Search

Genetic alterations implicated in malignant melanoma are still poorly understood. Malignant melanomas present highly variable histologic and cytologic patterns. The aim of the present study is to define genomic imbalances associated with the development of 2 histologic types of swine hereditary cutaneous melanoma. We have investigated 11 swine tumors by comparative genomic hybridization (CGH), 4 superficial spreading melanomas (SSMs) and 7 nodular melanomas (NMs). Following laser capture microdissection and degenerate oligonucleotide primed-polymerase chain reaction, we were able to isolate and then amplify DNA from the 2 histologic subtypes. Consensus regions of chromosome gains were identified on both histologic subtypes, on swine chromosomes 3p13-p17 (75% of the SSMs and 71% of the NMs), 12q (100% of the SSMs and 57% of the NMs) and 14q11-q21 (75% of the SSMs and 42% of NMs). Chromosomal loss was restricted to NM lesions and the swine 13q36-49 region was lost in 100% of the NMs. Interphase fluorescence in situ hybridization with a probe mapping to the 13q41-q42 region indicates loss of the corresponding region on NM lesions. Taking into account this CGH analysis and the comparative genomic data between swine and human genomes, we suggest that a role for the human chromosomes 3p11-qter and chromosome 21 losses should be investigated in human nodular melanoma progression., (Copyright 2004 Wiley-Liss, Inc.)

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., (Copyright 2004 Wiley-Liss, Inc.)

Some herds of miniature swine are genetically predisposed to cutaneous melanoma. To test if swine melanoma susceptibility could be linked to the CDKN2A gene, which is involved in a proportion of 9p21-linked human familial melanoma, we performed a genetic analysis of miniature pigs of the MeLiM strain. F(1) and backcross animals were generated by crossing 1 MeLiM boar with healthy Duroc sows. We isolated the swine CDKN2A gene and characterized a linked informative microsatellite marker, the S0644 marker. Using this marker and 2 flanking markers, we analyzed the segregation of the CDKN2A gene in a 3-generation pedigree. Allelic association, linkage analysis and haplotype analysis of these data led to exclusion of the CDKN2A gene as a candidate for melanoma susceptibility. Nonetheless, this analysis suggests an association with the swine 1q25 chromosomal region, which is homologous to the human 9p21 region., (Copyright 2002 Wiley-Liss, Inc.)