Germline mutations of the INK4a-ARF gene in patients with suspected genetic predisposition to melanoma.
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.
Soufir
N
N
Laboratoire de Biochimie Hormonale et Génétique, Hôpital Bichat-Claude Bernard, 46 rue henri Huchard, Paris 75018, France. nadem.soufir@bch.ap-hop-paris.fr
Lacapere
J J
JJ
Bertrand
G
G
Matichard
E
E
Meziani
R
R
Mirebeau
D
D
Descamps
V
V
Gérard
B
B
Archimbaud
A
A
Ollivaud
L
L
Bouscarat
F
F
Baccard
M
M
Lanternier
G
G
Saïag
P
P
Lebbé
C
C
Basset-Seguin
N
N
Crickx
B
B
Cave
H
H
Grandchamp
B
B
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*
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004273:DNA, Neoplasm; D025803:Tumor Suppressor Protein p14ARF