Network analysis of skin tumor progression identifies a rewired genetic architecture affecting inflammation and tumor susceptibility.
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 that 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 (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).


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, mitogen-activated protein (MAP) kinase signaling, and cancer susceptibility.
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA 94158, USA.
David A
DA
Quigley
Minh D
MD
To
Il Jin
IJ
Kim
Kevin K
KK
Lin
Donna G
DG
Albertson
Jonas
J
Sjolund
Jesús
J
Pérez-Losada
Allan
A
Balmain
D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D055028:Comparative Genomic Hybridization; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D007249:Inflammation / Q000235:genetics*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011110:Polymorphism, Genetic; D040641:Quantitative Trait Loci; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism
D014408:Biomarkers, Tumor; D020928:Mitogen-Activated Protein Kinases
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