Genetic predisposition affects the penetrance of tumor-initiating mutations, such as APC mutations that stabilize β-catenin and cause intestinal tumors in mice and humans. However, the mechanisms involved in genetically predisposed penetrance are not well understood. Here, we analyzed tumor multiplicity and gene expression in tumor-prone ApcMin/+ mice on highly variant C57BL/6J (B6) and PWD/Ph (PWD) genetic backgrounds. (B6 × PWD) F1 APCMin offspring mice were largely free of intestinal adenoma, and several chromosome substitution (consomic) strains carrying single PWD chromosomes on the B6 genetic background displayed reduced adenoma numbers. Multiple dosage-dependent modifier loci on PWD chromosome 5 each contributed to tumor suppression. Activation of β-catenin-driven and stem cell-specific gene expression in the presence of ApcMin or following APC loss remained moderate in intestines carrying PWD chromosome 5, suggesting that PWD variants restrict adenoma initiation by controlling stem cell homeostasis. Gene expression of modifier candidates and DNA methylation on chromosome 5 were predominantly cis controlled and largely reflected parental patterns, providing a genetic basis for inheritance of tumor susceptibility. Human SNP variants of several modifier candidates were depleted in colorectal cancer genomes, suggesting that similar mechanisms may also affect the penetrance of cancer driver mutations in humans. Overall, our analysis highlights the strong impact that multiple genetic variants acting in networks can exert on tumor development. SIGNIFICANCE: These findings in mice show that, in addition to accidental mutations, cancer risk is determined by networks of individual gene variants.

Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Institute for Medical Genetics Berlin Germany

Charité Universitätsmedizin Berlin corporate member of Freie Universität Berlin Humboldt Universität zu Berlin and Berlin Institute of Health Institute of Pathology Berlin Germany

College of Medicine and Public Health Flinders University Adelaide South Australia Australia

Department of Translational Epigenetics and Tumor Genetics University Hospital Cologne Cologne Germany

Institute of Molecular Genetics Academy of Sciences of the Czech Republic Vestec Prague Czech Republic

Leibniz Institute of Freshwater Ecology and Inland Fisheries Department of Ecophysiology and Aquaculture Berlin Germany

Max Planck Institute for Molecular Genetics Berlin Germany

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