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Screening for CDKN2A Mutations in Hereditary Melanoma

1997; Oxford University Press; Volume: 89; Issue: 10 Linguagem: Inglês

10.1093/jnci/89.10.676

1460-2105

Alisa M. Goldstein, M. A. Tucker,

Immunotherapy and Immune Responses

Cutaneous malignant melanoma (CMM) is a potentially fatal form of skin cancer whose etiology is heterogeneous and complex.Approximately 10% of the cases of CMM occur in persons with a familial predisposition (1), often in association with clinically dysplastic or atypical nevi (2).In 1993, a low-molecular-weight protein p16 INK4A was shown to inhibit the activity of the cyclin D1-cyclin-dependent kinase 4 or 6 (CDK4 or CDK6) complex (3).This complex phosphorylates the retinoblastoma protein, allowing the cell to pass through the G1 cell-cycle checkpoint.The CDKN2A gene that encodes p16 INK4A was localized to chromosome 9p21 (4,5), a region that has been implicated in melanoma by linkage, cytogenetic, and loss-of-heterozygosity studies (6)(7)(8)(9)(10)(11). Somatic mutations in this gene have frequently been detected in many melanoma cell lines (4,5).Although initial reports of germline mutations in melanomaprone families (selected for genetic analyses) suggested that the p16 INK4A protein might be important in approximately one half of inherited melanoma (12-14), subsequent studies have revealed lower frequencies of mutations.To date, germline CDKN2A mutations have been detected in approximately one fourth of melanoma-prone kindreds (defined as having two or more first-degree relatives with confirmed CMM) from North America, Europe, and Australia (12-21).In this issue of the Journal, Platz et al. ( 22) present the first report of screening for germline mutations in a population-based cohort of melanoma-prone families.The results provide further evidence that CDKN2A mutations may not be as prevalent as originally thought.Platz et al. ( 22) identified 177 melanoma-prone families, defined by the occurrence of two or more relatives (including first-, second-, and third-degree relatives) with histopathologically confirmed CMM, in the County of Stockholm, Sweden.A representative selection of 181 individuals with CMM, from 100 of these families, was screened for germline mutations in CDKN2A.Of the 100 families, 64 kindreds had at least two cases of melanoma in first-degree relatives; 24 kindreds had melanoma in two or more second-degree relatives; and 12 kindreds had melanomas in third-degree or more distant relatives.Both direct sequencing and single-strand conformation polymorphism (SSCP) analyses of exons 1 and 2 were conducted.Of the 64 families with two or more first-degree relatives with CMM, five (7.8%) had potentially disease-related mutations.Four of the five families with mutations had more than the