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

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Abstract
Approximately 8-12% of melanoma is inherited in an autosomal dominant fashion with variable penetrance1,2,3,4,5,6,7,8. A chromosome 9p21 locus has been linked to this disease in 50-80% of affected families5,6,7,9. CDKN2A (also known as P16, INK4, p16INK4A and MTS1) is allelic to this locus and encodes a cdk4/cdk6 kinase inhibitor that constrains cells from progressing through the G1 restriction point10,11,12. Although germline CDKN2A coding mutations cosegregate with melanoma in 25-60% of families predisposed to the disease8,9,13,14,15,16,17,18,19, there remains a number of mutation-negative families that demonstrate linkage of inherited melanoma to 9p21 markers9. 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.