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Charles A. Dana Division of Human Cancer Genetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02115 [M. F. K., G. M. G., R. K.], and Departments of Pathology [M. L. J. L. R. M., H. G.] and Surgery [J. M. J.], Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02115
Somatic mutations in DNA mismatch repair genes have been observed in sporadic tumors as well as cell lines and xenografts derived from such tumors implicating genetic defects of mismatch repair genes in the development of such tumors. However, the proportion of sporadic tumors in which mismatch repair genes have been inactivated has not been determined accurately. We have analyzed 66 sporadic colorectal tumors for the expression of hMLH1 by immunohistochemistry and identified 4 tumors that do not express hMLH1. These four colorectal tumors, a colon tumor cell line (SW48) and an endometrial tumor cell line (AN3CA), did not express hMLH1, despite the absence of mutations in its coding sequence. Cytosine methlation of the hMLH1 promoter region was found in these four colorectal tumors, whereas cytosine methylation of the hMLH1 promoter region was absent in adjacent normal tissue or in nine tumors that expressed hMLH1. In addition, cytosine methylation of the hMLH1 promoter region was observed in the SW48 and AN3CA cell lines that do not express hMLH1 but not in four tumor cell lines known to express hMLH1 mRNA. Our data indicate that DNA methylation is likely to be a common mode of mismatch repair gene inactivation in sporadic tumors.
1 Supported by NIH Grants CA67151 (to R. K.), CA44704 (to R. K., J. M. J., M. L., and H. G.), CA06516 (Dana-Farber Cancer Institute), and funds from the Starr Foundation (to R. K.).
2 To whom requests for reprints should be addressed, at the Charles A. Dana Division of Human Cancer Genetics, Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115; Phone: (617) 632-3806; Fax: (617) 632-4326.
Received 12/13/96. Accepted 1/15/97.
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S. E. R. Halford, A. J. Rowan, L. Lipton, O. M. Sieber, K. Pack, H. J. W. Thomas, S. V. Hodgson, W. F. Bodmer, and I. P. M. Tomlinson Germline Mutations but Not Somatic Changes at the MYH Locus Contribute to the Pathogenesis of Unselected Colorectal Cancers Am. J. Pathol., May 1, 2003; 162(5): 1545 - 1548. [Abstract] [Full Text] [PDF] |
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H. T. Lynch and A. de la Chapelle Hereditary Colorectal Cancer N. Engl. J. Med., March 6, 2003; 348(10): 919 - 932. [Full Text] [PDF] |
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J. R. Jass Serrated Adenoma of the Colorectum: A Lesion with Teeth Am. J. Pathol., March 1, 2003; 162(3): 705 - 708. [Full Text] [PDF] |
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L. Ricciardiello, A. Goel, V. Mantovani, T. Fiorini, S. Fossi, D. K. Chang, V. Lunedei, P. Pozzato, R. M. Zagari, L. De Luca, et al. Frequent Loss of hMLH1 by Promoter Hypermethylation Leads to Microsatellite Instability in Adenomatous Polyps of Patients with a Single First-Degree Member Affected by Colon Cancer Cancer Res., February 15, 2003; 63(4): 787 - 792. [Abstract] [Full Text] [PDF] |
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E. C. Matheson and A. G. Hall Assessment of mismatch repair function in leukaemic cell lines and blasts from children with acute lymphoblastic leukaemia Carcinogenesis, January 1, 2003; 24(1): 31 - 38. [Abstract] [Full Text] [PDF] |
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A. Hartmann, L. Zanardo, T. Bocker-Edmonston, H. Blaszyk, W. Dietmaier, R. Stoehr, J. C. Cheville, K. Junker, W. Wieland, R. Knuechel, et al. Frequent Microsatellite Instability in Sporadic Tumors of the Upper Urinary Tract Cancer Res., December 1, 2002; 62(23): 6796 - 6802. [Abstract] [Full Text] [PDF] |
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V. L. J. Whitehall, C. V. A. Wynter, M. D. Walsh, L. A. Simms, D. Purdie, N. Pandeya, J. Young, S. J. Meltzer, B. A. Leggett, and J. R. Jass Morphological and Molecular Heterogeneity within Nonmicrosatellite Instability-High Colorectal Cancer Cancer Res., November 1, 2002; 62(21): 6011 - 6014. [Abstract] [Full Text] [PDF] |
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I. Gazzoli, M. Loda, J. Garber, S. Syngal, and R. D. Kolodner A Hereditary Nonpolyposis Colorectal Carcinoma Case Associated with Hypermethylation of the MLH1 Gene in Normal Tissue and Loss of Heterozygosity of the Unmethylated Allele in the Resulting Microsatellite Instability-High Tumor Cancer Res., July 15, 2002; 62(14): 3925 - 3928. [Abstract] [Full Text] [PDF] |
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L. Gu, J. Wu, B.-B. Zhu, and G.-M. Li Deficiency of a novel mismatch repair activity in a bladder tumor cell line Nucleic Acids Res., July 1, 2002; 30(13): 2758 - 2763. [Abstract] [Full Text] [PDF] |
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S. S. Wahlberg, J. Schmeits, G. Thomas, M. Loda, J. Garber, S. Syngal, R. D. Kolodner, and E. Fox Evaluation of Microsatellite Instability and Immunohistochemistry for the Prediction of Germ-Line MSH2 and MLH1 Mutations in Hereditary Nonpolyposis Colon Cancer Families Cancer Res., June 1, 2002; 62(12): 3485 - 3492. [Abstract] [Full Text] [PDF] |
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A. Duval and R. Hamelin Mutations at Coding Repeat Sequences in Mismatch Repair-deficient Human Cancers: Toward a New Concept of Target Genes for Instability Cancer Res., May 1, 2002; 62(9): 2447 - 2454. [Abstract] [Full Text] [PDF] |
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B Shannon, S Gnanasampanthan, J Beilby, and B Iacopetta A polymorphism in the methylenetetrahydrofolate reductase gene predisposes to colorectal cancers with microsatellite instability Gut, April 1, 2002; 50(4): 520 - 524. [Abstract] [Full Text] [PDF] |
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K. Suzuki, T. Dai, I. Suzuki, Y. Dai, K. Yamashita, and M. Perucho Low Mutation Incidence in Polymorphic Noncoding Short Mononucleotide Repeats in Gastrointestinal Cancer of the Microsatellite Mutator Phenotype Pathway Cancer Res., April 1, 2002; 62(7): 1961 - 1965. [Abstract] [Full Text] [PDF] |
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J M D Wheeler, B F Warren, N J McC Mortensen, H C Kim, S C Biddolph, G Elia, N E Beck, G T Williams, N A Shepherd, A C Bateman, et al. An insight into the genetic pathway of adenocarcinoma of the small intestine Gut, February 1, 2002; 50(2): 218 - 223. [Abstract] [Full Text] [PDF] |
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A. O.-O. Chan, J.-P. J. Issa, J. S. Morris, S. R. Hamilton, and A. Rashid Concordant CpG Island Methylation in Hyperplastic Polyposis Am. J. Pathol., February 1, 2002; 160(2): 529 - 536. [Abstract] [Full Text] [PDF] |
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S. Baranovskaya, J. L. Soto, M. Perucho, and S. R. Malkhosyan Functional significance of concomitant inactivation of hMLH1 and hMSH6 in tumor cells of the microsatellite mutator phenotype PNAS, December 6, 2001; (2001) 251234498. [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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J. Young, L. A. Simms, K. G. Biden, C. Wynter, V. Whitehall, R. Karamatic, J. George, J. Goldblatt, I. Walpole, S.-A. Robin, et al. Features of Colorectal Cancers with High-Level Microsatellite Instability Occurring in Familial and Sporadic Settings : Parallel Pathways of Tumorigenesis Am. J. Pathol., December 1, 2001; 159(6): 2107 - 2116. [Abstract] [Full Text] [PDF] |
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T. Hinoi, M. Tani, P. C. Lucas, K. Caca, R. L. Dunn, E. Macri¶, M. Loda¶, H. D. Appelman, K. R. Cho, and E. R. Fearon Loss of CDX2 Expression and Microsatellite Instability Are Prominent Features of Large Cell Minimally Differentiated Carcinomas of the Colon Am. J. Pathol., December 1, 2001; 159(6): 2239 - 2248. [Abstract] [Full Text] [PDF] |
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J. Raedle, J. Trojan, A. Brieger, N. Weber, D. Schafer, G. Plotz, E. Staib-Sebler, S. Kriener, M. Lorenz, and S. Zeuzem Bethesda Guidelines: Relation to Microsatellite Instability and MLH1 Promoter Methylation in Patients with Colorectal Cancer Ann Intern Med, October 16, 2001; 135(8_Part_1): 566 - 576. [Abstract] [Full Text] [PDF] |
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H. Nakagawa, G. J. Nuovo, E. E. Zervos, E. W. Martin Jr., R. Salovaara, L. A. Aaltonen, and A. de la Chapelle Age-related Hypermethylation of the 5' Region of MLH1 in Normal Colonic Mucosa Is Associated with Microsatellite-unstable Colorectal Cancer Development Cancer Res., October 1, 2001; 61(19): 6991 - 6995. [Abstract] [Full Text] [PDF] |
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M. J. Shrubsole, F. Jin, Q. Dai, X.-O. Shu, J. D. Potter, J. R. Hebert, Y.-T. Gao, and W. Zheng Dietary Folate Intake and Breast Cancer Risk: Results from the Shanghai Breast Cancer Study Cancer Res., October 1, 2001; 61(19): 7136 - 7141. [Abstract] [Full Text] [PDF] |
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A. H. Wu, D. Shibata, M. C. Yu, M.-Y. Lai, and R. K. Ross Dietary heterocyclic amines and microsatellite instability in colon adenocarcinomas Carcinogenesis, October 1, 2001; 22(10): 1681 - 1684. [Abstract] [Full Text] [PDF] |
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N. J. Hawkins and R. L. Ward Sporadic Colorectal Cancers With Microsatellite Instability and Their Possible Origin in Hyperplastic Polyps and Serrated Adenomas J Natl Cancer Inst, September 5, 2001; 93(17): 1307 - 1313. [Abstract] [Full Text] [PDF] |
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