CDKN2A (P16(INK4a)) and CDK4 Mutation Analysis in 131 Australian Melanoma Probands: Effect of Family History and Multiple Primary Melanomas

Mutation analysis of two genes involved in melanoma susceptibility (CDKN2A/p16(INK4a) and CDK4) was undertaken in 131 probands with a family history of melanoma. Screening of all three exons of CDKN2A and exon 2 of CDK4 by single-strand conformation polymorphism (SSCP) analysis and/or direct sequencing identified a total of 10 different CDKN2A germline mutations, including 6 not previously described in the germline. All but one has been previously proven to, or is likely to, affect the structure and function of p16(INK4a). The incidence of CDKN2A mutation was 8.4% (11/131), but was significantly higher in families with three or more cases of melanoma (10/66, 15.1%) than in those in which only two relatives were affected (1/65, 1.5%). The incidence of CDKN2A mutation was also higher in families with three or more cases of melanoma and at least one member with multiple primary melanomas (6/19, 31.6%) than in similar families without multiple primary melanomas (4/47, 8.5%). One novel CDK4 variant of uncertain significance was found in a kindred that also carries a CDKN2A mutation. Genes Chromosomes Cancer 25:339-348, 1999.