Winter, J.Gildea, D.Andreas, J.Gatti, D.Williams, K.Lee, M.Hu, Y.Zhang, S.Mullikin, J.Wolfsberg, T.McDonnell, S.Fogarty, Z.Larson, M.French, A.Schaid, D.Thibodeau, S.Churchill, G.Crawford, N.2021-12-012021-12-012017Cell Systems, 2017; 4(1):31-452405-47122405-4712https://hdl.handle.net/2440/133483It is unclear how standing genetic variation affects the prognosis of prostate cancer patients. To provide one controlled answer to this problem, we crossed a dominant, penetrant mouse model of prostate cancer to Diversity Outbred mice, a collection of animals that carries over 40 million SNPs. Integration of disease phenotype and SNP variation data in 493 F1 males identified a metastasis modifier locus on Chromosome 8 (LOD = 8.42); further analysis identified the genes Rwdd4, Cenpu, and Casp3 as functional effectors of this locus. Accordingly, analysis of over 5,300 prostate cancer patient samples revealed correlations between the presence of genetic variants at these loci, their expression levels, cancer aggressiveness, and patient survival. We also observed that ectopic overexpression of RWDD4 and CENPU increased the aggressiveness of two human prostate cancer cell lines. In aggregate, our approach demonstrates how well-characterized genetic variation in mice can be harnessed in conjunction with systems genetics approaches to identify and characterize germline modifiers of human disease processes.en© 2017 Published by Elsevier Inc.neuroendocrine prostate cancer; metastasis; RWDD4; CENPU; CASP3; diversity outbred; DO; TRAMP mouse model; modifier locus mapping; germline modifiers; systems geneticsGerm CellsAnimalsHumansMiceProstatic NeoplasmsNeoplastic ProcessesNeoplasm MetastasisDisease Models, AnimalCell Cycle ProteinsChromosome MappingGenetics, PopulationMultifactorial InheritancePhenotypeGerm-Line MutationPolymorphism, Single NucleotideQuantitative Trait LociMaleCaspase 3Genome-Wide Association StudyCollaborative Cross MiceJournal article10.1016/j.cels.2016.10.0182021-12-01359246Winter, J. [0000-0002-2041-8602]