High Frequency of Multiple Melanomas and Breast and Pancreas Carcinomas in CDKN2A Mutation-Positive Melanoma Families

• DOI: 10.1093/jnci/92.15.1260
• Publication Date: 2002-07-26T18:35:58Z
• Authors: A. Borg; T. Sandberg; K. Nilsson; O. Johannsson; M. Klinker; A. Masback; J. Westerdahl; H. Olsson; C. Ingvar
• Keywords: Male; Risk; Sweden; Skin Neoplasms; Genes, p16; Molecular Sequence Data; Breast Neoplasms; Polymerase Chain Reaction; Pedigree; 3. Good health; Neoplasms, Multiple Primary; Pancreatic Neoplasms; 03 medical and health sciences; Sex Factors; 0302 clinical medicine; Mutation; Humans; Female; Amino Acid Sequence; Promoter Regions, Genetic; Melanoma; Polymorphism, Single-Stranded Conformational

Background: Inherited mutations in the CDKN2A tumor suppressor gene, which encodes p16INK4a protein, and cyclin-dependent kinase 4 (CDK4) gene confer susceptibility to cutaneous malignant melanoma. We analyzed families with two or more cases of melanoma for germline CDK4 elucidate contribution these defects familial occurrence other cancer types. Methods: The entire coding region exon 2 an affected member each 52 from southern Sweden at least first- second-degree relatives were screened by use polymerase chain reaction–single-strand conformation polymorphism analysis. Statistical tests two-sided. Results: found 10 (19%) families. Nine carried identical alteration consisting insertion arginine position 113 p16INK4a, one a missense mutation, valine 115 was replaced glycine. 113insArg mutant unable bind cdk4 cdk6 vitro binding assay. Six had multiple primary melanomas; also high frequency malignancies—in particular, breast (a total eight compared expected 2.1; P = .0014) pancreatic six 0.16; P<.0001). Families propensity melanomas females, suggesting that sex-dependent factor may modify phenotypic expression alterations. Conclusions: Our findings confirm majority CDKN2A-associated are due single founder mutation. They show mutation have increased risk not only carcinoma but cancer.