title: Genetic and functional evaluation of MITF as a candidate gene for cutaneous melanoma predisposition in pigs.
abstract: Cutaneous melanoma arises from transformed melanocytes and is caused mainly by environmental effects such as ultraviolet radiation and to a lesser extent by predisposing genetic variants. Only a few susceptibility genes for cutaneous melanoma have been identified so far in human; therefore, animal models represent a valuable alternative for genetic studies of this disease. In a previous quantitative trait locus (QTL) study, several susceptibility regions were identified in a swine biomedical model, the MeLiM (Melanoblastoma-bearing Libechov minipig) pigs. This article details the fine-mapping of a QTL located on SSC13 (Sus scrofa chromosome 13) through an increase in marker density. New microsatellites were used to confirm the results of the first analysis, and MITF (microphthalmia-associated transcription factor) was selected as a candidate gene for melanoma development. A single-marker association analysis was performed with single-nucleotide polymorphisms (SNPs) spread over the locus, but it did not reveal a significant association with diverse melanoma-related traits. In parallel, MITF alternative transcripts were characterized and their expression was investigated in different porcine tissues. The obtained results showed a complex transcriptional regulation concordant with the one present in other mammals. Notably, the ratio between MITF+ and MITF- isoforms in melanoma samples followed the same pattern as in human tumors, which highlights the adequacy of the MeLiM pig as a model for human melanoma. In conclusion, although MITF does not seem to be the causal gene of the QTL initially observed, we do not exclude a prominent role of its transcription and function in the outbreak and evolution of the tumors observed in pigs.
authors.affiliation: INRA, UMR Génétique Animale et Biologie Intégrative, Equipe Génétique Immunité Santé, 78352 Jouy-en-Josas, France. Emmanuelle.bourneuf@cea.fr
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Bourneuf
authors.forename: Zhi-Qiang
authors.initials: ZQ
authors.lastname: Du
authors.forename: Jordi
authors.initials: J
authors.lastname: Estellé
authors.forename: Hélène
authors.initials: H
authors.lastname: Gilbert
authors.forename: Françoise
authors.initials: F
authors.lastname: Créchet
authors.forename: Guillaume
authors.initials: G
authors.lastname: Piton
authors.forename: Denis
authors.initials: D
authors.lastname: Milan
authors.forename: Claudine
authors.initials: C
authors.lastname: Geffrotin
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Florence
authors.initials: F
authors.lastname: Demenais
authors.forename: Claire
authors.initials: C
authors.lastname: Rogel-Gaillard
authors.forename: Silvia
authors.initials: S
authors.lastname: Vincent-Naulleau
mesh_terms: D000818:Animals; D005260:Female; D005786:Gene Expression Regulation; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism; D051739:Microphthalmia-Associated Transcription Factor / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D012333:RNA, Messenger; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism; D034421:Sus scrofa
chemical_list: D051739:Microphthalmia-Associated Transcription Factor; D012333:RNA, Messenger