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Role of the CDKN2A Locus in Patients With Multiple Primary Melanomas

From the Dermatology Department and Genetics Service, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi Sunyer, Universitat de Barcelona; Centre de Genètica Mèdica i Molecular, Institut de Recerca Oncològica Hospital Duran i Reynals, L'Hospitalet de Llobregat, Barcelona; Genetic Counseling of Cancer; Dermatology Department, Hospital Sant Joan, Universitat de Rovira i Virgili, Reus, Spain

Address reprint requests to Susana Puig, MD, Dermatology Department, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain; e-mail: spuig{at}clinic.ub.es

PURPOSE: We have studied a consecutive case series of patients with multiple primary melanoma (MPM) for the involvement of the melanoma susceptibility loci CDKN2A and CDK4.

PATIENTS AND METHODS: One hundred four MPM patients (81 patients with two primary melanomas, 14 with three, five with four, one with five, two with six, and one with seven) were included.

RESULTS: Seven different CDKN2A germline mutations were identified in 17 patients (16.3%). In total, we identified 15 CDKN2A exon 2, one exon 1 missense mutation, and one exon 1ß frameshift mutation. The age of onset was significantly lower and the number of primary melanomas higher in patients with mutations. CDKN2A mutations were more frequent in patients with familial history of melanoma (35.5%) compared with patients without (8.2%), with a relative risk (RR) of 4.32 (95% CI, 1.76 to 10.64; P = .001), and in patients with more than two melanomas (39.1%) compared with patients with only two melanomas (10%) with an RR of 3.29 (95% CI, 1.7 to 6.3; P = .002). The A148T polymorphism was more frequent in patients with MPMs than in the control population (P = .05). A variant of uncertain significance, A127S, was also detected in one patient. No CDK4 mutations were identified, suggesting that it has a low impact in susceptibility to MPM.

CONCLUSION: MPM patients are good candidates for CDKN2A mutational screening. These patients and some of their siblings should be included in a program of specific follow-up with total body photography and digital dermoscopy, which will result in the early detection of melanoma in this subset of high-risk patients and improve phenotypic characterization.

Supported by grants 01/1546 and 03/0019 from Fondo de Investigaciones Sanitarias; V2003-REDC03/03 and /07; grant RO-1 CA 83115 (fund 538226 from the National Cancer Institute, Bethesda, MD), and a personal grant to Francisco Cuellar CONACYT, Personal Scholarship 152256/158706, Mexico City, Mexico.

Authors' current affiliations are as follows: Molecular Haematology, Institute of Child Health, London UK; Dermatology Department, Clínica Platon, Barcelona; Dermatology Department, Hospital General de Catalunya, Sant Cugat; Dermatology Department, Hospital Arnau de Vilanova, Universitat de Lleida, Lleida, Spain.

Initial results from analysis of some patients have been previously reported (Puig et al, 1997; Ruiz et al, 1999; Rizos et al, 2001; Yakobson et al, 2003).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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