The contribution of large genomic deletions at the CDKN2A locus to the burden of familial melanoma.
Mutations in two genes encoding cell cycle regulatory proteins have been shown to cause familial cutaneous malignant melanoma (CMM). About 20% of melanoma-prone families bear a point mutation in the CDKN2A locus at 9p21, which encodes two unrelated proteins, p16(INK4a) and p14(ARF). Rare mutations in CDK4 have also been linked to the disease. Although the CDKN2A gene has been shown to be the major melanoma predisposing gene, there remains a significant proportion of melanoma kindreds linked to 9p21 in which germline mutations of CDKN2A have not been identified through direct exon sequencing. The purpose of this study was to assess the contribution of large rearrangements in CDKN2A to the disease in melanoma-prone families using multiplex ligation-dependent probe amplification. We examined 214 patients from independent pedigrees with at least two CMM cases. All had been tested for CDKN2A and CDK4 point mutation, and 47 were found positive. Among the remaining 167 negative patients, one carried a novel genomic deletion of CDKN2A exon 2. Overall, genomic deletions represented 2.1% of total mutations in this series (1 of 48), confirming that they explain a very small proportion of CMM susceptibility. In addition, we excluded a new gene on 9p21, KLHL9, as being a major CMM gene.
Lesueur
F
F
Groupe Mélanome, Institut Gustave Roussy, FRE2939 CNRS-Université Paris-Sud, Villejuif, France.
de Lichy
M
M
Barrois
M
M
Durand
G
G
Bombled
J
J
Avril
M-F
MF
Chompret
A
A
Boitier
F
F
Lenoir
G M
GM
Bressac-de Paillerets
B
B
Baccard
Monique
M
Bachollet
Bertrand
B
Berthet
Pascaline
P
Bonadona
Valérie
V
Bonnetblanc
Jean-Marie
JM
Caron
Olivier
O
Chevrant-Breton
Jacqueline
J
Cuny
Jean-François
JF
Dalle
Stéphane
S
Delaunay
Michèle
M
Demange
Liliane
L
De Quatrebarbes
Julie
J
Doré
Jean-François
JF
Frénay
Marc
M
Fricker
Jean-Pierre
JP
Gauthier-Villars
Marion
M
Gesta
Paul
P
Giraud
Sophie
S
Gorry
Philippe
P
Grange
Florent
F
Green
Andrew
A
Huiart
Laetitia
L
Janin
Nicolas
N
Joly
Pascal
P
Kérob
Delphine
D
Lasset
Christine
C
Leroux
Dominique
D
Limacher
Jean-Marc
JM
Longy
Michel
M
Mansard
Sandrine
S
Marrou
Karine
K
Martin-Denavit
Tanguy
T
Mateus
Christine
C
Maubec
Eve
E
Olivier-Faivre
Laurence
L
Orlandini
Vincent
V
Pujol
Pascal
P
Sassolas
Bruno
B
Stoppa-Lyonnet
Dominique
D
Thomas
Luc
L
Vabres
Pierre
P
Venat
Laurence
L
Wierzbicka
Ewa
E
Zattara
Hélène
H
D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics; D002899:Chromosomes, Human, Pair 9; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005091:Exons; D005260:Female; D017353:Gene Deletion; D019942:Genes, p16; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D010375:Pedigree; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics
D002352:Carrier Proteins; D019941:Cyclin-Dependent Kinase Inhibitor p16; C473356:KLHL6 protein, human; D025803:Tumor Suppressor Protein p14ARF