RGD Reference Report - 1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice. - Rat Genome Database

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1,2-Dimethylhydrazine-induced colon carcinoma and lymphoma in msh2(-/-) mice.

Authors: Colussi, C  Fiumicino, S  Giuliani, A  Rosini, S  Musiani, P  Macrí, C  Potten, C S  Crescenzi, M  Bignami, M 
Citation: Colussi C, etal., J Natl Cancer Inst. 2001 Oct 17;93(20):1534-40. doi: 10.1093/jnci/93.20.1534.
RGD ID: 126790556
Pubmed: PMID:11604476   (View Abstract at PubMed)
DOI: DOI:10.1093/jnci/93.20.1534   (Journal Full-text)


BACKGROUND: Defective mismatch repair (MMR) in humans is particularly associated with familial colorectal cancer, but defective repair in mice is generally associated with lymphoma in the absence of experimental exposure to carcinogens. Loss of MMR also confers resistance to the toxic effects of methylating agents. We investigated whether resistance to methylation contributes to increased susceptibility to colorectal cancer in mice by exposing mice with defects in the MMR gene msh2 to a methylating agent.
METHODS: Tumor incidence and time of death in msh2(+/+), msh2(+/-), and msh2(-/-) mice were analyzed after weekly exposure (until tumor appearance) to the methylating agent 1,2-dimethylhydrazine (DMH). Chemically induced and spontaneous tumors were characterized by frequency, type, and location. The tumor incidence in untreated and treated mice of each genotype was compared by a Mann-Whitney U test. Carcinogen-induced apoptosis in histologic sections of small and large intestines was also determined. All statistical tests were two-sided.
RESULTS: Homozygous inactivation of the msh2 gene statistically significantly accelerated (P<.0001) death due to the development of DMH-induced colorectal tumors and lymphomas. Rates of death from DMH-induced colorectal adenocarcinoma were similar in msh2 heterozygous and wild-type mice, but only msh2 heterozygotes (msh(+/-)) developed additional, noncolorectal malignancies (notably trichofolliculoma [two of 21], angiosarcoma of the kidney capsule [two of 21], and lymphoma [one of 21]), suggesting that heterozygosity for msh2 slightly increases DMH susceptibility. DMH induced apoptosis in small intestinal and colonic epithelial crypts that was dependent on active msh2.
CONCLUSIONS: Inactivation of msh2 allows the proliferation of gastrointestinal tract cells damaged by methylating agents. Furthermore, MMR constitutes a powerful defense against colorectal cancer induced by DNA methylation.

RGD Manual Disease Annotations    Click to see Annotation Detail View
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
colorectal adenocarcinoma disease_progressionISOMsh2 (Mus musculus)126790556; 126790556 RGD 
colorectal adenocarcinoma disease_progressionIMP 126790556 RGD 

Objects Annotated

Genes (Rattus norvegicus)
Msh2  (mutS homolog 2)

Genes (Mus musculus)
Msh2  (mutS homolog 2)

Genes (Homo sapiens)
MSH2  (mutS homolog 2)


Additional Information