PWD/Ph-Encoded Genetic Variants Modulate the Cellular Wnt/beta-Catenin Response to Suppress Apc(Min)-Triggered Intestinal Tumor Formation

0544778 - ÚMG 2022 RIV US eng J - Journal Article
Farrall, A.L. - Lienhard, M. - Grimm, C. - Kuhl, H. - Sluka, S.H.M. - Caparros, M. - Forejt, Jiří - Timmermann, B. - Herwig, R. - Herrmann, B.G. - Morkel, M.
PWD/Ph-Encoded Genetic Variants Modulate the Cellular Wnt/beta-Catenin Response to Suppress Apc(Min)-Triggered Intestinal Tumor Formation.
Cancer Research. Roč. 81, č. 1 (2021), s. 38-49. ISSN 0008-5472. E-ISSN 1538-7445
Institutional support: RVO:68378050
Keywords : colorectal-cancer * human colon * stem-cells * mutation * mouse * neoplasia * adenoma * differentiation * identification * expression
OECD category: Oncology
Impact factor: 13.312, year: 2021
Method of publishing: Limited access
https://cancerres.aacrjournals.org/content/81/1/38

Genetic predisposition affects the penetrance of tumor-initiating mutations, such as APC mutations that stabilize beta-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 Apc(Min/+) mice on highly variant C57BL/6J (B6) and PWD/Ph (PWD) genetic backgrounds. (B6 x PWD) F1 APC(Min) 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 beta-catenin-driven and stem cell-specific gene expression in the presence of Apc(Min) 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.
Permanent Link: http://hdl.handle.net/11104/0321587