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, 9 (45), 27682-27697

New Susceptibility Loci for Cutaneous Melanoma Risk and Progression Revealed Using a Porcine Model

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New Susceptibility Loci for Cutaneous Melanoma Risk and Progression Revealed Using a Porcine Model

Emmanuelle Bourneuf et al. Oncotarget.

Abstract

Despite major advances, it is estimated that a large part of melanoma predisposing genes remains to be discovered. Animal models of spontaneous diseases are valuable tools and experimental crosses can be used to identify and fine-map new susceptibility loci associated with melanoma. We performed a Genome-Wide Association Study (GWAS) of melanoma occurrence and progression (clinical ulceration and presence of metastasis) in a porcine model of spontaneous melanoma, the MeLiM pig. Five loci on chromosomes 2, 5, 7, 8 and 16 showed genome-wide significant associations (p < 5 × 10-6) with either one of these phenotypes. Suggestive associations (p < 5 × 10-5) were also found at 16 additional loci. Moreover, comparison of the porcine results to those reported by human melanoma GWAS indicated shared association signals notably at CDKAL1 and TERT loci but also nearby CCND1, FTO, PLA2G6 and TMEM38B-RAD23B loci. Extensive search of the literature revealed a potential key role of genes at the identified porcine loci in tumor invasion (DST, PLEKHA5, CBY1, LIMK2 and ETV5) and immune response modulation (ETV5, HERC3 and DICER1) of the progression phenotypes. These biological processes are consistent with the clinico-pathological features of MeLiM tumors and can open new routes for future melanoma research in humans.

Keywords: GWAS; biomedical model; comparative genomics; melanoma; pig.

Conflict of interest statement

CONFLICTS OF INTEREST None.

Figures

Figure 1
Figure 1. Manhattan plots depicting the results obtained by a genome-wide association analysis of three melanoma phenotypes using the mixed model
(A) Melanoma occurrence, (B) Clinical ulceration, (C) Metastasis. The x axis represents chromosomal location and the y axis represents -log10 (p-value) for the test of association between each SNP and phenotype. The horizontal dashed lines correspond to –log10 (p-values) of the genome-wide significance threshold of 5 × 10–6 and suggestive threshold of 5 × 10–5.
Figure 2
Figure 2. A MeLiM Pig karyotype highlighting melanoma-associated regions on different autosomes

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