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Germline p16 mutations in familial melanoma.

Author(s): Nicholas Higgins, N C Dracopoli, Dominic Tucker, C Hussussian, M Sheahan, J Struewing, Howard Clark, Steve A N Goldstein, D S Ally

Publication date: 1994-08-31

Journal: Nature genetics

Keywords: Base Sequence, Carrier Proteins, Chromosome Mapping, Chromosomes, Human, Pair 9, Cyclin-Dependent Kinase Inhibitor p16, Dysplastic Nevus Syndrome, genetics, Female, Germ-Line Mutation, Humans, Interferon-alpha, Lod Score, Male, Melanoma, Molecular Sequence Data, Pedigree, Polymorphism, Single-Stranded Conformational, Skin Neoplasms

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Abstract

The p16 gene is located in chromosome 9p21, a region that is linked to familial melanoma and homozygously deleted in many tumour cell lines. We describe eight p16 germline substitutions (one nonsense, one splice donor site and six missense) in 13/18 familial melanoma kindreds. Six of these mutations were identified in 33/36 melanoma cases in nine families, whereas two were detected in normal controls and are not disease-related. The melanoma-specific mutations were detected in 9p21-linked, but not in 1p36-linked, families, thereby confirming previous reports of genetic heterogeneity. Functional analyses of these mutations will confirm those causally related to the development of familial melanoma.

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Most cited references 16

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Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers.

T Nobori, K. Miura, D. Wu … (1994)

Cytogenetic abnormalities of chromosome 9p21 are characteristic of malignant melanomas, gliomas, lung cancers and leukaemias. From a panel of 46 human malignant cell lines, we localized by positional cloning the most frequently deleted region on 9p21. Sequence analysis of the isolated fragment reveals two open reading frames identical to the recently described complementary DNA for the inhibitor of cyclin-dependent kinase 4 (CDK4). Polymerase chain reaction and Southern blot analysis confirmed the frequent deletion or rearrangement of the CDK4-inhibitor gene in melanomas, gliomas, lung cancers and leukaemias, and the absence of detectable gene transcripts. One carcinoma had a deletion entirely within the CDK4-inhibitor gene. The CDK4-inhibitor gene from a patient with dysplastic nevus syndrome had a germ-line nonsense mutation. The CDK4 inhibitor is thought to be a physiological suppressor of proliferation. Cells unable to produce the inhibitor may be prone to neoplastic transformation.