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Mapping Complex Traits in a Diversity Outbred F1 Mouse Population Identifies Germline Modifiers of Metastasis in Human Prostate Cancer.
Winter, Jean M; Gildea, Derek E; Andreas, Jonathan P; Gatti, Daniel M; Williams, Kendra A; Lee, Minnkyong; Hu, Ying; Zhang, Suiyuan; Mullikin, James C; Wolfsberg, Tyra G; McDonnell, Shannon K; Fogarty, Zachary C; Larson, Melissa C; French, Amy J; Schaid, Daniel J; Thibodeau, Stephen N; Churchill, Gary A; Crawford, Nigel P S.
Afiliación
  • Winter JM; Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • Gildea DE; Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • Andreas JP; Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • Gatti DM; The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • Williams KA; Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • Lee M; Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • Hu Y; Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Rockville, MD 20892, USA.
  • Zhang S; Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • Mullikin JC; NIH Intramural Sequencing Center, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • Wolfsberg TG; Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • McDonnell SK; Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
  • Fogarty ZC; Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
  • Larson MC; Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
  • French AJ; Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
  • Schaid DJ; Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
  • Thibodeau SN; Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
  • Churchill GA; The Jackson Laboratory, Bar Harbor, ME 04609, USA.
  • Crawford NP; Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: crawforn@mail.nih.gov.
Cell Syst ; 4(1): 31-45.e6, 2017 01 25.
Article en En | MEDLINE | ID: mdl-27916600
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.
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Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Mapeo Cromosómico Tipo de estudio: Prognostic_studies Idioma: En Revista: Cell Syst Año: 2017 Tipo del documento: Article

Texto completo: 1 Base de datos: MEDLINE Asunto principal: Neoplasias de la Próstata / Mapeo Cromosómico Tipo de estudio: Prognostic_studies Idioma: En Revista: Cell Syst Año: 2017 Tipo del documento: Article