Background: : Inherited mutations in the CDKN2A tumor suppressor gene, which encodes the p16(INK4a) protein, and in the cyclin-dependent kinase 4 (CDK4) gene confer susceptibility to cutaneous malignant melanoma. We analyzed families with two or more cases of melanoma for germline mutations in CDKN2A and CDK4 to elucidate the contribution of these gene defects to familial malignant melanoma and to the occurrence of other cancer types.
Methods: : The entire CDKN2A coding region and exon 2 of the CDK4 gene of an affected member of each of 52 families from southern Sweden with at least two cases of melanoma in first- or second-degree relatives were screened for mutations by use of polymerase chain reaction-single-strand conformation polymorphism analysis. Statistical tests were two-sided.
Results: : CDKN2A mutations were found in 10 (19%) of the 52 families. Nine families carried an identical alteration consisting of the insertion of arginine at position 113 of p16(INK4a), and one carried a missense mutation, in which the valine at position 115 was replaced with a glycine. The 113insArg mutant p16(INK4a) was unable to bind cdk4 and cdk6 in an in vitro binding assay. Six of the 113insArg families had at least one member with multiple primary melanomas; the 113insArg families also had a high frequency of other malignancies-in particular, breast cancer (a total of eight cases compared with the expected 2.1; P =.0014) and pancreatic cancer (a total of six cases compared with the expected 0.16; P<.0001). Families with breast cancer also had a propensity for multiple melanomas in females, suggesting that a sex-dependent factor may modify the phenotypic expression of CDKN2A alterations.
Conclusions: : Our findings confirm that the majority of CDKN2A-associated melanoma families in Sweden are due to a single founder mutation. They also show that families with the CDKN2A 113insArg mutation have an increased risk not only of multiple melanomas and pancreatic carcinoma but also of breast cancer.