512
CLINICAL REPORT Advances in dermatology and venereology ActaDV Acta Dermato-Venereologica ActaDV
Characteristics of Familial Melanoma in Valencia, Spain, Based on the Presence of CDKN2A Mutations and MC1R Variants
Claudia HUERTA 1, 2, Zaida GARCIA-CASADO 3, José BAÑULS 4, Manuel MORAGON 5, Vicente OLIVER 6, Blanca UNAMUNO 7, Celia REQUENA 1, Rajiv KUMAR 8 and Eduardo NAGORE 1, 2
1
Department of Dermatology, 3 Laboratory of Molecular Biology, Instituto Valenciano de Oncología, 2 School of Medicine, Universidad Católica de Valencia“ San Vicente Martir”, Valencia, Departments of Dermatology, 4 Hospital General Universitario de Alicante-ISABIAL, 5 Hospital Universitario San Juan, Alicante, 6 Consorcio Hospital General Universitario and 7 Hospital Universitario y Politécnico La Fe, Valencia, Spain, and 8 Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany
Melanoma results from a complex interplay between environmental factors and individual genetic susceptibility. Familial melanoma is attributable to predisposition genes with variable penetrance. The aim of this study was to identify differences between familial melanoma and sporadic cases in our population, based on the presence of CDKN2A mutations and MC1R variants. Comparing 107 patients with familial melanoma from 87 families( 17 % CDKN2A mutated) with 1,390 cases of sporadic melanomas, the former were younger and exhibited an increased prevalence of atypical naevi and squamous cell carcinoma( SCC). CDKN2A mutation carriers presented more atypical naevi, multiple melanomas, and basal cell carcinoma, while non-carriers were more likely to have light-coloured hair, atypical naevi, and SCC. MC1R variants decreased the age at diagnosis in all groups and were associated with an increased prevalence of SCC, especially in patients with familial melanoma without CDKN2A mutations. These characteristics may help to establish prevention measures targeting patients with familial melanoma in the Mediterranean area.
Key words: cutaneous malignant melanoma; genetic susceptibility; risk factors; CDKN2A; MC1R.
Accepted Feb 5, 2018; Epub ahead of print Feb 6, 2018 Acta Derm Venereol 2018; 98: 512 – 516.
Corr: Eduardo Nagore, School of Medicine, Universidad Católica de Valencia“ San Vicente Mártir”, c / Quevedo, 2, ES-46009 València, Spain. E-mail: eduardo _ nagore @ ono. com
Melanoma is an increasingly common and potentially deadly cancer that develops through interactions between environmental factors, mainly ultraviolet( UV) radiation, and genetically determined phenotypic characteristics( 1 – 8). Numerous low-to-moderate penetrance genes found in a relatively high proportion of the general population contribute to the genetic risk of developing melanoma, and sporadic melanoma in particular. These genes are involved in skin pigmentation( MC1R, ASIP, OCA2, Tyrp1, TYR, SCL45A2 and MITF), number of naevi( 9p21, 22q13 and 6p25-p23)( 9, 10), immune response( IFNW1 and IL6R), DNA repair( XRCC3) and vitamin D metabolism( GC and VDR)( 11 – 13). Numerous high-penetrance gene mutations( CDKN2A, CDK4,
MITF, BAP1, TERT promoter and POT1 mutations) are also mainly associated with cases of multiple or familial melanoma( 5, 14 – 17).
Given that familial melanoma is associated with an increased genetic load compared with sporadic melanoma, one can assume that environmental factors play a smaller role in its aetiology and pathogenesis. The aetiopathogenic pathways involved in both conditions can be modified by low-penetrance genes, resulting in different gene expression patterns associated with particular clinical and pathological phenotypes.
The main aim of this study was to characterize familial melanoma according to the presence or absence of both CDKN2A mutations and MC1R variants. A secondary aim was to investigate differences among familial melanoma, subgroups of familial melanoma, and sporadic melanoma.
PATIENTS AND METHODS
A retrospective, cross-sectional, descriptive, analytical, epidemiological, case-case study was performed of melanoma cases from the cutaneous melanoma database at the Instituto Valenciano de Oncología, which is the reference centre for the genetic assessment of familial melanoma in the Community of Valencia, Spain. The study was approved by the ethics committee of the institute. Data analysed were obtained from 1 January 2000 to 23 November 2014.
The database contains information on patients who received definitive treatment at the centre, and patients with melanoma referred for genetic testing due to a family history of melanoma.
The present study excluded patients with extracutaneous melanomas, melanomas of unknown primary origin, and those with a family history of melanoma who had not undergone genetic testing.
Patients were initially classified into 2 groups: sporadic melanoma and familial melanoma. Familial melanoma was defined as a case in which at least 2 first- or second-degree relatives had a diagnosis of melanoma. This group was further divided into 2 groups according to the presence or absence of a germline CD- KN2A mutation. The following variables were compared between groups:( i) demographic variables: age( ≤ 50 vs. > 50 years) and sex( male vs. female).( ii) Skin phenotype: skin phototype( I – II vs. III – V), freckles in childhood( yes vs. no), solar lentigines( yes vs. no), actinic keratosis( yes vs. no), number of common melanocytic naevi(< 20, 20 – 50 vs. 50 – 100, > 100), and presence of ≥ 1 clinically atypical melanocytic naevus( yes vs. no).( iii) Environmental exposure: personal history of severe sunburn( no, 1 – 5 episodes vs. 6 – 10, > 10) and job involving sun exposure( yes vs. no).( iv) Personal and family history( first- or second-degree doi: 10.2340 / 00015555-2898 Acta Derm Venereol 2018; 98: 512 – 516
This is an open access article under the CC BY-NC license. www. medicaljournals. se / acta Journal Compilation © 2018 Acta Dermato-Venereologica.