Population‐based prevalence of CDKN2A and CDK4 mutations in patients with multiple primary melanomas

Abstract

The presence of multiple primary cutaneous melanomas (MPM) has been advocated as guidance to identifying melanoma families. 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 = 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 previously have been reported in melanoma families (Glu27X, Met53Ile, Arg87Trp, and Ala127Pro). A large deletion (g.13623_23772del10150) encompassing exon 1alpha and the 5' 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 mutations was lower than previously reported in other studies, an observation which probably is due to the population-based design of our study.

Genetic risk factors for melanoma

“…Only 2% of the families in the Geno-MEL carried CDK4 mutations (Goldstein et al 2006), and less than 15 such families have been reported worldwide (Helsing et al 2008;Molven et al 2005;Pjanova et al 2009;SouWr et al 1998SouWr et al , 2007Zuo et al 1996). In a Norwegian population-based study, three out of 390 patients diagnosed with MPM carried a CDK4 mutation (0.8%), and these patients were all later conWrmed to belong to a large melanoma-prone family (Molven et al 2005).…”

Skin Pigmentation Genetics for the Clinic

“…The germline Arg24Cys mutation in CDK4 generates a dominant oncogene that is resistant to normal physiological inhibition by p16/INK4A in the senescence pathway [96] , and has been used successfully to culture naevocytes, overcoming their arrested growth [97] . Notably, a higher frequency of MC1R RHC alleles has also been reported in CDK4 gene mutation melanoma-prone family members with multiple primary melanomas [95,98] .…”

“…Both somatic and germline mutations of CDK4 have been identified in melanoma cells and in families. Mutations within the CDK4 gene are even less frequent than those within CDKN2A [95] . The germline Arg24Cys mutation in CDK4 generates a dominant oncogene that is resistant to normal physiological inhibition by p16/INK4A in the senescence pathway [96] , and has been used successfully to culture naevocytes, overcoming their arrested growth [97] .…”

Streamlining Molecular Pathobiology of Malignant Melanoma

“…Each of them corresponds to a pair of oligonucleotides that hybridize next each other on a specific chromosome site [68][69][70][71][72]. In addition to target-specific sites, both oligonucleotides contain a universal PCR primer.…”

“…Globally, p16 mutations are present in 25-40% of CMM families with more than two CMM, while the proportion of p16 mutations is lower in families with two CMM only [79]. In addition, individuals with multiple primary CMM are more likely to have p16 mutations [80].…”