CDKN2A germ-line mutations in individuals with multiple cutaneous melanomas

Germ-line CDKN2A mutations are present in some kindreds with hereditary cut aneous melanoma, and in Sweden a founder mutation with an extra arginine in codon 113 (113insR) has been identified, We screened 80 individuals with a t least two primary cutaneous melanomas, who were identified mainly by a se arch of a regional cancer registry, for germ-line CDKN2A mutations. In nine patients, CDKN2A alterations that may contribute to melanoma predispositio n were detected. In six individuals with a family history of melanoma, the 113insR founder mutation was present. One patient, who also had a family hi story of melanoma, had a 24-bp deletion that included codons 62-69, An in v itro binding assay established that the resulting mutant p16 protein was un able to bind cyclin-dependent kinase 4 and cyclin-dependent kinase 6, Two p atients without a family history of melanoma had CDKN2A alterations: (a) on e had a mutation in the 5' noncoding sequence (-14C/T); and (6) the other h ad an insertion of an extra T in codon 28, which results in a stop signal i n codon 43, The median age at diagnosis of the first melanoma was significa ntly lower, the number of primary melanomas was significantly higher, and t he presence of a family history of melanoma was significantly more common i n patients with CDKN2A mutations than in those without germ-line mutations. The proportion of CDKN2A mutation carriers was significantly higher among patients treated for three or more primary melanomas compared with those wi th two tumors only, We conclude that mutation screening of individuals with multiple primary melanomas Is a useful strategy to identify new melanoma k indreds with CDKN2A germ-line mutations.