Mutation of the CDKN2A 5′ UTR creates an aberrant initiation codon and predisposes to melanoma

Approximately 8-12% Of melanoma is inherited in an autosomal dominant fashion with variable penetrance(1-8). A chromosome 9p21 locus has been linked to this disease in 50-80% of affected families(5-7,9). CDKN2A (also known as P16, INK4, p16(INK4A) and MTS1) is allelic to this locus and encodes a cdk4/cdk6 kinase inhibitor that constrains cells from progressing through the G1 restriction point(10-12). Although germline CDKN2A coding mutations cosegregate with melanoma in 25-60% of families predisposed to the disease(8,9,13-19), there remains a number of mutation-negative families that demonstrate linkage of inherited melanoma to 9p21 markers(9). We show here that a subset of these kindreds possess a G-->T transversion at base -34 of CDKN2A, designated G-34T. This mutation gives rise to a novel AUG translation initiation codon that decreases translation from the wild-type AUG. The G-34T mutation is not seen in controls, segregates with melanoma in families and, on the basis of haplotyping studies, probably arose from a common founder in the United Kingdom. Characterization of this and other CDKN2A non-coding mutations should have an impact on current efforts to identify susceptible melanoma-prone families and individuals.