PWD/Ph-Encoded Genetic Variants Modulate the Cellular Wnt/β-Catenin Response to Suppress ApcMin-Triggered Intestinal Tumor Formation
| Autor: | Bernhard G. Herrmann, Bernd Timmermann, Susanna H. M. Sluka, Jiri Forejt, Ralf Herwig, Heiner Kuhl, Marta Caparros, Matthias Lienhard, Markus Morkel, Christina Grimm, Alexandra L. Farrall |
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| Přispěvatelé: | University of Zurich, Herrmann, Bernhard G, Morkel, Markus |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Genetics Cancer Research Wnt signaling pathway Chromosome Cancer 610 Medicine & health Biology medicine.disease Penetrance 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Oncology 10036 Medical Clinic 030220 oncology & carcinogenesis Catenin Gene expression DNA methylation Genetic predisposition medicine 2730 Oncology 1306 Cancer Research |
| Zdroj: | Cancer research : an official organ of the American Association for Cancer Research |
| ISSN: | 1538-7445 0008-5472 |
| DOI: | 10.1158/0008-5472.can-20-1480 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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