Prostate cancer (PC) is the most commonly diagnosed cancer in men. However, relatively few (<13%) cases result in death, with many men undergoing unnecessary and invasive treatments. New approaches for assessing patients at higher risk of developing metastatic disease are vital for preventing over-treatment and improving outcomes. We aimed to identify aggressive PC susceptibility genes using the C57BL/6-Tg(TRAMP)8247Ng/J (TRAMP) mouse model of neuroendocrine PC, which demonstrates a particularly aggressive form of oncogenesis. TRAMP mice were bred to Diversity Outbred (J:DO) mice and a cohort of 498 TRAMP x J:DO males was developed in order to identify genetic regions associated with susceptibility to aggressive disease. Modifier locus mapping revealed one locus spanning ~4Mb on Chromosome 8 associated with distant metastasis free survival (LOD=8.42, p=5.33e-6). Candidate genes within this locus were identified by RNA-seq analysis of 195 TRAMP x J:DO tumors. Trait-correlation and expression quantitative trait locus data for transcripts within this locus were integrated with strain-specific SNP data to distinguish eleven candidate metastasis susceptibility genes. Relevance of these genes to aggressive human PC was investigated via in silico validation, in a cohort size over 5,550 prostate cancer patients, which encompassed three independent human PC tumor gene expression datasets and two human PC genome-wide association studies. This identified two novel aggressive PC susceptibility genes: CENPU (MLF1IP) and RWDD4. Interestingly, CENPU acts as a transcriptional suppressor and chromosome segregation protein, and has recently been the focus as a potential gene therapy target for human prostate cancer. The data presented here demonstrate how systems genetics approaches centered on the use of a mouse model of PC can help us understand how hereditary variation influences disease outcomes of aggressive PC. Ongoing work is focusing on in vitro and in vivo functional characterization of these two genes to better understand their role in metastatic PC.