Identification of prostate cancer modifier pathways using parental strain expression mapping

Inherited genetic risk factors play an important role in cancer. However, other than the Mendelian fashion cancer susceptibility genes found in familial cancer syndromes, little is known about risk modifiers that control individual susceptibility. Here we developed a strategy, parental strain expres...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2007-11, Vol.104 (45), p.17771-17776
Main Authors: Xu, Qing, Majumder, Pradip K, Ross, Kenneth, Shim, Yeonju, Golub, Todd R, Loda, Massimo, Sellers, William R
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Cell Division
Datasets
Gene expression
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Genes
Genetic Predisposition to Disease
Genetic Variation
Genome
Genomics
Genotype & phenotype
Glycolysis
Humans
Inbred strains
Male
Mice
Mice, Inbred Strains
Phenotypes
Prostate
Prostate cancer
Prostatic Neoplasms - genetics
Prostatic Neoplasms - pathology
Prostatic Neoplasms - physiopathology
Risk factors
RNA, Messenger - genetics
Rodents
Species Specificity
Transcription, Genetic
Transgenic animals
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Summary:Inherited genetic risk factors play an important role in cancer. However, other than the Mendelian fashion cancer susceptibility genes found in familial cancer syndromes, little is known about risk modifiers that control individual susceptibility. Here we developed a strategy, parental strain expression mapping, that utilizes the homogeneity of inbred mice and genome-wide mRNA expression analyses to directly identify candidate germ-line modifier genes and pathways underlying phenotypic differences among murine strains exposed to transgenic activation of AKT1. We identified multiple candidate modifier pathways and, specifically, the glycolysis pathway as a candidate negative modulator of AKT1-induced proliferation. In keeping with the findings in the murine models, in multiple human prostate expression data set, we found that enrichment of glycolysis pathways in normal tissues was associated with decreased rates of cancer recurrence after prostatectomy. Together, these data suggest that parental strain expression mapping can directly identify germ-line modifier pathways of relevance to human disease.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.0708476104