title: Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma.
abstract: Germline anomalies of the INK4a-ARF and Cdk4 genes were sought in a series of 89 patients suspected of having a genetic predisposition to melanoma. Patients were selected based on the following criteria: (a) familial melanoma (23 cases), (b) multiple primary melanoma (MPM; 18 cases), (c) melanoma and additional unrelated cancers (13 cases), (d) age at diagnosis less than 25 years (21 cases), and (e) nonphoto-induced melanoma (NPIM; 14 cases). Mutations of INK4a-ARF and Cdk4 were characterised by automated sequencing, and germline deletions of INK4a-ARF were also examined by real-time quantitative PCR. Seven germline changes of INK4a-ARF, five of which were novel, were found in seven patients (8%). Four were very likely to be pathogenic mutations and were found in three high-risk melanoma families and in a patient who had a pancreatic carcinoma in addition to melanoma. Three variants of uncertain significance were detected in one MPM patient, one patient <25 years, and one NPIM patient. No germline deletion of INK4a-ARF was found in 71 patients, and no Cdk4 mutation was observed in the 89 patients. This study confirms that INK4a-ARF mutations are infrequent outside stringent familial criteria, and that germline INK4a-ARF deletions are rarely involved in genetic predisposition to melanoma.
authors.affiliation: Laboratoire de Biochimie Hormonale et Génétique, Hôpital Bichat-Claude Bernard, 46 rue henri Huchard, Paris 75018, France. nadem.soufir@bch.ap-hop-paris.fr
authors.forename: N
authors.initials: N
authors.lastname: Soufir
authors.forename: J J
authors.initials: JJ
authors.lastname: Lacapere
authors.forename: G
authors.initials: G
authors.lastname: Bertrand
authors.forename: E
authors.initials: E
authors.lastname: Matichard
authors.forename: R
authors.initials: R
authors.lastname: Meziani
authors.forename: D
authors.initials: D
authors.lastname: Mirebeau
authors.forename: V
authors.initials: V
authors.lastname: Descamps
authors.forename: B
authors.initials: B
authors.lastname: Gérard
authors.forename: A
authors.initials: A
authors.lastname: Archimbaud
authors.forename: L
authors.initials: L
authors.lastname: Ollivaud
authors.forename: F
authors.initials: F
authors.lastname: Bouscarat
authors.forename: M
authors.initials: M
authors.lastname: Baccard
authors.forename: G
authors.initials: G
authors.lastname: Lanternier
authors.forename: P
authors.initials: P
authors.lastname: Saïag
authors.forename: C
authors.initials: C
authors.lastname: Lebbé
authors.forename: N
authors.initials: N
authors.lastname: Basset-Seguin
authors.forename: B
authors.initials: B
authors.lastname: Crickx
authors.forename: H
authors.initials: H
authors.lastname: Cave
authors.forename: B
authors.initials: B
authors.lastname: Grandchamp
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008875:Middle Aged; D010375:Pedigree; D016133:Polymerase Chain Reaction; D012307:Risk Factors; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics*
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D025803:Tumor Suppressor Protein p14ARF