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Cell Syst. 2017 Jan 25;4(1):31-45.e6. doi: 10.1016/j.cels.2016.10.018. Epub 2016 Dec 1.

Mapping Complex Traits in a Diversity Outbred F1 Mouse Population Identifies Germline Modifiers of Metastasis in Human Prostate Cancer.

Author information

1
Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
2
Computational and Statistical Genomics Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
3
The Jackson Laboratory, Bar Harbor, ME 04609, USA.
4
Center for Biomedical Informatics and Information Technology, National Cancer Institute, NIH, Rockville, MD 20892, USA.
5
NIH Intramural Sequencing Center, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
6
Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
7
Department of Laboratory Medicine and Pathology, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA.
8
Genetics and Molecular Biology Branch, National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA. Electronic address: crawforn@mail.nih.gov.

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.

KEYWORDS:

CASP3; CENPU; DO; RWDD4; TRAMP mouse model; diversity outbred; germline modifiers; metastasis; modifier locus mapping; neuroendocrine prostate cancer; systems genetics

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