Expression of hMLH1 is inactivated in the gastric adenomas with enhanced microsatellite instability

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Microsatellite instability (MSI) and frameshift mutations in the genes containing coding nucleotide repeats have been reported in a subset of gastric adenomas, however the inactivation profiles of DNA mismatch repair genes in MSI-positive gastric adenomas have not been characterized. To address the origin of MSI in gastric adenomas, expressions of hMLH1 and hMSH2 were explored in 86 gastric adenomas. Gastric carcinomas, of which 16 were MSI-positive and 22 MSI-negative, were used as controls. MSI was found in 15 (17%) of gastric adenomas. Absent or decreased hMLH1 expression by immunohistochemistry was noted in most of the MSI-positive adenomas (13/15, 87%) and carcinomas (14/16, 88%), and all of these tumours showed methylation of the hMLH1 gene promoter. In contrast, rare inactivation of hMLH1 expression was found in MSI-negative adenomas (3/71, 4%) and carcinomas (2/22, 9%). Intense expression of hMSH2 gene product was observed in most of the gastric adenomas and carcinomas regardless of MSI status. These findings indicate that the inactivation of hMLH1 gene expression by promoter methylation is an early event and might be the origin of MSI-positive gastric adenomas. © 2001 Cancer Research Campaign

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  1. Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Powell SM, Jen J, Hamilton SR, Petersen GH, Kinzler KW, Vogelstein B and de la Chapelle A (1993) Clues to the pathogenesis of familial colorectal cancer. Science (Washington, DC) 260: 812–816

  2. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN and Srivastava S (1998) A national cancer institute workshop on microsatellite instability for cancer detection and familial predisposition: Development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 58: 5248–5257

  3. Chung YJ, Song JM, Lee JY, Jung YT, Seo EJ, Choi SW and Rhyu MG (1996) Microsatellite instability-associated mutations associate preferentially with the intestinal type of primary gastric carcinomas in a high-risk population. Cancer Res 56: 4662–4665

  4. Cunningham JM, Christensen ER, Tester DJ, Kim CY, Roche PC, Burgart LJ and Thibodeau SN (1998) Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res 58: 3455–3460

  5. Deng G, Chen A, Hong J, Chae HS and Kim YS (1999) Methylation of CpG in a small region of the hMLH1 promoter invariably correlates with the absence of gene expression. Cancer Res 59: 2029–2033

  6. Esteller M, Levine R, Baylin SB, Ellenson LH and Herman JG (1998) MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas. Oncogene 16: 2413–2417

  7. Esteller M, Catasus L, Matias-Guiu X, Mutter GL, Prat J, Baylin SB and Herman JG (1999) hMLH1 promoter hypermethylation is an early event in human endometrial tumorigenesis. Am J Pathol 155: 1767–1772

  8. Fleisher AS, Esteller M, Wang S, Tamura G, Suzuki H, Yin J, Zou TT, Abraham JM, Kong D, Smolinski KN, Shi YQ, Rhyu MG, Powell SM, James SP, Wilson KT, Herman JG and Meltzer SJ (1999) Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. Cancer Res 59: 1090–1095

  9. Gurin CC, Federici MG, Kang L and Boyd J (1999) Causes and consequences of microsatellite instability in endometrial carcinoma. Cancer Res 59: 462–466

  10. Han HJ, Yanagisawa A, Kato Y, Park JG and Nakamura Y (1993) Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res 53: 5087–5089

  11. Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB (1996) Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 93: 9821–9826

  12. Herman JG, Umar A, Polyak K, Graff JR, Ahuja N, Issa JP, Markowitz S, Willson JK, Hamilton SR, Kinzler KW, Kane MF, Kolodner RD, Vogelstein B, Kunkel TA and Baylin SB (1998) Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 95: 6870–6875

  13. Ionov Y, Peinado MA, Malkhosyan S, Shibata D and Perucho M (1993) Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363: 558–561

  14. Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM and Kolodner R (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57: 808–811

  15. Kim JJ, Baek MJ, Kim L, Kim NG, Lee YC, Song SY, Noh SH and Kim H (1999) Accumulated frameshift mutations at coding nucleotide repeats during the progression of gastric carcinoma with microsatellite instability. Lab Invest 79: 1113–1120

  16. Kinzler KW and Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87: 159–170

  17. Leung SY, Yuen ST, Chung LP, Chu KM, Chan AS and Ho JC (1999) hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability. Cancer Res 59: 159–164

  18. Lin JT, Wu MS, Shun CT, Lee WJ, Wang JT, Wang TH and Sheu JC (1995) Microsatellite instability in gastric carcinoma with special references to histopathology and cancer stages. Eur J Cancer 31A: 1879–1882

  19. Loeb LA (1994) Microsatellite instability: marker of a mutator phenotype in cancer. Cancer Res 54: 5059–5063

  20. Peltomaki P and Vasen HF The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer (1997) Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. Gastroenterology 113: 1146–1158

  21. Rhyu MG, Park WS and Meltzer SJ (1994) Microsatellite instability occurs frequently in human gastric carcinoma. Oncogene 9: 29–32

  22. Semba S, Yokozaki H, Yamamoto S, Yasui W and Tahara E (1996) Microsatellite instability in precancerous lesions and adenocarcinomas of the stomach. Cancer 77: 1620–1627

  23. Simpkins SB, Bocker T, Swisher EM, Mutch DG, Gersell DJ, Kovatich AJ, Palazzo JP, Fishel R and Goodfellow PJ (1999) MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. Hum Mol Genet 8: 661–666

  24. Strand M, Prolla TA, Liskay RM and Petes TD (1993) Destabilization of tracts of simple repetitive DNA in yeast by mutations affecting DNA mismatch repair. Nature 365: 274–276

  25. Suzuki H, Itoh F, Toyota M, Kikuchi T, Kakiuchi H, Hinoda Y and Imai K (1999) Distinct methylation pattern and microsatellite instability in sporadic gastric cancer. Int J Cancer 83: 309–313

  26. Tamura G, Sakata K, Maesawa C, Suzuki Y, Terashima M, Satoh K, Sekiyama S, Suzuki A, Eda Y and Satodate R (1995) Microsatellite alterations in adenoma and differentiated adenocarcinoma of the stomach. Cancer Res 55: 1933–1936

  27. Thibodeau SN, Bren G and Schaid D (1993) Microsatellite instability in cancer of the proximal colon. Science (Washington, DC) 260: 816–819

  28. Thibodeau SN, French AJ, Roche PC, Cunningham JM, Tester DJ, Lindor NM, Moslein G, Baker SM, Liskay RM, Burgart LJ, Honchel R and Halling KC (1996) Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. Cancer Res 56: 4836–4840

  29. Thibodeau SN, French AJ, Cunningham JM, Tester D, Burgart LJ, Roche PC, McDonnell SK, Schaid DJ, Vockley CW, Michels VV, Farr GH Jr and O’Connell MJ (1998) Microsatellite instability in colorectal cancer: Different mutator phenotypes and the principal involvement of hMLH1. Cancer Res 58: 1713–1718

  30. Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K, Baylin SB and Issa JP (1999) Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res 59: 5438–5442

  31. Wu MS, Lee CW, Shun CT, Wang HP, Lee WJ, Sheu JC and Lin JT (1998) Clinicopathological significance of altered loci of replication error and microsatellite instability-associated mutations in gastric cancer. Cancer Res 58: 1494–1497

  32. Yanagisawa Y, Akiyama Y, Iida S, Ito E, Nomizu T, Sugihara K, Yuasa Y and Maruyama K (2000) Methylation of the hMLH1 promoter in familial gastric cancer with microsatellite instability. Int J Cancer 85: 50–53

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Baek, M., Kang, H., Kim, S. et al. Expression of hMLH1 is inactivated in the gastric adenomas with enhanced microsatellite instability. Br J Cancer 85, 1147–1152 (2001) doi:10.1054/bjoc.2001.2051

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  • gastric adenoma
  • gastric carcinoma
  • microsatellite instability
  • hMLH1
  • hMSH2

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