title: Germline p16INK4A mutation and protein dysfunction in a family with inherited melanoma.
abstract: The gene encoding the cell cycle inhibitor p16INK4A (also known as p16, MTS1, CDKN2 and INK4) has been mapped to human chromosome band 9p21, a region that also contains a putative melanoma susceptibility gene. Although germline mutations in the coding region of the p16INK4A gene have been detected in some families with inherited melanoma, many other families show no evidence of such mutations and hence the role of p16INK4A in the development of this tumor is still unclear. In this report, we describe a family with inherited melanoma in which a novel mutation in exon 2 of the p16INK4A gene segregates with the disease. The mutant gene encodes a protein with an in-frame deletion of two amino acids (Asp96 and Leu97). We show that the mutant protein is functionally abnormal: it is unable to bind cdk4 in vitro and does not inhibit colony formation in tertiary passage rat embryo fibroblasts. Moreover, in a metastatic lesion from one patient the wild type p16INK4A allele was deleted and the mutant allele retained. We conclude that family members carrying this germline mutation in the p16INK4A gene are predisposed to melanoma. By extension, these findings implicate the p16INK4A gene in the development of some cases of familial melanoma.
authors.affiliation: Oncology Research Division, Toronto Hospital, Ontario, Canada.
authors.forename: L
authors.initials: L
authors.lastname: Liu
authors.forename: N J
authors.initials: NJ
authors.lastname: Lassam
authors.forename: J M
authors.initials: JM
authors.lastname: Slingerland
authors.forename: D
authors.initials: D
authors.lastname: Bailey
authors.forename: D
authors.initials: D
authors.lastname: Cole
authors.forename: R
authors.initials: R
authors.lastname: Jenkins
authors.forename: D
authors.initials: D
authors.lastname: Hogg
mesh_terms: D000483:Alleles; D000818:Animals; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002478:Cells, Cultured; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D004247:DNA / Q000235:genetics; D004622:Embryo, Mammalian / Q000166:cytology; D004791:Enzyme Inhibitors / Q000378:metabolism; D005091:Exons; D005192:Family Health; D005260:Female; D005347:Fibroblasts / Q000166:cytology; D030342:Genetic Diseases, Inborn / Q000235:genetics; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000556:secondary; D008969:Molecular Sequence Data; D009362:Neoplasm Metastasis; D010375:Pedigree; D018807:Polymorphism, Single-Stranded Conformational; D047428:Protein Kinase Inhibitors; D051381:Rats; D017422:Sequence Analysis, DNA; D014162:Transfection; D014410:Tumor Stem Cell Assay
chemical_list: D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D004247:DNA; D018844:Cyclin-Dependent Kinases