Universität zu Köln

Farrall, Alexandra L., Lienhard, Matthias, Grimm, Christina ORCID: 0000-0002-4676-8870, Kuhl, Heiner, Sluka, Susanna H. M., Caparros, Marta, Forejt, Jiri, Timmermann, Bernd, Herwig, Ralf, Herrmann, Bernhard G. and Morkel, Markus ORCID: 0000-0002-2553-9999 (2021). PWD/Ph-Encoded Genetic Variants Modulate the Cellular Wnt/beta-Catenin Response to Suppress Apc(Min)-Triggered Intestinal Tumor Formation. Cancer Res., 81 (1). S. 38 - 50. PHILADELPHIA: AMER ASSOC CANCER RESEARCH. ISSN 1538-7445

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Abstract

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. Significance These findings in mice show that, in addition to accidental mutations, cancer risk is determined by networks of individual gene variants.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Farrall, Alexandra L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lienhard, Matthias UNSPECIFIED UNSPECIFIED UNSPECIFIED Grimm, Christina UNSPECIFIED orcid.org/0000-0002-4676-8870 UNSPECIFIED Kuhl, Heiner UNSPECIFIED UNSPECIFIED UNSPECIFIED Sluka, Susanna H. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Caparros, Marta UNSPECIFIED UNSPECIFIED UNSPECIFIED Forejt, Jiri UNSPECIFIED UNSPECIFIED UNSPECIFIED Timmermann, Bernd UNSPECIFIED UNSPECIFIED UNSPECIFIED Herwig, Ralf UNSPECIFIED UNSPECIFIED UNSPECIFIED Herrmann, Bernhard G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Morkel, Markus UNSPECIFIED orcid.org/0000-0002-2553-9999 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-599279
DOI:	10.1158/0008-5472.CAN-20-1480
Journal or Publication Title:	Cancer Res.
Volume:	81
Number:	1
Page Range:	S. 38 - 50
Date:	2021
Publisher:	AMER ASSOC CANCER RESEARCH
Place of Publication:	PHILADELPHIA
ISSN:	1538-7445
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language COLORECTAL-CANCER; HUMAN COLON; STEM-CELLS; MUTATION; MOUSE; NEOPLASIA; ADENOMA; DIFFERENTIATION; IDENTIFICATION; EXPRESSION Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59927