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INVESTIGATIVE REPORT ActaDV ActaDV Advances in dermatology and venereology Acta Dermato-Venereologica
CDKN2A / CDK4 Status in Greek Patients with Familial Melanoma and Association with Clinico-epidemiological Parameters
Fani KARAGIANNI 1 # , Ching-Ni NJAUW 2 # , Katerina P . KYPREOU 1 , Aravela STERGIOPOULOU 1 , Michaela PLAKA 1 , Dorothea POLYDOROU 1 , Vasiliki CHASAPI 1 , Leontios PAPPAS 3 , Ιoannis A . STRATIGOS 4 , Gregory CHAMPSAS 1 , Peter PANAGIOTOU 5 , Helen GOGAS 6 , Evangelos EVANGELOU 7 , 8 , Hensin TSAO 2 , Alexander J . STRATIGOS 1 and Irene STEFANAKI 1
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1 st Department of Dermatology , Andreas Sygros Hospital , Medical School , National and Kapodistrian University of Athens , Greece , 2 Wellman Center for Photomedicine and Department of Dermatology , Massachusetts General Hospital , Harvard University , Boston , USA , 3 Boston University School of Medicine , Boston , 4 Queen Mary University of London , Biomedical Sciences , London , UK , 5 Plastic Surgery Department , “ KAT ” General Hospital , 6 1 st Department of Internal Medicine , Laikon Hospital , Athens , 7 Clinical and Molecular Epidemiology Unit , Department of Hygiene and Epidemiology , School of Medicine , University of Ioannina , Ioannina , Greece , and 8 Department of Epidemiology and Biostatistics , Imperial College London , St Mary ’ s Campus , London , UK
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These authors contributed equally to this manuscript
Approximately 5 – 10 % of melanoma cases occur in a familial context . CDKN2A / CDK4 were the first highpenetrance melanoma genes identified . The aims of this study were to evaluate CDKN2A / CDK4 variants in Greek familial melanoma patients and to correlate the mutational status with specific clinico-epidemiological characteristics . A cross-sectional study was conducted by genotyping CDKN2A / CDK4 variants and selected MC1R polymorphisms in 52 melanoma-prone families . Descriptive statistics were calculated and comparisons were made using the χ 2 test , Fisher ’ s exact test and Student ’ s t-test for statistical analysis , as appropriate . CDKN2A variants were detected in 46.2 % of melanoma-prone families , while a CDK4 variant was found in only one family . This study confirmed that , in the Greek population , the age at melanoma diagnosis was lower in patients carrying a variant in CDKN2A compared with wild-type patients . No statistically significant associations were found between CDKN2A mutational status and MC1R polymorphisms .
Key words : familial melanoma ; CDKN2A ; CDK4 ; MC1R ; Greece . Accepted May 17 , 2018 ; Epub ahead of print May 18 , 2018 Acta Derm Venereol 2018 ; 98 : 862 – 866 .
Corr : Irene Stefanaki , 1 st Department of Dermatology , University of Athens School of Medicine , Andreas Sygros Hospital for Skin and Venereal Diseases , 5 Ionos Dragoumi Street , GR-161 21 Athens , Greece . E-mail : irenestefanaki @ hotmail . com
Melanoma is one of the most aggressive types of skin cancer because of its tendency to metastasize ( 1 ). The incidence of melanoma is increasing rapidly in Caucasian populations ( 2 ), with more than 230,000 new cases and 55,000 deaths estimated worldwide in 2012 ( Globocan , 2012 , World Health Organization ( WHO ); http :// globocan . iarc . fr ). Τhe aetiology of melanoma is complex and is driven by the interaction of environmental , phenotypic , and genetic factors . The main environmental risk factor for melanoma is excessive ultraviolet ( UV ) radiation exposure , either from sunlight or from indoor tanning beds ( 3 ). Phenotypic characteristics , such as red or blond hair , blue or green eyes , fair skin with low tanning ability , eye colour , hair colour , freckles , multiple
SIGNIFICANCE
Melanoma is the most aggressive skin cancer . Although the majority of affected individuals are sporadic cases , a minor group is at high risk because of its family history . Cases among the same family often share the same mutations in melanoma-associated genes . Our study represents the largest familial melanoma series in Greece and delineates the need for screening members of affected families for particular genetic alterations . Carriers should undergo frequent clinical follow-up , since they are at high risk for developing melanoma at an early age .
melanocytic naevi , and the presence of clinically atypical naevi , are associated with an increased risk of developing melanoma ( 4 ). A personal history of melanoma increases the risk of developing a second melanoma by 5 – 8 % ( 5 , 6 ), while a family history has been associated with a 1.74 relative risk for melanoma ( 7 ), supporting the role of genetic risk factors . A recent study of familial cancer risk in twins from Nordic countries estimated that cutaneous malignant melanoma ( CMM ) had the highest heritability ( 58 %; 95 % confidence interval ( CI ): 43 – 73 %) among all common cancers ( 8 ).
Approximately 5 – 10 % of melanoma cases occur in a familial context ( 2 ). Although the underlying genetic basis in the majority of melanoma-prone families is unknown , certain highly penetrant genes , such as the cyclin-dependent kinase inhibitor 2A ( CDKN2A ) gene ( 9 , 10 ) and cyclin-dependent kinase 4 ( CDK4 ), have been implicated ( 11 – 13 ). CDKN2A is responsible for melanoma susceptibility in approximately 10 % of 2-case melanoma families and 30 – 40 % of families with 3 or more cases of melanoma up to third-degree relatives ( 14 ), whereas its incidence among sporadic melanomas is very low ( less than 3 %) ( 15 ). It encodes 2 distinct proteins : p16INK4A ( p16 ) and p14ARF ( p14 ), both of which function in cell cycle regulation ( 15 ). CDKN2A mutation carriers are also at increased risk of the development of pancreatic cancer compared with the general population ( 14 , 16 , 17 ).
Variants in the CDK4 gene have been observed in only a small number of melanoma families ( 11 – 13 ). All variants doi : 10.2340 / 00015555-2969 Acta Derm Venereol 2018 ; 98 : 862 – 866
This is an open access article under the CC BY-NC license . www . medicaljournals . se / acta Journal Compilation © 2018 Acta Dermato-Venereologica .