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

Mamm Genome. 2011 Oct;22(9-10):602-12. doi: 10.1007/s00335-011-9334-6. Epub 2011 May 28.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Female
  • Gene Expression Regulation
  • Genetic Linkage
  • Genetic Predisposition to Disease*
  • Male
  • Melanoma / genetics*
  • Melanoma / metabolism
  • Microphthalmia-Associated Transcription Factor / genetics*
  • Microphthalmia-Associated Transcription Factor / metabolism
  • Molecular Sequence Data
  • Polymorphism, Single Nucleotide
  • Quantitative Trait Loci
  • RNA, Messenger
  • Skin Neoplasms / genetics*
  • Skin Neoplasms / metabolism
  • Sus scrofa

Substances

  • Microphthalmia-Associated Transcription Factor
  • RNA, Messenger

Associated data

  • GENBANK/GU097381
  • GENBANK/GU097382
  • GENBANK/GU097383