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.

journal_name

Cell Syst

journal_title

Cell systems

authors

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,Craw

doi

10.1016/j.cels.2016.10.018

subject

Has Abstract

pub_date

2017-01-25 00:00:00

pages

31-45.e6

issue

1

eissn

2405-4712

issn

2405-4720

pii

S2405-4712(16)30361-1

journal_volume

4

pub_type

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