Genetic and functional evaluation of MITF as a candidate gene for cutaneous melanoma predisposition in pigs

• DOI: 10.1007/s00335-011-9334-6
• Publication Date: 2011-05-27T10:29:42Z
• Authors: Emmanuelle Bourneuf; Zhi-Qiang Du; Jordi Estellé; Hélène Gilbert; Françoise Créchet; Guillaume Piton; Denis Milan; Claudine Geffrotin; Mark Lathrop; Florence Demenais; Claire Rogel-Gail...; Silvia Vincent-Na...
• Keywords: pig; [SDV.SA]Life Sciences [q-bio]/Agricultural sciences; Male; Microphthalmia-Associated Transcription Factor; 0303 health sciences; Skin Neoplasms; Genetic Linkage; Molecular Sequence Data; Quantitative Trait Loci; Sus scrofa; 610; candidate gene; Polymorphism, Single Nucleotide; 630; cutaneous melanoma; 03 medical and health sciences; mitf; Gene Expression Regulation; Animals; Female; Genetic Predisposition to Disease; RNA, Messenger; Melanoma

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.