Mapping Complex Traits in a Diversity Outbred F1 Mouse Population Identifies Germline Modifiers of Metastasis in Human Prostate Cancer.
Document Type
Article
Publication Date
1-25-2017
JAX Source
Cell Syst 2017 Jan 25; 4(1):31-45.e6
Volume
4
Issue
1
First Page
31
Last Page
45
ISSN
2405-4712
PMID
27916600
Grant
GM070683
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. Cell Syst 2017 Jan 25; 4(1):31-45.e6
Recommended Citation
Winter J,
Gildea D,
Andreas J,
Gatti DM,
Williams K,
Lee M,
Hu Y,
Zhang S,
Mullikin J,
Wolfsberg T,
McDonnell S,
Fogarty Z,
Larson M,
French A,
Schaid D,
Thibodeau S,
Churchill G,
Crawford N.
Mapping Complex Traits in a Diversity Outbred F1 Mouse Population Identifies Germline Modifiers of Metastasis in Human Prostate Cancer. Cell Syst 2017 Jan 25; 4(1):31-45.e6