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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 31-45.e6 |
| Journal | Cell Systems |
| Volume | 4 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 25 2017 |
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Keywords
- CASP3
- CENPU
- diversity outbred
- DO
- germline modifiers
- metastasis
- modifier locus mapping
- neuroendocrine prostate cancer
- RWDD4
- systems genetics
- TRAMP mouse model
ASJC Scopus subject areas
- Pathology and Forensic Medicine
- Histology
- Cell Biology
Cite this
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.
In: Cell Systems, Vol. 4, No. 1, 25.01.2017, p. 31-45.e6.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Mapping Complex Traits in a Diversity Outbred F1 Mouse Population Identifies Germline Modifiers of Metastasis in Human Prostate Cancer
AU - Winter, Jean M.
AU - Gildea, Derek E.
AU - Andreas, Jonathan P.
AU - Gatti, Daniel M.
AU - Williams, Kendra A.
AU - Lee, Minnkyong
AU - Hu, Ying
AU - Zhang, Suiyuan
AU - Mullikin, James C.
AU - Wolfsberg, Tyra G.
AU - McDonnell, Shannon K.
AU - Fogarty, Zachary C.
AU - Larson, Melissa C.
AU - French, Amy J.
AU - Schaid, Daniel J
AU - Thibodeau, Stephen N
AU - Churchill, Gary A.
AU - Crawford, Nigel P S
PY - 2017/1/25
Y1 - 2017/1/25
N2 - 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.
AB - 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.
KW - CASP3
KW - CENPU
KW - diversity outbred
KW - DO
KW - germline modifiers
KW - metastasis
KW - modifier locus mapping
KW - neuroendocrine prostate cancer
KW - RWDD4
KW - systems genetics
KW - TRAMP mouse model
UR - http://www.scopus.com/inward/record.url?scp=85007506884&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85007506884&partnerID=8YFLogxK
U2 - 10.1016/j.cels.2016.10.018
DO - 10.1016/j.cels.2016.10.018
M3 - Article
VL - 4
SP - 31-45.e6
JO - Cell Systems
JF - Cell Systems
SN - 2405-4712
IS - 1
ER -