Abstract
BackgroundGermline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility. We and others have shown that analysis of this genetic architecture can identify single genes and whole pathways that influence complex traits, including inflammation and cancer susceptibility. Whether germline variants affect gene expression in tumors that have undergone somatic alterations, and the extent to which these variants influence tumor progression, is unknown.ResultsUsing an integrated linkage and genomic analysis of a mouse model of skin cancer that produces both benign tumors and malignant carcinomas, we document major changes in germline control of gene expression during skin tumor development resulting from cell selection, somatic genetic events, and changes in the tumor microenvironment. The number of significant expression quantitative trait loci (eQTL) is progressively reduced in benign and malignant skin tumors when compared to normal skin. However, novel tumor-specific eQTL are detected for several genes associated with tumor susceptibility, including IL18 (Il18), Granzyme E (Gzme), Sprouty homolog 2 (Spry2), and Mitogen-activated protein kinase kinase 4 (Map2k4).ConclusionsWe conclude that the genetic architecture is substantially altered in tumors, and that eQTL analysis of tumors can identify host factors that influence the tumor microenvironment, mitogen-activated protein (MAP) kinase signaling, and cancer susceptibility.
Highlights
Germline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility
Germline control of gene expression is altered in tumors Skin tumors were induced on a cohort of 71 [SPRET/Ei X FVB/N] X FVB/N (FVBBX) mice by treatment of dorsal back skin with dimethyl benzanthracene (DMBA) and tetradecanoyl-phorbol acetate (TPA)
Gene expression analysis was performed on mRNA extracted from 68 of these papillomas: two papillomas from each of 31 FVBBX mice and a single papilloma from six additional FVBBX mice
Summary
Germline polymorphisms can influence gene expression networks in normal mammalian tissues and can affect disease susceptibility. We and others have shown that analysis of this genetic architecture can identify single genes and whole pathways that influence complex traits, including inflammation and cancer susceptibility. Common genetic variants have been shown to affect many complex traits, including cancer susceptibility [1]. Factors responsible for most of the expected heritable risk of cancer development have not yet been identified. Finding these alleles and isolating the causal polymorphisms is challenging because the heritable component of susceptibility is influenced by many alleles exerting modest effects that may be pleiotropic, epistatic, or context-dependent [2,3]. Genetically heterogeneous mouse crosses permit analysis of the combinatorial responses to skin tumors and are associated with tumor susceptibility
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