PWD/Ph-Encoded Genetic Variants Modulate the Cellular Wnt/beta-Catenin Response to Suppress Apc(Min)-Triggered Intestinal Tumor Formation
The result's identifiers
Result code in 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>
Result on the web
<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>
Alternative languages
Result language
angličtina
Original language name
PWD/Ph-Encoded Genetic Variants Modulate the Cellular Wnt/beta-Catenin Response to Suppress Apc(Min)-Triggered Intestinal Tumor Formation
Original language description
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.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
30204 - Oncology
Result continuities
Project
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Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2021
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Cancer Research
ISSN
0008-5472
e-ISSN
1538-7445
Volume of the periodical
81
Issue of the periodical within the volume
1
Country of publishing house
US - UNITED STATES
Number of pages
12
Pages from-to
38-49
UT code for WoS article
000606529700006
EID of the result in the Scopus database
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