Summary
Inactivation of the hMLH1 gene by promoter hypermethylation is one of the major mechanisms that induces the microsatellite instability phenotype in endometrial cancers. The aim of the present study was to examine the methylation profile of a large number of CpG sites spread over the hMLH1 promoter in endometrial cancers, as well as in normal endometria, and to investigate the correlation with protein expression and MSI phenotype. We found that the hMLH1 promoter is frequently methylated in endometrial cancers. Surprisingly, the histologically normal endometrium of patients with endometrial cancers also exhibited frequent hypermethylation of hMLHl promoter and with a similar profile of methylation to that in cancer lesions. These findings suggest that hypermethylation of the hMLH1 gene is the early step for endometrial carcinogenesis, supporting the concept that epigenetic changes in DNA mismatch repair genes are the initial events that trigger the genetic alterations involved in endometrial carcinogenesis. In addition, irregular methylation of the hMLH1 promoter may be a useful molecular marker with which to screen or diagnose precancerous and early endometrial malignancies.
The data presented in this paper have been published previously (Kanaya T, Kyo S, Maida Y et al. (2003). Oncogene 22:2352–2360)
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References
Inoue M (2001) Current molecular aspects of the carcinogenesis of the uterine endometrium. Int J Gynecol Cancer 11:339–348
Thibodeau SN, Bren G, Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science 260:816–819
Ionov Y, Peinado MA, Malkhosyan S et al. (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363:558–561
Burks RT, Kessis TD, Cho KR et al. (1994) Microsatellite instability in endometrial carcinoma. Oncogene 9:1163–1166
Gurin CC, Federici MG, Kang L et al. (1999) Causes and consequences of microsatellite instability in endometrial carcinoma. Cancer Res 59:462–466
Duggan B, Felix J, Muderspach L et al. (1994) Microsatellite instability in sporadic endometrial carcinoma. J Natl Cancer Inst 86:1216–1221
Bronner CE, Baker SM, Morrison PT et al. (1994) Mutation in the DNA mismatch repair gene homologue hMLHl is associated with hereditary nonpolyposis colon cancer. Nature 368:258–261
Fishel R, Lescoe MK, Rao MRS et al. (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75:1027–1038
Papadopoulos N, Lindblom A (1997) Molecular basis of HNPCC: Mutations of MMR genes. Hum Mutat 10:89–99
Peltomaki P, de la Chapelle A (1997) Mutations predisposing to hereditary nonpolyposis colorectal cancer. Adv Cancer Res 71:93–119
Liu B, Nicolaides NC, Markowitz S et al. (1995) Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nat Genet 9:48–55
Katabuchi H, van Rees B, Lambers AR et al. (1995) Mutations in DNA mismatch repair genes are not responsible for microsatellite instability in most sporadic endometrial carcinomas. Cancer Res 55:5556–5560
Esteller M, Corn PG, Baylin SB et al. (2001) A gene hypermethylation profile of human cancer. Cancer Res 61:3225–3329
Herman JG, Umar A, Polyak K et al. (1998) Incidence and functional consequences of hMLHl promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95:6870–6875
Toyota M, Ahuja N, Ohe-Toyota M et al. (1999) CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 96:8681–8686
Toyota M, Ahuja N, Suzuki H et al. (1999) Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res 59:5438–5442
Esteller M, Levine R, Baylin SB et al. (1998) MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene 17:2413–2417
Simpkins SB, Bocker T, Swisher EM et al. (1999) MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. Hum Mol Genet 8:661–666
Kanaya T, Kyo S, Maida Y et al. (2003). Oncogene 22:2352–2360
Nakagawa H, Nuovo GJ, Zervos EE et al. (2001) Age-related hypermethylation of the 5' region of MLH1 in normal colonic mucosa is associated with microsatellite-unstable colorectal cancer development. Cancer Res 61:6991–6995
Esteller M, Catasus L, Matisa-Guiu X et al. (1999) hMLHl promoter hypermethylation is an early event in human endometrial tumorigenesis. Am J Pathol 155:1767–1772
Herman JG, Graff JR, Myohanen S et al. (1996) Methylation-specific PCR: A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93:9821–9826
Deng G, Chen A, Hong J et al. (1999) Methylation of CpG in a small region of the hMLHl promoter invariably correlates with the absence of gene expression. Cancer Res 59:2029–2033
Deng G, Chen A, Pong E et al. (2001) Methylation in hMLHl promoter interferes with its binding to transcription factor CBF and inhibits gene expression. Oncogene 20:7120–7127
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Kyo, S., Kanaya, T., Inoue, M. (2003). Role of hMLH1 Gene Hypermethylation in Endometrial Carcinogenesis. In: Kuramoto, H., Nishida, M. (eds) Cell and Molecular Biology of Endometrial Carcinoma. Springer, Tokyo. https://doi.org/10.1007/978-4-431-53981-0_16
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DOI: https://doi.org/10.1007/978-4-431-53981-0_16
Publisher Name: Springer, Tokyo
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