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Myh deficiency enhances intestinal tumorigenesis in multiple intestinal neoplasia (Apc(Min/+)) mice

Sieber, OM; Howarth, KM; Thirlwell, C; Rowan, A; Mandir, N; Goodlad, RA; Gilkar, A; ... Tomlinson, IPM; + view all (2004) Myh deficiency enhances intestinal tumorigenesis in multiple intestinal neoplasia (Apc(Min/+)) mice. CANCER RES , 64 (24) 8876 - 8881.

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Abstract

Monoallelic APC and biallelic MYH (homolog of Escherichia coli mutY germ-line mutations are independently associated with a strong predisposition to colorectal adenomas and carcinoma in humans. Whereas mic heterozygous for mutant Ape develop intestinal tumors, mice homozygous for mutant Myh do not show increased tumor susceptibility. We analyzed the phenotype of Apc(Min/+)/Myh(-/-) mice and found that they developed significantly more adenomas in the small intestine than did Apc(Min/+)/Myh(+/+) or Apc(Min/+)/Myh(+/-) mice (median 231 versus 151 versus 152). I the large bowel, Apc(Min/+)/Myh(-/-) mice showed significant increases in the number of aberrant crypt foci. In addition, Apc(Min/+)/Myh(-/-) mice developed an increased number of mammary tumors. Molecular analyse suggested that at least 19% of intestinal tumors from Apc(Min/+)/Myh(-/-) mice had acquired intragenic Apc mutations rather than allelic loss Consistent with a defect in base excision repair, three intragenic Apc mutations in polyps without allelic loss from Apc(Min/+)/Myh(-/-) mice were shown to be G:C to T:A transversions which resulted in termination codons; no such mutations were found in polyps from Apc(Min/+)/Myh(+/+) or Apc(Min/+)/Myh(+/-) mice. Tumors from Apc(Min/+)/Myh(+/-) mice harbored neither somatic mutations nor allelic loss at Myh. Thus, homozygous, but not heterozygous, Myh deficiency enhanced intestinal tumorigenesis in Apc(Min/+) mice. The excess small-bowel adenomas in Apc(Min/+)/Myh(-/-) mice, therefore, appear to be a model of MYH-associated polyposis in humans. humans.

Type: Article
Title: Myh deficiency enhances intestinal tumorigenesis in multiple intestinal neoplasia (Apc(Min/+)) mice
Keywords: SOMATIC G-C->T-A MUTATIONS, MIN MICE, ADENOMATOUS POLYPOSIS, HUMAN HOMOLOG, FUNCTIONAL EXPRESSION, COLORECTAL ADENOMAS, GERMLINE MUTATIONS, DNA GLYCOSYLASE, APC MUTATIONS, COLON
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
URI: http://discovery.ucl.ac.uk/id/eprint/318935
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