurological symptoms of brain vascular lesions, such as focal neurological deficits, epilepsy and hemorrhagic stroke in the case of lesion rupture, further research is mandatory to shed light on the molecular mechanisms implicated.

In conclusion, given that almost 500 patients were included in our research we believe there is strong evidence indicating the lack of involvement of the MC1R gene in the development or progression of vascular malformations.


The research at the Melanoma Unit in Barcelona is partially funded by Spanish Fondo de Investigaciones Sanitarias grants PI15/00716 and PI15/00956, of the Instituto de Salud Carlos III, Spain, co-financed by European Development Regional Fund “A way to achieve Europe” ERDF; AGAUR 2017_SGR_1134 of the Catalan Government, Spain; European Commission under the 7th Framework Program, Diagnoptics; a grant from “Fundación Científica de la Asociación Española Contra el CáncerGCB15152978SOEN, Spain; a grant from the European Academy of Dermatology and Venereology (EADV) (PPRC-2017/19), and CERCA Program/Generalitat de Catalunya. Part of the work was carried out at the Esther Koplowitz Center, Barcelona. Elisabeta Candrea is a recipient of a mobility fellowship MC2017-0669 from UEFISCDI, Romania.


Special thanks to the other authors of this paper who have made a significant contribution to the development of the manuscript. Gemma Tell-Marti and Miriam Potrony from the Biochemistry and Molecular Genetics Department, and Javier Moreno Negrete from the Radiology Department, Hospital Clinic of Barcelona, University of Barcelona, Barcelona, Spain.

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