Msh2 deficiency enhances somatic Apc and p53 mutations in Apc+/-Msh2-/- mice

Sohn, Kyoung‐Jin; Choi, Monica; Song, Jacquelin; Chan, Sofeene; Medline, Alan; Gallinger, Steven; Kim, Young–In

doi:10.1093/carcin/24.2.217

Cited by 19 publications

(16 citation statements)

References 35 publications

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“…This raises the possibility that the impact of TRAIL-R-loss on colorectal carcinogenesis may be under-appreciated due to intrinsic limitations in the APC min mouse model. [23][24][25] Grosse-Wilde and colleagues subjected TRAIL-R-deficient mice to a classical two-stage initiation-promotion skin carcinogenesis protocol in rodents, using the DNA-damaging PAH 7,12-dimethyl-benz-anthracene (DMBA) as a tumor initiator and 12-O-tetradecanoylphorbol-13-acetate-induced (TPA) as a tumor promoter. 2 On a molecular level, pre-malignant tumors that develop under this protocol frequently display activating mutations of the Ha-ras oncogene 26 whereas p53-mutations are a late event, observed in around 30% of all tumors.…”

Section: Trail and Trail-r In Tumor Etiologymentioning

confidence: 99%

TRAIL death receptors as tumor suppressors and drug targets

Finnberg

El‐Deiry²

2008

Cell Cycle

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Various ways of targeting TRAIL-death receptors for the treatment of a diverse set of malignancies are being explored in ongoing clinical trials. Recent data of ours and others suggest that loss of the only death signaling receptor in mice (TRAIL-R) is associated with susceptibility to various stages of lymphomagenesis and carcinogenesis, perhaps in a complex cell-and model-specific manner. 1,2 Myc-overexpressing B cell lymphomas with an intact TRAIL-R locus displayed a number of gene expression changes indicating resistance to TRAIL-R signaling. Herein we show some data on the use of recombinant human TRAIL (rhTRAIL) and γ-radiation (10 Gy) in combination in an autochthonous mouse model for hepatocellular carcinoma. As cell death signaling through the death receptors is evolutionary conserved from zebra fish to man, novel genetically engineered mouse tumor models may prove useful in establishing in vivo models that excel our fundamental understanding of resistance to TRAIL-death receptor signaling, off-target effects from TRAILdeath receptor targeting compounds and help in identifying a clinically cogent rationale for efficient targeting of TRAIL death receptors in patients. Once established, mouse tumor models may prove to be a useful tool in understanding TRAIL-death receptor signaling.

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Section: Trail and Trail-r In Tumor Etiologymentioning

confidence: 99%

TRAIL death receptors as tumor suppressors and drug targets

Finnberg

El‐Deiry²

2008

Cell Cycle

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“…The PCR products were then sequenced using ABI 377 sequencer (Applied Biosystems). Similarly, a 2.74 kb fragment in exon 15 of the Apc gene, which includes the MCR, was PCR amplified and analysed for sequence alterations using three sets of overlapping primers as previously described (Sohn et al, 2003).…”

Section: Screening For K-ras and Apc Gene Mutationmentioning

confidence: 99%

Carcinogen-induced colon tumors in mice are chromosomally stable and are characterized by low-level microsatellite instability

et al. 2004

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The azoxymethane (AOM)-induced mouse colon tumor model recapitulates many of the histopathological features associated with the multistage progression of human sporadic colorectal cancers (CRCs). To better define the genetic events associated with tumorigenesis in this murine model, we analysed tumors from A/J mice for chromosomal (CIN) and microsatellite (MSI) instabilities, two fundamental pathways of genomic instability that play a critical role in the pathogenesis of human CRCs. Male A/ J mice, 6-week old, were injected with either AOM (n ¼ 5) (10 mg/kg b.w., i.p.) or vehicle (n ¼ 5) (0.9% NaCl solution) once a week for 6 weeks. At 32 weeks after the last dose, comparative genomic hybridization (CGH) was performed on 16 tumors harvested from five animals. Although 25% of the tumors displayed either a gain of chromosome 2 or loss of Y, the majority (75%) showed no genomic imbalances. Further analysis of chromosomal aberrations, using CGH and spectral karyotyping (SKY) was performed in our recently established A/J colon tumor-derived cell line, AJ02-NM 0 . Results showed a pseudotetraploid karyotype with loss of only the Y chromosome in these cultured cells, thereby providing additional evidence for the minimal role of CIN in the primary AOM-induced tumors. Interestingly, the majority (81%) of A/J tumors displayed low-level microsatellite instability (MSI-L) when analysed using mono-and dinucleotide repeat markers, and showed a significant expansion to high-level instability (MSI-H) in the AJ02-NM 0 cells. This finding in cultured cells additionally provides evidence that a mild mutator pathway may contribute to the development of behaviorally benign carcinomas in situ in A/J mice. To better understand the tumorigenic process in the A/J colons, we screened for mutational alterations in key regions of the K-ras and Apc genes. Results showed a very low frequency (6%) of K-ras activating mutations, together with the absence of Apc truncation mutations in primary tumors and AJ02-NM 0 cells. However, these tumors displayed intense nuclear accumulation of b-catenin protein, indicating activation of the Wnt signaling pathway. Based on our molecular and cytogenetic findings, we propose that carcinogen-induced tumors may develop via mechanisms independent of the 'classical' CIN or MSI pathways.

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“…A difference is that brain tumors are very rare and neurofibromas and CLS are absent in mouse MMR knockouts. In Msh2 deficient mice there is an increasing rate of somatic mutations in genes associated with tumorigenesis [13]. Knockout mutants of the three major MMR genes in zebrafish mimic distinct features of the human disease and are complementary to mouse models.…”

Section: Introductionmentioning

confidence: 99%

Homozygosity of MSH2 c.1906G→C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I

et al. 2008

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Hereditary non-polyposis colorectal cancer is a cancer predisposition syndrome known to be caused by heterozygous germline mutations in DNA mismatch repair genes (MMR) most commonly hMLH1, hMSH2, hMSH6. Heterozygous mutations in one of these genes confer an increased risk, mainly for colon and endometrial cancer. Recently, several publications identified that biallelic mutations in the MMR genes are associated with a more severe phenotype, including childhood malignancies and signs of neurofibromatosis type I (NF1). We report on a non-consanguineous Ashkenazi Jewish family with two affected siblings with features of NF1, colon cancer and astrocytoma at age 13 and 14. Their mother developed endometrial cancer at age 54. Their father had leukoplakia of the vocal cords with a family history of pancreatic cancer. Molecular and pathology studies were done on the tumor tissue and on genomic DNA of family members. Tumor testing demonstrated a high degree of microsatellite instability (MSI analysis), expression of MLH1 and absence of expression of both MSH2 and MSH6 proteins. A biallelic c.1906G > C (p.A636P) mutation in the hMSH2 gene was detected in the blood of one affected child. Parental genetic testing showed that each parent was heterozygote for the mutation. The c.1906G > C mutation is a founder mutation in the Ashkenazi Jewish population. To our knowledge this is the first report of homozygosity for this founder mutation.

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Msh2 deficiency enhances somatic Apc and p53 mutations in Apc+/-Msh2-/- mice

Cited by 19 publications

References 35 publications

TRAIL death receptors as tumor suppressors and drug targets

TRAIL death receptors as tumor suppressors and drug targets

Carcinogen-induced colon tumors in mice are chromosomally stable and are characterized by low-level microsatellite instability

Homozygosity of MSH2 c.1906G→C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I

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