Mapping complex traits in a diversity outbred f1 mouse population identifies germline modifiers of metastasis in human prostate cancer

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dc.contributor.authorWinter, J.
dc.contributor.authorGildea, D.
dc.contributor.authorAndreas, J.
dc.contributor.authorGatti, D.
dc.contributor.authorWilliams, K.
dc.contributor.authorLee, M.
dc.contributor.authorHu, Y.
dc.contributor.authorZhang, S.
dc.contributor.authorMullikin, J.
dc.contributor.authorWolfsberg, T.
dc.contributor.authorMcDonnell, S.
dc.contributor.authorFogarty, Z.
dc.contributor.authorLarson, M.
dc.contributor.authorFrench, A.
dc.contributor.authorSchaid, D.
dc.contributor.authorThibodeau, S.
dc.contributor.authorChurchill, G.
dc.contributor.authorCrawford, N.
dc.date.issued2017
dc.description.abstractIt 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.
dc.description.statementofresponsibilityJean M. Winter, Derek E. Gildea, Jonathan P. Andreas, Daniel M. Gatti, Kendra A. Williams, Minnkyong Lee ... et al.
dc.identifier.citationCell Systems, 2017; 4(1):31-45
dc.identifier.doi10.1016/j.cels.2016.10.018
dc.identifier.issn2405-4712
dc.identifier.issn2405-4712
dc.identifier.orcidWinter, J. [0000-0002-2041-8602]
dc.identifier.urihttps://hdl.handle.net/2440/133483
dc.language.isoen
dc.publisherElsevier
dc.relation.grantU01 CA 89600 (CA-89600)
dc.rights© 2017 Published by Elsevier Inc.
dc.source.urihttps://doi.org/10.1016/j.cels.2016.10.018
dc.subjectneuroendocrine prostate cancer; metastasis; RWDD4; CENPU; CASP3; diversity outbred; DO; TRAMP mouse model; modifier locus mapping; germline modifiers; systems genetics
dc.subject.meshGerm Cells
dc.subject.meshAnimals
dc.subject.meshHumans
dc.subject.meshMice
dc.subject.meshProstatic Neoplasms
dc.subject.meshNeoplastic Processes
dc.subject.meshNeoplasm Metastasis
dc.subject.meshDisease Models, Animal
dc.subject.meshCell Cycle Proteins
dc.subject.meshChromosome Mapping
dc.subject.meshGenetics, Population
dc.subject.meshMultifactorial Inheritance
dc.subject.meshPhenotype
dc.subject.meshGerm-Line Mutation
dc.subject.meshPolymorphism, Single Nucleotide
dc.subject.meshQuantitative Trait Loci
dc.subject.meshMale
dc.subject.meshCaspase 3
dc.subject.meshGenome-Wide Association Study
dc.subject.meshCollaborative Cross Mice
dc.titleMapping complex traits in a diversity outbred f1 mouse population identifies germline modifiers of metastasis in human prostate cancer
dc.typeJournal article
pubs.publication-statusPublished

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