A Two-Locus System Controls Susceptibility to Colitis-Associated Colon Cancer in Mice

Kraak, Lauren Van Der; Meunier, Charles; Turbide, Claire; Jothy, Serge; Gaboury, Louis; Marcus, Victoria; Chang, Sing Yun; Beauchemin, Nicole; Gros, Philippe

doi:10.18632/oncotarget.177

Cited by 16 publications

(2 citation statements)

References 34 publications

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“…Approximately 20 quantitative trait loci for CRC susceptibility have been mapped by crossing mouse strains resistant to and susceptible to chemically induced colon cancer or by looking for modifiers of transgenic mutations such as Apc Min which cause spontaneous development of intestinal adenomas. [14][15][16][17][18][19][20][21][22][23] Mouse models of chemically induced CRC follow a similar multistage disease progression and develop tumors with many of the same mutations observed in human CIN tumors. 24 This similarity suggests that the genes controlling cancer susceptibility in mice will be relevant to humans.…”

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confidence: 99%

Allele‐specific imbalance mapping at human orthologs of mouse susceptibility to colon cancer (Scc) loci

Gerber

Hampel

Zhou

et al. 2015

Intl Journal of Cancer

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Colorectal cancer (CRC) can be classified into different types. Chromosomal instable (CIN) colon cancers are thought to be the most common type of colon cancer. The risk of developing a CIN-related CRC is due in part to inherited risk factors. Genomewide association studies have yielded over 40 single nucleotide polymorphisms (SNPs) associated with CRC risk, but these only account for a subset of risk alleles. Some of this missing heritability may be due to gene-gene interactions. We developed a strategy to identify interacting candidate genes/loci for CRC risk that utilizes both linkage and RNA-seq data from mouse models in combination with allele-specific imbalance (ASI) studies in human tumors. We applied our strategy to three previously identified CRC susceptibility loci in the mouse that show evidence of genetic interaction: Scc4, Scc5 and Scc13. 525 SNPs from genes showing differential expression in the mouse and/or a previous role in cancer from the literature were evaluated for allele-specific imbalance in 194 paired human normal/tumor DNAs from CIN-related CRCs. One hundred three SNPs showing suggestive evidence of ASI (31 variants with uncorrected p values < 0.05) were genotyped in a validation set of 296 paired DNAs. Two variants in SNX10 (SCC13) showed significant evidence of allelic selection after multiple comparisons testing. Future studies will evaluate the role of these variants in combination with interacting genetic partners in colon cancer risk in mouse and humans.Colorectal cancer (CRC) is the third leading cause of cancerrelated death in the United States.1 Genetic alterations drive the transformation of normal colon epithelium into adenomas and ultimately malignant adenocarcinomas.2 Pathways such as chromosomal instability (CIN), microsatellite instability, and CpG island methylator phenotype lead to genomic alterations and thus promote tumorigenesis.3 Estimates suggest that as many as 80% to 85% of sporadic colorectal cancers demonstrate CIN, which is marked by an accelerated rate of gains or losses of whole or partial chromosomes.3 In CRC, CIN is typically coupled with mutational activation of proto-oncogenes like KRAS, inactivation of tumor suppressor genes like APC and TP53, and loss of heterozygosity at 18q. One mechanism by which CIN leads to activation and inactivation of oncogenes and tumor suppressor genes, respectively, is by altering gene dosage as a result of copy number alterations.Array comparative genomic hybridization (aCGH) studies can be used to identify refined regions of somatic copy number alterations in human colorectal tumors. Such studies have led to the identification of oncogenes and tumor suppressor

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confidence: 99%

Allele‐specific imbalance mapping at human orthologs of mouse susceptibility to colon cancer (Scc) loci

Gerber

Hampel

Zhou

et al. 2015

Intl Journal of Cancer

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“…As there is a well-known association between colitis and CRC risk [60][61][62] , reduced tuft cell abundance may be relevant in colitis-associated CRC (CA-CRC) also. The potential relevance of 11q23.1 genes in CA-CRC is compounded by genetic mapping studies identifying the homologous region in mice to mediate susceptibility of mouse models to CA-CRC 63 . Notably, recent work has also implicated TET2/3 as critical mediators of the response of mice to chemically induced colitis by regulation of POU2F3 methylation and small intestinal tuft cell abundance 64 , further supporting the importance of this cell-type in governing immune response in the gut.…”

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confidence: 99%

Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activatorPOU2AF2

Rajasekaran,

Harris,

Osborn

et al. 2023

Preprint

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Common genetic variation at 11q23.1 is associated with colorectal cancer (CRC) risk, and exerts local (cis) expression quantitative trait locus (cis-eQTL) effects on POU2AF2, COLCA1 and POU2AF3 genes. However, complex linkage disequilibrium and correlated expression at the 11q23.1 locus has thus far hindered elucidation of the mechanisms by which genetic variants impart CRC risk. Here, we establish that rs3087967 is the likely causal eQTL at this locus, co-localising with expression of POU2AF2 and CRC risk. Furthermore, we show trans-eQTL effects on 21 distant target genes, which are highly enriched for Tuft cell markers. Analysis of available scRNAseq, ChIPseq and scATACseq data implicates POU2AF2 as the primary controller of the tuft cell specific trans-genes through POU2F3-correlated genetic regulation. Immunofluorescence demonstrates that the rs3087967 risk genotype (T) is associated with lower tuft cell abundance in human colonic epithelium. CRISPR-mediated deletion of the 11q23.1 risk locus in the mouse germline exacerbated the ApcMin/+ mouse phenotype upon abrogation of Pou2af2 expression specifically. Taken together, we implicate a key protective role of tuft cells in the large bowel and the importance of mis-regulation of POU2AF2 as the prime tuft cell transcriptional activator at this locus.

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Mapping hyper-susceptibility to colitis-associated colorectal cancer in FVB/NJ mice

et al. 2016

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Inbred strains of mice differ in susceptibility to colitis-associated colorectal cancer (CA-CRC). We tested 10 inbred strains of mice for their response to azoxymethane/dextran sulfate sodium-induced CA-CRC and identified a bimodal inter-strain distribution pattern when tumor multiplicity was used as a phenotypic marker of susceptibility. The FVB/NJ strain was particularly susceptible showing a higher tumor burden than any other susceptible strains (12.5-week post-treatment initiation). FVB/NJ hyper-susceptibility was detected as early as 8-week post-treatment initiation with FVB/NJ mice developing 5.5-fold more tumors than susceptible A/J or resistant B6 control mice. Linkage analysis by whole genome scan in informative (FVB/NJ×C3H/HeJ)F2 mice identified a novel susceptibility locus designated as C olon c ancer s usceptibility 6 (Ccs6) on proximal mouse chromosome 6. When gender was used as a covariate, a LOD score of 5.4 was computed with the peak marker being positioned at rs13478727, 43.8 Mbp. Mice homozygous for FVB/NJ alleles at this locus had increased tumor multiplicity compared to homozygous C3H/HeJ mice. Positional candidates in this region of chromosome 6 were analyzed with respect to a possible role in carcinogenesis and a role in inflammatory response using a new epigenetic gene scoring tool (Myeloid Inflammation Score).

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A Two-Locus System Controls Susceptibility to Colitis-Associated Colon Cancer in Mice

Cited by 16 publications

References 34 publications

Allele‐specific imbalance mapping at human orthologs of mouse susceptibility to colon cancer (Scc) loci

Allele‐specific imbalance mapping at human orthologs of mouse susceptibility to colon cancer (Scc) loci

Genetic variation at 11q23.1 confers colorectal cancer risk by dysregulation of colonic tuft cell transcriptional activatorPOU2AF2

Mapping hyper-susceptibility to colitis-associated colorectal cancer in FVB/NJ mice

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