PWD/Ph-Encoded Genetic Variants Modulate the Cellular Wnt/β-Catenin Response to Suppress ApcMin-Triggered Intestinal Tumor Formation
- 1 January 2021
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 81 (1), 38-49
- https://doi.org/10.1158/0008-5472.can-20-1480
Abstract
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 and PWD/Ph genetic backgrounds. (C57BL/6J x PWD/Ph) F1 APCMin offspring mice were largely free of intestinal adenoma, and several consomic strains carrying single PWD/Ph chromosomes on the C57BL/6J genetic background displayed reduced adenoma numbers. Multiple dosage-dependent modifier loci on PWD/Ph 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/Ph chromosome 5, suggesting that PWD/Ph 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.Other Versions
Funding Information
- Bundesministerium für Bildung und Forschung (PKT-01GS08111)
- Bundesministerium für Bildung und Forschung (PKT-01GS08111)
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