CDKN2A germ-line mutations in individuals with multiple cutaneous melanomas.

• Germ-line CDKN2A mutations are present in some kindreds with hereditary cutaneous melanoma, and in Sweden a founder mutation with an extra arginine in codon 113 (113insR) has been identified. We screened 80 individuals with at least two primary cutaneous melanomas, who were identified mainly by a search of a regional cancer registry, for germ-line CDKN2A mutations. In nine patients, CDKN2A alterations that may contribute to melanoma predisposition were detected. In six individuals with a family history of melanoma, the 113insR founder mutation was present. One patient, who also had a family history of melanoma, had a 24-bp deletion that included codons 62-69. An in vitro binding assay established that the resulting mutant p16 protein was unable to bind cyclin-dependent kinase 4 and cyclin-dependent kinase 6. Two patients without a family history of melanoma had CDKN2A alterations: (a) one had a mutation in the 5' noncoding sequence (-14C/T); and (b) the other had an insertion of an extra T in codon 28, which results in a stop signal in codon 43. The median age at diagnosis of the first melanoma was significantly lower, the number of primary melanomas was significantly higher, and the presence of a family history of melanoma was significantly more common in patients with CDKN2A mutations than in those without germ-line mutations. The proportion of CDKN2A mutation carriers was significantly higher among patients treated for three or more primary melanomas compared with those with two tumors only. We conclude that mutation screening of individuals with multiple primary melanomas is a useful strategy to identify new melanoma kindreds with CDKN2A germ-line mutations.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Cancer och onkologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Cancer and Oncology (hsv//eng)

Nyckelord

Adolescent

Adult

Age of Onset

Base Sequence

Codon

Cyclin-Dependent Kinase 4

Cyclin-Dependent Kinase 6

Cyclin-Dependent Kinase Inhibitor p16

metabolism

Cyclin-Dependent Kinases

metabolism

DNA

Complementary

metabolism

Exons

Family Health

Female

Founder Effect

Gene Deletion

Genes

p16

genetics

Genetic Predisposition to Disease

Germ-Line Mutation

Humans

Male

Melanoma

genetics

Middle Aged

Molecular Sequence Data

Mutation

Polymorphism

Single-Stranded Conformational

Protein Binding

Protein-Serine-Threonine Kinases

metabolism

Proto-Oncogene Proteins

Sequence Analysis

DNA

Skin Neoplasms

genetics

Publikations- och innehållstyp

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