Identification of five chromosomal regions involved in predisposition to melanoma by genome-wide scan in the MeLiM swine model.
In human familial melanoma, 3 risk susceptibility genes are already known, CDKN2A, CDK4 and MC1R. However, various observations suggest that other melanoma susceptibility genes have not yet been identified. To search for new susceptibility loci, we used the MeLiM swine as an animal model of hereditary melanoma to perform a genome scan for linkage to melanoma. Founders of the affected MeLiM stock were crossed with each other and with healthy Duroc pigs, generating MeLiM, F1 and backcross families. As we had previously excluded the MeLiM CDKN2A gene, we paid special attention to CDK4 and MC1R, as well as to other candidates such as BRAF and the SLA complex, mapping them on the swine radiation hybrid map and/or isolating close microsatellite markers to introduce them into the genome scan. The results revealed, first, that swine melanoma was inherited as an autosomal dominant trait with incomplete penetrance, preferably in black animals. Second, 4 chromosomal regions potentially involved in melanoma susceptibility were identified on Sus Scrofa chromosomes (SSC) 1, 2, 7 and 8, respectively, in intervals 44-103, 1.9-18, 59-73 and 47-62 cM. A fifth region close to MC1R was revealed on SSC 6 by analyzing an individual marker located at position 7.5 cM. Lastly, CDK4 and BRAF were unlikely to be melanoma susceptibility genes in the MeLiM swine model. The 3 regions on SSC 1, 6 and 7, respectively, have counterparts on human chromosomes (HSA) 9p, 16q and 6p, harboring melanoma candidate loci. The 2 others, on SSC 2 and 8, have counterparts on HSA 11 and 4, which might therefore be of interest for human studies.
Geffrotin
Claudine
C
Laboratoire de Radiobiologie et d'Etude du Génome, Commissariat à l'Energie Atomique, Institut National de la Recherche Agronomique, 78352 Jouy-en-Josas Cedex, France. geff@jouy.inra.fr
Crechet
Françoise
F
Le Roy
Pascale
P
Le Chalony
Catherine
C
Leplat
Jean-Jacques
JJ
Iannuccelli
Nathalie
N
Barbosa
Angela
A
Renard
Christine
C
Gruand
Joseph
J
Milan
Denis
D
Horak
Vratislav
V
Tricaud
Yves
Y
Bouet
Stéphan
S
Franck
Michel
M
Frelat
Gérard
G
Vincent-Naulleau
Silvia
S
D000818:Animals; D002874:Chromosome Mapping; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D016678:Genome; D005838:Genotype; D008297:Male; D008545:Melanoma / Q000235:genetics*; D018895:Microsatellite Repeats; D011518:Proto-Oncogene Proteins; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf / Q000235:genetics*; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D013552:Swine
D011518:Proto-Oncogene Proteins; D044102:Receptor, Melanocortin, Type 1; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D019908:Proto-Oncogene Proteins c-raf; D051358:Cyclin-Dependent Kinase 4; D018844:Cyclin-Dependent Kinases