This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sieber, O. M. Articles by Tomlinson, I. P. M. Search for Related Content PubMed PubMed Citation Articles by Sieber, O. M. Articles by Tomlinson, I. P. M.

Myh Deficiency Enhances Intestinal Tumorigenesis in Multiple Intestinal Neoplasia (Apc^Min/+) Mice

¹ Molecular and Population Genetics Laboratory, ² Histopathology Unit, and ³ Experimental Pathology Laboratory, London Research Institute, Cancer Research United Kingdom, London, United Kingdom; ⁴ Colorectal Cancer Unit, Cancer Research United Kingdom, St. Mark’s Hospital, Harrow, United Kingdom; ⁵ Molecular Biology Institute, University of California, Los Angeles, California; and ⁶ Academic Unit of Pathology, Leeds General Infirmary, Leeds, United Kingdom

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 mice heterozygous for mutant Apc 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). In 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 analyses 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.

This article has been cited by other articles:

				A. K. Rustgi The genetics of hereditary colon cancer Genes & Dev., October 15, 2007; 21(20): 2525 - 2538. [Abstract] [Full Text] [PDF]

				A. Gregorieff and H. Clevers Giving APCmin tumours a SPARC Gut, October 1, 2007; 56(10): 1341 - 1343. [Full Text] [PDF]

				N. Suraweera, J. Haines, A. McCart, P. Rogers, A. Latchford, M. Coster, G. Polanco-Echeverry, T. Guenther, J. Wang, O. Sieber, et al. Genetic determinants modulate susceptibility to pregnancy-associated tumourigenesis in a recombinant line of Min mice Hum. Mol. Genet., December 1, 2006; 15(23): 3429 - 3435. [Abstract] [Full Text] [PDF]

				M Nielsen, P F Franken, T H C M Reinards, M M Weiss, A Wagner, H van der Klift, S Kloosterman, J J Houwing-Duistermaat, C M Aalfs, M G E M Ausems, et al. Multiplicity in polyp count and extracolonic manifestations in 40 Dutch patients with MYH associated polyposis coli (MAP) J. Med. Genet., September 1, 2005; 42(9): e54 - e54. [Abstract] [Full Text] [PDF]

				J. M. Tucker, J. T. Murphy, N. Kisiel, P. Diegelman, K. W. Barbour, C. Davis, M. Medda, L. Alhonen, J. Janne, D. L. Kramer, et al. Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase Cancer Res., June 15, 2005; 65(12): 5390 - 5398. [Abstract] [Full Text] [PDF]

				J. Haines, V. Johnson, K. Pack, N. Suraweera, P. Slijepcevic, E. Cabuy, M. Coster, M. Ilyas, J. Wilding, O. Sieber, et al. Genetic basis of variation in adenoma multiplicity in ApcMin/+ Mom1S mice PNAS, February 22, 2005; 102(8): 2868 - 2873. [Abstract] [Full Text] [PDF]