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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 .