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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F21%3A00544778" target="_blank" >RIV/68378050:_____/21:00544778 - isvavai.cz</a>

Výsledek na webu

<a href="https://cancerres.aacrjournals.org/content/81/1/38" target="_blank" >https://cancerres.aacrjournals.org/content/81/1/38</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1158/0008-5472.CAN-20-1480" target="_blank" >10.1158/0008-5472.CAN-20-1480</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

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OECD FORD obor

30204 - Oncology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cancer Research

ISSN

0008-5472

e-ISSN

1538-7445

Svazek periodika

81

Číslo periodika v rámci svazku

1

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

12

Strana od-do

38-49

Kód UT WoS článku

000606529700006

EID výsledku v databázi Scopus

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