title: Functional, structural, and genetic evaluation of 20 CDKN2A germ line mutations identified in melanoma-prone families or patients.
abstract: Germline mutations of the CDKN2A gene are found in melanoma-prone families and individuals with multiple sporadic melanomas. The encoded protein, p16(INK4A), comprises four ankyrin-type repeats, and the mutations, most of which are missense and occur throughout the entire coding region, can disrupt the conformation of these structural motifs as well as the association of p16(INK4a) with its physiological targets, the cyclin-dependent kinases (CDKs) CDK4 and CDK6. Assessing pathogenicity of nonsynonymous mutations is critical to evaluate melanoma risk in carriers. In the current study, we investigate 20 CDKN2A germline mutations whose effects on p16(INK4A) structure and function have not been previously documented (Thr18_Ala19dup, Gly23Asp, Arg24Gln, Gly35Ala, Gly35Val, Ala57Val, Ala60Val, Ala60Arg, Leu65dup, Gly67Arg, Gly67_Asn71del, Glu69Gly, Asp74Tyr, Thr77Pro, Arg80Pro, Pro81Thr, Arg87Trp, Leu97Arg, Arg99Pro, and [Leu113Leu;Pro114Ser]). By considering genetic information, the predicted impact of each variant on the protein structure, its ability to interact with CDK4 and impede cell proliferation in experimental settings, we conclude that 18 of the 20 CDKN2A variants can be classed as loss of function mutations, whereas the results for two remain ambiguous. Discriminating between mutant and neutral variants of p16(INK4A) not only adds to our understanding of the functionally critical residues in the protein but provides information that can be used for melanoma risk prediction.
authors.affiliation: Service de Génétique, Institut Gustave Roussy, Villejuif, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Kannengiesser
authors.forename: Sharon
authors.initials: S
authors.lastname: Brookes
authors.forename: Anna Gutierrez
authors.initials: AG
authors.lastname: del Arroyo
authors.forename: Danielle
authors.initials: D
authors.lastname: Pham
authors.forename: Johny
authors.initials: J
authors.lastname: Bombled
authors.forename: Michel
authors.initials: M
authors.lastname: Barrois
authors.forename: Olivier
authors.initials: O
authors.lastname: Mauffret
authors.forename: Marie-Françoise M
authors.initials: MF
authors.lastname: Avril
authors.forename: Agnès
authors.initials: A
authors.lastname: Chompret
authors.forename: Gilbert M
authors.initials: GM
authors.lastname: Lenoir
authors.forename: Alain
authors.initials: A
authors.lastname: Sarasin
authors.forename: Gordon
authors.initials: G
authors.lastname: Peters
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bressac-de Paillerets
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D005192:Family Health; D005820:Genetic Testing; D018095:Germ-Line Mutation; D006801:Humans; D008545:Melanoma / Q000175:diagnosis / Q000235:genetics*; D008958:Models, Molecular; D020125:Mutation, Missense; D011485:Protein Binding; D017434:Protein Structure, Tertiary
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; C495900:CDK4 protein, human; D051358:Cyclin-Dependent Kinase 4