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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.