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Departments of Oncology [M. E., A. S., M. T., S. B. B., J. G. H.] and Otolaryngology-Head and Neck Surgery, Division of Head and Neck Cancer Research [M. S-C., D. S.], The Johns Hopkins Oncology Center, Baltimore, Maryland 21231; Institut Catala d’Oncologia and Institut de Recerca Oncologica, 08907 Barcelona, Spain [G. C., M. A. P., S. G., G. T.]; and Department of Medicine (Gastroenterology Division), Greenbaum Cancer Center, University of Maryland School of Medicine and Baltimore Veterans Affairs Hospital, Baltimore, Maryland 21201 [S. J. M.]
Germ-line mutations in the tumor suppressor gene APC are associated with hereditary familial adenomatous polyposis (FAP), and somatic mutations are common in sporadic colorectal tumors. We now report that methylation in the promoter region of this gene constitutes an alternative mechanism for gene inactivation in colon and other tumors of the gastrointestinal tract. The APC promoter is hypermethylated in 18% of primary sporadic colorectal carcinomas (n = 108) and adenoma (n = 48), and neoplasia with APC methylation fails to express the APC transcript. Methylation affects only wild-type APC in 95% of cases and is not observed in tumors from FAP patients who have germ-line APC mutations. As with APC mutation, aberrant APC methylation occurs early in colorectal carcinogenesis. When other tumor types are analyzed (n = 208), methylation of the APC promoter is not restricted to the colon but is present in tumors originating elsewhere in the gastrointestinal tract but rarely in other tumors. Our data suggest that hypermethylation of APC provides an important mechanism for impairing APC function and further underscores the importance of the APC pathway in gastrointestinal tumorigenesis.
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R. Maruyama, S. Toyooka, K. O. Toyooka, A. K. Virmani, S. Zochbauer-Muller, A. J. Farinas, J. D. Minna, J. McConnell, E. P. Frenkel, and A. F. Gazdar Aberrant Promoter Methylation Profile of Prostate Cancers and Its Relationship to Clinicopathological Features Clin. Cancer Res., February 1, 2002; 8(2): 514 - 519. [Abstract] [Full Text] [PDF]
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H. Usadel, J. Brabender, K. D. Danenberg, C. Jeronimo, S. Harden, J. Engles, P. V. Danenberg, S. Yang, and D. Sidransky Quantitative Adenomatous Polyposis Coli Promoter Methylation Analysis in Tumor Tissue, Serum, and Plasma DNA of Patients with Lung Cancer Cancer Res., January 1, 2002; 62(2): 371 - 375. [Abstract] [Full Text] [PDF]
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 M. Esteller, M. F. Fraga, M. Guo, J. Garcia-Foncillas, I. Hedenfalk, A. K. Godwin, J. Trojan, C. Vaurs-Barriere, Y.-J. Bignon, S. Ramus, et al. DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis Hum. Mol. Genet., December 1, 2001; 10(26): 3001 - 3007. [Abstract] [Full Text] [PDF]
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R. Maruyama, S. Toyooka, K. O. Toyooka, K. Harada, A. K. Virmani, S. Zochbauer-Muller, A. J. Farinas, F. Vakar-Lopez, J. D. Minna, A. Sagalowsky, et al. Aberrant Promoter Methylation Profile of Bladder Cancer and Its Relationship to Clinicopathological Features Cancer Res., December 1, 2001; 61(24): 8659 - 8663. [Abstract] [Full Text] [PDF]
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A. Andreassen, R. Vikse, I.-L. Steffensen, J. E. Paulsen, and J. Alexander Intestinal tumours induced by the food carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine in multiple intestinal neoplasia mice have truncation mutations as well as loss of the wild-type Apc+ allele Mutagenesis, July 1, 2001; 16(4): 309 - 315. [Abstract] [Full Text] [PDF]
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S. M. Dong, H.-S. Kim, S.-H. Rha, and D. Sidransky Promoter Hypermethylation of Multiple Genes in Carcinoma of the Uterine Cervix Clin. Cancer Res., July 1, 2001; 7(7): 1982 - 1986. [Abstract] [Full Text] [PDF]
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A. K. Virmani, A. Rathi, U. G. Sathyanarayana, A. Padar, C. X. Huang, H. T. Cunnigham, A. J. Farinas, S. Milchgrub, D. M. Euhus, M. Gilcrease, et al. Aberrant Methylation of the Adenomatous Polyposis Coli (APC) Gene Promoter 1A in Breast and Lung Carcinomas Clin. Cancer Res., July 1, 2001; 7(7): 1998 - 2004. [Abstract] [Full Text] [PDF]
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T. Iwama Somatic Mutation Rate of the APC Gene Jpn. J. Clin. Oncol., May 1, 2001; 31(5): 185 - 187. [Abstract] [Full Text] [PDF]
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S. B. Baylin, M. Esteller, M. R. Rountree, K. E. Bachman, K. Schuebel, and J. G. Herman Aberrant patterns of DNA methylation, chromatin formation and gene expression in cancer Hum. Mol. Genet., April 1, 2001; 10(7): 687 - 692. [Abstract] [Full Text] [PDF]
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N. S. Fearnhead, M. P. Britton, and W. F. Bodmer The ABC of APC Hum. Mol. Genet., April 1, 2001; 10(7): 721 - 733. [Abstract] [Full Text] [PDF]
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P. Peltomaki Deficient DNA mismatch repair: a common etiologic factor for colon cancer Hum. Mol. Genet., April 1, 2001; 10(7): 735 - 740. [Abstract] [Full Text] [PDF]
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M. Esteller, C. Cordon-Cardo, P. G. Corn, S. J. Meltzer, K. S. Pohar, D. N. Watkins, G. Capella, M. A. Peinado, X. Matias-Guiu, J. Prat, et al. p14ARF Silencing by Promoter Hypermethylation Mediates Abnormal Intracellular Localization of MDM2 Cancer Res., April 1, 2001; 61(7): 2816 - 2821. [Abstract] [Full Text]
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M. Esteller, P. G. Corn, S. B. Baylin, and J. G. Herman A Gene Hypermethylation Profile of Human Cancer Cancer Res., April 1, 2001; 61(8): 3225 - 3229. [Abstract] [Full Text]
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I P M Tomlinson, R Roylance, and R S Houlston Two hits revisited again J. Med. Genet., February 1, 2001; 38(2): 81 - 85. [Abstract] [Full Text]
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