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Network Analysis of Skin Tumor Progression Identifies a Rewired Genetic Architecture Affecting Inflammation and Tumor Susceptibility (carcinomas)

ABSTRACT: Germline polymorphisms influence gene expression networks in normal mammalian tissues. Analysis of this genetic architecture can identify single genes and whole pathways that influence to complex traits including inflammation and cancer susceptibility. Changes in the genetic architecture during the development of benign and malignant tumours have not been investigated. Here, we document major changes in germline control of gene expression during skin tumour development as a consequence of cell selection, somatic genetic events, and changes in tumour microenvironment. Immune response genes such as Interleukin 18 and Granzyme E are under germline control in tumours but not in normal skin. Gene expression networks linked to tumour susceptibility and hair follicle stem cell markers in normal skin undergo significant reorganization during tumour progression. Our data highlight opposing roles of Interleukin-1 signaling networks in tumour susceptibility and tumour progression and have implications for the development of chemopreventive strategies to reduce cancer incidence.

ORGANISM(S): Mus musculus

PROVIDER: GSE21247 | GEO | 2010/12/22

SECONDARY ACCESSION(S): PRJNA129719

REPOSITORIES: GEO

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Project description:Background: 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. Whether germline variants affect gene expression in tumors which have undergone somatic alterations, and the extent to which these variants influence tumor progression, is unknown. Results: Using 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 (eQTLs) is progressively reduced in benign and malignant skin tumors when compared to normal skin. However, novel tumor-specific eQTLs are detected for several genes associated with tumor susceptibility, including Interleukin 18, Granzyme E, Sprouty homolog 2, and MAP kinase kinase 4. Conclusions: We 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, MAP kinase signaling, and cancer susceptibility. A backcross was generated using male Mus spretus and female FVB/N mice; female F1 hybrids were mated with male FVB/N mice. Backcross mice (8-12 weeks old) received a single dose of DMBA (25 µg per mouse in 200 µl acetone). Starting one week after the initiation tumors were promoted with TPA (200 µl of 10-4 M solution in acetone) twice weekly for 20 weeks. Initiation and promotion were performed on doral back skin. DNA from 62 Carcinomas and matched untreated tails (used for normal DNA comparison) was obtained from tissue that was snap frozen when animals were sacrificed.

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Network Analysis of Skin Tumor Progression Identifies a Rewired Genetic Architecture Affecting Inflammation and Tumor Susceptibility (carcinomas)

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