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

• Published in: Cell systems Vol. 4; no. 1; pp. 31 - 45.e6
• Main Authors: 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.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 25.01.2017
• Subjects: Animals; CASP3; Caspase 3 - genetics; Cell Cycle Proteins - genetics; Cell Cycle Proteins - physiology; CENPU; Chromosome Mapping - methods; Collaborative Cross Mice - genetics; Disease Models, Animal; diversity outbred; Genetics, Population - methods; Genome-Wide Association Study; Germ Cells - pathology; Germ-Line Mutation - genetics; germline modifiers; Humans; Male; metastasis; Mice; modifier locus mapping; Multifactorial Inheritance - genetics; Neoplasm Metastasis - genetics; Neoplastic Processes; neuroendocrine prostate cancer; Phenotype; Polymorphism, Single Nucleotide; Prostatic Neoplasms - genetics; Prostatic Neoplasms - metabolism; Quantitative Trait Loci; RWDD4; systems genetics; TRAMP mouse model; diversity outbred; CENPU; modifier locus mapping; systems genetics; RWDD4; metastasis; CASP3; TRAMP mouse model; DO; neuroendocrine prostate cancer; germline modifiers
• ISSN: 2405-4712; 2405-4720
• DOI: 10.1016/j.cels.2016.10.018

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. [Display omitted] •Comparative genetics is a powerful alternative to GWAS to identify modifier genes•Highly polymorphic “Diversity Outbred” mice enable high-resolution genetic mapping•Modifiers identified by integrating human and mouse germline and expression data•CENPU, RWDD4, and CASP3 are germline modifiers of aggressive prostate cancer Integration of germline and transcriptomic data from humans and highly genetically diverse mice and functional data from human cell lines facilitates the identification of new germline modifiers of aggressive prostate cancer.