Distribution of MC1R variants among melanoma subtypes: p.R163Q is associated with lentigo maligna melanoma in a Mediterranean population

Distribution of MC1R variants among melanoma subtypes: p.R163Q is associated with lentigo maligna melanoma in a Mediterranean population

LINK:  https://doi.org/10.1111/bjd.12418

Funding sources The research at the Melanoma Unit in Barcelona was partially funded by Grants 03/0019, 05/0302, 06/0265 and 09/01393 from Fondo de Investigaciones Sanitarias, Spain; by the CIBER de Enfermedades Raras of the Instituto de Salud Carlos III, Spain; by the AGAUR 2009 SGR 1337 of the Catalan Government, Spain; by the European Commission under the 6th Framework Programme, contract no. LSHC‐CT‐2006‐018702 (GenoMEL) and by the National Cancer Institute of the U.S. National Institutes of Health (CA83115). The work was carried out at the Esther Koplowitz Centre, Barcelona, Spain. The samples from the Instituto Valenciano de Oncología were collected from the Biobanco del Instituto Valenciano de Oncología.

Background

Cutaneous melanoma tumour is classified into clinicohistopathological subtypes that may be associated with different genetic and host factors. Variation in the MC1R gene is one of the main factors of risk variation in sporadic melanoma. The relationship between MC1R variants and the risk of developing a specific subtype of melanoma has not been previously explored.

Objectives

To analyse whether certain MC1R variants are associated with particular melanoma subtypes with specific clinicohistopathological features.

Methods

An association study was performed between MC1R gene variants and clinicopathological subtypes of primary melanoma derived from 1679 patients.

Results

We detected 53 MC1R variants (11 synonymous and 42 nonsynonymous). Recurrent nonsynonymous variants were p.V60L (30·0%), p.V92M (11·7%), p.D294H (9·4%), p.R151C (8·8%), p.R160W (6·2%), p.R163Q (4·2%) p.R142H (3·3%), p.I155T (3·8%), p.V122M (1·5%) and p.D84E (1·0%). Melanoma subtypes showed differences in the total number of MC1R variants (P = 0·028) and the number of red hair colour variants (P = 0·035). Furthermore, an association between p.R163Q and lentigo maligna melanoma was detected under a dominant model of heritance (odds ratio 2·16, 95% confidence interval 1·07–4·37; P = 0·044). No association was found between p.R163Q and Fitzpatrick skin phototype, eye colour or skin colour, indicating that the association was independent of the role of MC1R in pigmentation. No association was observed between MC1R polymorphisms and other melanoma subtypes.

Conclusions

Our findings suggest that certain #MC1R variants could increase melanoma risk due to their impact on pathways other than pigmentation, and may therefore be linked to specific melanoma subtypes

 

#malvehy #susanapuig #cristinacarrera  #paulaaguilera #jmalvehy #melanoma #skincancer  #mc1r #genomel

J.A. Puig‐Butillé C. Carrera R. Kumar Z. Garcia‐Casado P. Aguilera J. Malvehy E. Nagore S. Pui

 

MICROSCOPIA CONFOCAL: las cuatro características clave que debe conocer para el diagnóstico de cáncer de piel tipo melanoma y no melanoma.

Pellacani G, Alcance A, Gonzalez S  Guitera P , Farnetani F , Malvehy J, Witkowski A , De Carvalho N , Lupi O , Longo C 

Resumen

FONDO:

El diagnóstico de cáncer de piel basado en microscopía confocal de reflectancia (RCM) requiere competencia.

OBJETIVOS:

Identificar una lista corta de características RCM clave de los cánceres de piel y probar su utilidad de diagnóstico.

MÉTODOS:

Identificamos las características clave de RCM a través del consenso entre seis expertos que utilizan un método Delphi modificado. Para probar la utilidad diagnóstica de estas características clave de RCM, diez lectores novatos de RCM evaluaron un subconjunto de 100 casos de RCM a partir de un conjunto de datos retrospectivo de neoplasias de piel benignas y malignas.

RESULTADOS:

Los expertos identificaron 18 características RCM como altamente valiosas para el diagnóstico de cáncer de piel, de 56 características reportadas en la literatura. Sobre la base de las definiciones de consenso, estas características de RCM se agruparon en dos características clave específicas para el melanoma: "células atípicas" y "desorden de la unión dérmico-epidérmica", una característica clave específica del carcinoma de células basales (BCC), "cuerdas basaloides / islas ', y un carcinoma de células escamosas (SCC) - característica clave específica -' desorden de queratinocitos '. El estudio de lectura para principiantes mostró que la presencia de al menos una de las cuatro características clave se asoció con una sensibilidad general para el diagnóstico de cáncer de piel del 91%, con sensibilidad para el melanoma: 93%, BCC: 92% y SCC: 77%; y una especificidad global del 57%.

CONCLUSIONES:

Una lista corta de terminología de consenso, que identifica las cuatro características clave del RCM para el diagnóstico de cáncer de piel, puede facilitar la diseminación del RCM a los usuarios novatos.

Fuente: PubMed

Reflectance Confocal Microscopy made easy: the four must-know key features for the diagnosis of melanoma and non-melanoma skin cancers.

Abstract

BACKGROUND:

Reflectance confocal microscopy (RCM)-based skin cancer diagnosis requires proficiency.

AIMS:

To identify a shortlist of key RCM features of skin cancers and test their diagnostic utility.

METHODS:

We identified key RCM features through consensus among six experts using a modified-Delphi method. To test diagnostic utility of these RCM key-features, ten novice RCM readers evaluated a subset of 100 RCM cases from a retrospective dataset of benign and malignant skin neoplasms.

RESULTS:

The experts identified 18 RCM features as highly valuable for skin cancer diagnosis, from 56 features reported in the literature. Based on consensus definitions, these RCM features were further clustered into two melanoma-specific key-features - 'atypical cells' and 'dermal-epidermal junction disarray', one basal cell carcinoma (BCC)-specific key-feature - 'basaloid cords/islands', and one squamous cell carcinoma (SCC)-specific key-feature - 'keratinocyte disarray'. The novice reading study showed that the presence of at least one of the four key-feature was associated with an overall sensitivity for skin cancer diagnosis of 91% - with sensitivity for melanoma-93%, BCC-92% and SCC-77%; and an overall specificity of 57%.

CONCLUSIONS:

A consensus terminology shortlist, identifying the four RCM key-features for skin cancer diagnosis, may facilitate dissemination of RCM to novice users.

Variantes de MC1R en el melanoma infantil y adolescente: un análisis agrupado retrospectivo de una cohorte multicéntrica.

Pellegrini C , Botta F , Massi D , Martorelli C , Facchetti F , Gandini S , Maisonneuve P , Avril MF , Demenais F , Bressac-de Paillerets B , Hoiom V , Cust AE , Anton-Culver H , Gruber SB , Gallagher RP , Marrett L , Zanetti R , Dwyer T , Thomas NE , Begg CB , Berwick M, Puig S, Potrony M, Nagore E , Ghiorzo P , Menin C , Manganoni AM, Rodolfo M , Brugnara S , Passoni E , Sekulovic LK , Baldini F , Guida G, Stratigos A , Ozdemir F , Ayala F , Fernandez-de-Misa R, Quaglino P , Ribas G , Romanini A , Migliano E , Stanganelli I, Kanetsky PA, Pizzichetta MA , García-Borrón JC , Nan H , Landi MT , Little J ,Newton-Bishop J , Sera F , Fargnoli MC , Raimondi S ; Grupo de Estudio IMI ; Grupo de estudio GEM ; Grupo de estudio M-SKIP .

Resumen

FONDO:

Las variantes de la línea germinal en el gen del receptor de melanocortina 1 (MC1R) pueden aumentar el riesgo de melanoma infantil y en la adolescencia, pero una conclusión clara es un desafío debido al bajo número de estudios y casos. Evaluamos la asociación de las variantes de MC1R con melanoma infantil y adolescente en un estudio grande que comparó la prevalencia de las variantes de MC1R en niños o adolescentes con melanoma en pacientes adultos con melanoma y en controles adultos sanos.

MÉTODOS:

En este análisis agrupado retrospectivo, utilizamos el Proyecto M-SKIP, el Intergrupo de Melanoma Italiano y otros grupos europeos (con participantes de Australia, Canadá, Francia, Grecia, Italia, Países Bajos, Serbia, España, Suecia, Turquía y USA) para armar una cohorte multicéntrica internacional. Recopilamos datos fenotípicos y genéticos de niños o adolescentes diagnosticados con melanoma cutáneo esporádico de una sola edad a los 20 años o menos, pacientes adultos con melanoma cutáneo esporádico y de una sola edad diagnosticados a partir de los 35 años y personas adultas sanas como controles. Se calcularon los odds ratios (OR) para el melanoma infantil y adolescente asociado a las variantes de MC1R mediante regresión logística multivariable. El análisis de subgrupos se realizó para niños de 18 años o menos y de 14 años o menos.

RECOMENDACIONES:

Analizamos los datos de 233 pacientes jóvenes, 932 pacientes adultos y 932 controles adultos sanos. Los niños y adolescentes tenían mayores probabilidades de portar variantes de MC1R r que los pacientes adultos (OR 1 · 54, IC 95% 1 · 02-2 · 33), incluso cuando el análisis se limitaba a pacientes de 18 años o menos (1 · 80, 1 · 06-3 · 07). Todas las variantes investigadas, excepto Arg160Trp, tendieron, en mayor o menor grado, a tener frecuencias más altas en pacientes jóvenes que en pacientes adultos, con frecuencias significativamente mayores encontradas para Val60Leu (OR 1 · 60, IC 95% 1 · 05-2 · 44; p = 0 · 04) y Asp294His (2 · 15, 1 · 05-4 · 40; p = 0 · 04). En comparación con los controles sanos, los pacientes jóvenes con melanoma tenían frecuencias significativamente más altas de cualquier variante de MC1R.

INTERPRETACIÓN:

Nuestro análisis agrupado de datos genéticos de MC1R de pacientes jóvenes con melanoma mostró que las variantes de MC1R eran más prevalentes en melanomas infantiles y en adolescentes que en adultos, especialmente en pacientes de 18 años o menos. Nuestros hallazgos apoyan el papel de MC1R en la susceptibilidad del melanoma infantil y adolescente, con una relevancia clínica potencial para el desarrollo temprano de la detección del melanoma y las estrategias preventivas.

Fuente: PubMed

MC1R variants in childhood and adolescent melanoma: a retrospective pooled analysis of a multicentre cohort.

Abstract

BACKGROUND:

Germline variants in the melanocortin 1 receptor gene (MC1R) might increase the risk of childhood and adolescent melanoma, but a clear conclusion is challenging because of the low number of studies and cases. We assessed the association of MC1R variants with childhood and adolescent melanoma in a large study comparing the prevalence of MC1R variants in child or adolescent patients with melanoma to that in adult patients with melanoma and in healthy adult controls.

METHODS:

In this retrospective pooled analysis, we used the M-SKIP Project, the Italian Melanoma Intergroup, and other European groups (with participants from Australia, Canada, France, Greece, Italy, the Netherlands, Serbia, Spain, Sweden, Turkey, and the USA) to assemble an international multicentre cohort. We gathered phenotypic and genetic data from children or adolescents diagnosed with sporadic single-primary cutaneous melanoma at age 20 years or younger, adult patients with sporadic single-primary cutaneous melanoma diagnosed at age 35 years or older, and healthy adult individuals as controls. We calculated odds ratios (ORs) for childhood and adolescent melanoma associated with MC1R variants by multivariable logistic regression. Subgroup analysis was done for children aged 18 or younger and 14 years or younger.

FINDINGS:

We analysed data from 233 young patients, 932 adult patients, and 932 healthy adult controls. Children and adolescents had higher odds of carrying MC1R r variants than did adult patients (OR 1·54, 95% CI 1·02-2·33), including when analysis was restricted to patients aged 18 years or younger (1·80, 1·06-3·07). All investigated variants, except Arg160Trp, tended, to varying degrees, to have higher frequencies in young patients than in adult patients, with significantly higher frequencies found for Val60Leu (OR 1·60, 95% CI 1·05-2·44; p=0·04) and Asp294His (2·15, 1·05-4·40; p=0·04). Compared with those of healthy controls, young patients with melanoma had significantly higher frequencies of any MC1R variants.

INTERPRETATION:

Our pooled analysis of MC1R genetic data of young patients with melanoma showed that MC1R r variants were more prevalent in childhood and adolescent melanoma than in adult melanoma, especially in patients aged 18 years or younger. Our findings support the role of MC1R in childhood and adolescent melanoma susceptibility, with a potential clinical relevance for developing early melanoma detection and preventive strategies.

Melanocortin 1 receptor (MC1R) polymorphisms' influence on size and dermoscopic features of nevi.

Melanocortin 1 receptor (MC1R) polymorphisms' influence on size and dermoscopic features of nevi.

https://www.ncbi.nlm.nih.gov/pubmed/28950052

Abstract

The melanocortin 1 receptor (MC1R) is a highly polymorphic gene. The loss-of-function MC1R variants ("R") have been strongly associated with red hair color phenotype and an increased melanoma risk. We sequenced the MC1R gene in 175 healthy individuals to assess the influence of MC1R on nevus phenotype. We identified that MC1R variant carriers had larger nevi both on the back [p-value = .016, adjusted for multiple parameters (adj. p-value)] and on the upper limbs (adj. p-value = .007). Specifically, we identified a positive association between the "R" MC1R variants and visible vessels in nevi [p-value = .033, corrected using the FDR method for multiple comparisons (corrected p-value)], dots and globules in nevi (corrected p-value = .033), nevi with eccentric hyperpigmentation (corrected p-value = .033), a high degree of freckling (adj. p-value = .019), and an associative trend with presence of blue nevi (corrected p-value = .120). In conclusion, the MC1R gene appears to influence the nevus phenotype.

#melanocortin #josepmalvehy #susanapuig #dermoscopic #confocal #Mohs #dermatology #topdoctors #mc1r #melanoma #skincancer #dermatologiabarcelona #clinicadermatologica #cedilp