title: Mapping Complex Traits in a Diversity Outbred F1 Mouse Population Identifies Germline Modifiers of Metastasis in Human Prostate Cancer.
abstract: It 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.
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Jean M
authors.initials: JM
authors.lastname: Winter
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Derek E
authors.initials: DE
authors.lastname: Gildea
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Jonathan P
authors.initials: JP
authors.lastname: Andreas
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Gatti
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Kendra A
authors.initials: KA
authors.lastname: Williams
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Minnkyong
authors.initials: M
authors.lastname: Lee
authors.affiliation: Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Rockville, MD 20892, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Suiyuan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: NIH Intramural Sequencing Center, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.affiliation: NIH Intramural Sequencing Center, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: James C
authors.initials: JC
authors.lastname: Mullikin
authors.affiliation: Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Tyra G
authors.initials: TG
authors.lastname: Wolfsberg
authors.affiliation: Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Shannon K
authors.initials: SK
authors.lastname: McDonnell
authors.affiliation: Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Fogarty
authors.affiliation: Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Melissa C
authors.initials: MC
authors.lastname: Larson
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Amy J
authors.initials: AJ
authors.lastname: French
authors.affiliation: Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Schaid
authors.affiliation: Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
authors.forename: Stephen N
authors.initials: SN
authors.lastname: Thibodeau
authors.affiliation: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors.forename: Gary A
authors.initials: GA
authors.lastname: Churchill
authors.affiliation: Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: crawforn@mail.nih.gov.
authors.forename: Nigel P S
authors.initials: NP
authors.lastname: Crawford
mesh_terms: D000818:Animals; D053148:Caspase 3 / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics / Q000502:physiology; D002874:Chromosome Mapping / Q000379:methods*; D000076724:Collaborative Cross Mice / Q000235:genetics; D004195:Disease Models, Animal; D005828:Genetics, Population / Q000379:methods; D055106:Genome-Wide Association Study; D005854:Germ Cells / Q000473:pathology; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D008297:Male; D051379:Mice; D020412:Multifactorial Inheritance / Q000235:genetics; D009362:Neoplasm Metastasis / Q000235:genetics; D009385:Neoplastic Processes; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D040641:Quantitative Trait Loci
chemical_list: D018797:Cell Cycle Proteins; C585527:MLF1-IP protein, mouse; C505409:Casp3 protein, mouse; D053148:Caspase 3
keywords: CASP3; CENPU; DO; RWDD4; TRAMP mouse model; diversity outbred; germline modifiers; metastasis; modifier locus mapping; neuroendocrine prostate cancer; systems genetics