Population-Based Prevalence of CDKN2A and CDK4 Mutations in Patients with Multiple Primary Melanomas Per Helsing, 1 * Dag Andre Nymoen, 2 Sarah Ariansen, 2 Solrun J. Steine, 3 Lovise Maehle, 4 Steinar Aamdal, 5 Frøydis Langmark, 6 Mitchell Loeb, 7 Lars A. Akslen, 3,8 Anders Molven, 3,8 and Per Arne Andresen 2 1 Department of Dermatology,Rikshospitalet-Radiumhospitalet Medical Center, N- 0027 Oslo, Norway 2 Pathology Clinic, Molecular Pathology,Rikshospitalet-Radiumhospitalet Medical Center, N- 0027 Oslo, Norway 3 Section for Pathology,The Gade Institute,University of Bergen, N-5020 Bergen, Norway 4 Department of Medical Genetics,Rikshospitalet-Radiumhospitalet Medical Center, N- 0310 Oslo, Norway 5 Department of Oncology,Rikshospitalet-Radiumhospitalet Medical Center, N- 0310 Oslo,Norway 6 Cancer Registry of Norway, Montebello, N- 0369 Oslo, Norway 7 SINTEF Health Research, N- 0373 Oslo, Norway 8 Department of Pathology,Haukeland University Hospital, N-5021Bergen, Norway The presence of multiple primary cutaneous melanomas (MPM) has been advocated as guidance to identifying melanoma fami- lies. Frequencies of CDKN2A mutations in materials of sporadic MPM cases from pigmented lesion clinics vary between 8 and 15%. Patients with MPM have therefore been regarded as good candidates for CDKN2A mutational screening. We describe a population-based study where all persons in Norway diagnosed with MPM between 1953 and 2004 (n 5 738 alive per April 2004) were invited to participate. Three-hundred-and-ninety patients (52.8%) responded confidentially. Mutations in CDKN2A were found in 6.9% of the respondents. Eighty-one MPM patients (20.8%) reported that they belonged to melanoma families, and 17 (21.0%) of these harboured a CDKN2A mutation, compared to 3.2% of the nonfamilial cases. The probability of finding a CDKN2A mutation increased when the patients had three or more melanomas, or a young age of onset of first melanoma. We identified five novel CDKN2A variants (Ala57Gly, Pro81Arg, Ala118Val, Leu130Val, and Arg131Pro) and four that previ- ously have been reported in melanoma families (Glu27X, Met53Ile, Arg87Trp, and Ala127Pro). A large deletion (g.13623_23772del10150) encompassing exon 1a and the 5 0 part of exon 2 was detected in six patients with a family history of melanoma. Three patients, belonging to the same family, had the CDK4 Arg24His mutation. The frequency of CDKN2A muta- tions was lower than previously reported in other studies, an observation which probably is due to the population-based design of our study. V V C 2007 Wiley-Liss, Inc. INTRODUCTION Cutaneous melanoma is a potentially lethal dis- ease, with a rapidly increasing incidence in the Scandinavian countries and other populations (Garbe and Blum, 2001). Of melanoma patients, 5% – 8.5% will subsequently develop another mel- anoma (Tucker et al., 1985; Giles et al., 1995), a proportion that is significantly higher than expected, based on the estimated lifetime risk (Monzon et al., 1998). Patients with multiple pri- mary melanomas (MPM) often have a positive family history of melanoma (Johnson et al., 1998). This clustering is explained by both non-genetic and genetic factors, but many cases of concurrent MPM and familial melanoma are likely to be caused primarily by hereditary susceptibility to the disease. Variants of two genetic loci have been shown to predispose to melanoma (Hayward, 2003). The CDKN2A locus (MIM no. 600160) is positioned at 9p21 and encodes two proteins, p16 INK4A and p14 ARF , which both are tumour suppressor proteins involved in cell cycle regulation. The p16 INK4A - encoding part of this locus consists of exons 1a, 2, and 3, and mutations of functional significance in familial malignant melanoma are found in exons 1a and 2. So far, more than 70 different exonic sequence variants of CDKN2A, associated or likely to be associated with melanoma development, have been registered in the Human Gene Mutation Database (www.hgmd.cf.uk/ac), as have some *Correspondence to: Per Helsing, Department of Dermatology, Rikshospitalet-Radiumhospitalet Medical Center, N-0027 Oslo, Norway. E-mail: per.helsing@rikshospitalet.no Supported by: Norwegian Cancer Society. Received 10 May 2007; Accepted 17 October 2007 DOI 10.1002/gcc.20518 Published online 19 November 2007 in Wiley InterScience (www.interscience.wiley.com). V V C 2007 Wiley-Liss, Inc. GENES, CHROMOSOMES & CANCER 47:175–184 (2008)