Melanoma Families

Background: Inherited mutations in the CDKN2A tumor suppressor gene, which encodes the p16INK4a 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 muta-tions in CDKN2A and CDK4 to eluci-date the contribution of these gene de-fects 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 poly-merase 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 consist-ing of the insertion of arginine at posi-tion 113 of p16INK4a, and one carried a missense mutation, in which the valine at position 115 was replaced with a gly-cine. The 113insArg mutant p16INK4a was unable to bind cdk4 and cdk6 in an in vitro binding assay. Six of the 113ins-Arg families had at least one member with multiple primary melanomas; the 113insArg families also had a high fre-quency of other malignancies—in par-ticular, breast cancer (a total of eight cases compared with the expected 2.1; P =.0014) and pancreatic cancer (a to-tal of six cases compared with the ex-pected 0.16; P<.0001). Families with breast cancer also had a propensity for multiple melanomas in females, sug-gesting 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 pan-creatic carcinoma but also of breas