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.
journal_name
Cell Systjournal_title
Cell systemsauthors
Winter JM,Gildea DE,Andreas JP,Gatti DM,Williams KA,Lee M,Hu Y,Zhang S,NISC Comparative Sequencing Program.,Mullikin JC,Wolfsberg TG,McDonnell SK,Fogarty ZC,Larson MC,French AJ,Schaid DJ,Thibodeau SN,Churchill GA,Crawdoi
10.1016/j.cels.2016.10.018subject
Has Abstractpub_date
2017-01-25 00:00:00pages
31-45.e6issue
1eissn
2405-4712issn
2405-4720pii
S2405-4712(16)30361-1journal_volume
4pub_type
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