@article{958298741ded4e18bd6f103e9fb714ef,
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.",
keywords = "CASP3, CENPU, DO, RWDD4, TRAMP mouse model, diversity outbred, germline modifiers, metastasis, modifier locus mapping, neuroendocrine prostate cancer, systems genetics",
author = "Winter, {Jean M.} and Gildea, {Derek E.} and Andreas, {Jonathan P.} and Gatti, {Daniel M.} and Williams, {Kendra A.} and Minnkyong Lee and Ying Hu and Suiyuan Zhang and Mullikin, {James C.} and Wolfsberg, {Tyra G.} and McDonnell, {Shannon K.} and Fogarty, {Zachary C.} and Larson, {Melissa C.} and French, {Amy J.} and Schaid, {Daniel J.} and Thibodeau, {Stephen N.} and Churchill, {Gary A.} and Crawford, {Nigel P.S.}",
note = "Funding Information: This research was supported in part by the Intramural Research Program of the National Human Genome Research Institute, NIH ( HG200366-05 ). D.M.G. and G.A.C. were funded by NIGMS grant R01GM070683 . S.K.Mc.D., Z.C.F., M.C.L., A.J.F., D.J.S., and S.N.T. were funded by grants from the DOD ( W81XWH-11-1-0261 ), from the U.S. Public Health Service, NIH ( CA151254 , CA157881 , and CA15083 ), and U01 CA 89600 ( CA-89600 ). We would like to thank Darla Miller and the University of North Carolina Systems Genetics Core Facility for the assistance with MegaMUGA genotyping and Steven Munger for his advice regarding Seqnature software. We would like to thank Julia Fekecs and Darryl Leja for assistance with image presentation. This study utilized the high-performance computational capabilities of the Biowulf Linux cluster at the NIH, Bethesda, MD ( https://hpc.nih.gov ). ",
year = "2017",
month = jan,
day = "25",
doi = "10.1016/j.cels.2016.10.018",
language = "English (US)",
volume = "4",
pages = "31--45.e6",
journal = "Cell Systems",
issn = "2405-4712",
publisher = "Cell Press",
number = "1",
}