Different genetic mechanisms mediate spontaneous versus UVR-induced malignant melanoma

Abstract

wordsGenetic variation conferring resistance and susceptibility to carcinogen-induced tumorigenesis is frequently studied in mice. We have now turned this to melanoma using the collaborative cross (CC), a resource of mouse strains designed to discover genes for complex diseases. We studied melanomaprone transgenic progeny across seventy CC genetic backgrounds. We mapped a strong quantitative trait locus for rapid onset spontaneous melanoma onset to Prkdc, a gene involved in detection and repair of DNA damage. In contrast, rapid onset UVR-induced melanoma was linked to the ribosomal subunit gene Rrp15. Ribosome biogenesis was upregulated in skin shortly after UVR exposure, Mechanistically, variation in the "usual suspects" by which UVR may exacerbate melanoma, defective DNA repair, melanocyte proliferation, or inflammatory cell infiltration, did not explain melanoma susceptibility or resistance across the CC. Instead, events occurring soon after exposure, such as dysregulation of ribosome function, which alters many aspects of cellular metabolism, may be important.neutrophil monoclonal antibody Abcam ab2557: NIMP-R14 (Cambridge, UK) at a concentration of 1:100. Neutrophil depletion:Each NOD/Cdk4 R24C/+ ::NRAS pup was injected intraperitoneally, with either 100ug InVivo MAb antimouse Ly6G (Bio C Cell, Beverly, MA, USA) or PBS (as a control) at P2, P3 and P5. At P3, all pups were also given UVR treatment. As the depletion was done using anti-Ly6G, staining to differentiate between depleted and non-depleted skin was done using Myeloperoxidase staining (Abnova rabbit anti-MPO, Taipei, Taiwan) at a concentration of 1:75. Statistical Analysis:One-way Anova tests were used to determine the significant difference between means, using R. The survival of mice in each treatment group was estimated using Kaplan-Meier analysis (PRISM TM ), and the Log-Rank (Mantel-Cox) test was used to test for differences between the groups. For correlation comparisons Pearson correlation r value was calculated in PRISM along with the p-value for significant correlation.