PWD/Ph-EncodedGeneticVariantsModulatetheCellular Wnt/b-Catenin Response to Suppress ApcMin-Triggered Intestinal Tumor Formation

Alexandra L. Farrall, Matthias Lienhard, Christina Grimm, Heiner Kuhl, Susanna H.M. Sluka, Marta Caparros, Jiri Forejt, Bernd Timmermann, Ralf Herwig, Bernhard G. Herrmann, Markus Morkel

Research output: Contribution to journalArticlepeer-review

Abstract

Genetic predisposition affects the penetrance of tumor-initiating mutations, such as APC mutations that stabilize b-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/þ 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 b-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.

Original languageEnglish
Pages (from-to)38-49
Number of pages12
JournalCancer Research
Volume81
Issue number1
DOIs
Publication statusPublished - 1 Jan 2021

Keywords

  • PWD/Ph-Encoded Genetic Variants
  • Wnt/β-Catenin
  • intestinal cancer
  • ApcMin

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