Login to MyKarger

New to MyKarger? Click here to sign up.



Login with Facebook

Forgot your password?

Authors, Editors, Reviewers

For Manuscript Submission, Check or Review Login please go to Submission Websites List.

Submission Websites List

Institutional Login
(Shibboleth or Open Athens)

For the academic login, please select your country in the dropdown list. You will be redirected to verify your credentials.

Original Paper

Promoter Methylation Status of the DNA Repair Genes hMLH1 and MGMT in Gastric Carcinoma and Metaplastic Mucosa

Oue N.a · Sentani K.a · Yokozaki H.a · Kitadai Y.b · Ito R.a · Yasui W.a

Author affiliations

First Departments of aPathology and bInternal Medicine, Hiroshima University School of Medicine, Hiroshima,Japan

Related Articles for ""

Pathobiology 2001;69:143–149

Do you have an account?

Login Information





Contact Information











I have read the Karger Terms and Conditions and agree.



Login Information





Contact Information











I have read the Karger Terms and Conditions and agree.



To view the fulltext, please log in

To view the pdf, please log in

Buy

  • FullText & PDF
  • Unlimited re-access via MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

CHF 38.00 *
EUR 35.00 *
USD 39.00 *

Select

KAB

Buy a Karger Article Bundle (KAB) and profit from a discount!

If you would like to redeem your KAB credit, please log in.


Save over 20% compared to the individual article price.
Learn more

Rent/Cloud

  • Rent for 48h to view
  • Buy Cloud Access for unlimited viewing via different devices
  • Synchronizing in the ReadCube Cloud
  • Printing and saving restrictions apply

Rental: USD 8.50
Cloud: USD 20.00


Select

Subscribe

  • Access to all articles of the subscribed year(s) guaranteed for 5 years
  • Unlimited re-access via Subscriber Login or MyKarger
  • Unrestricted printing, no saving restrictions for personal use
read more

Subcription rates


Select

* The final prices may differ from the prices shown due to specifics of VAT rules.

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Published online: February 27, 2002
Issue release date: February 2002

Number of Print Pages: 7
Number of Figures: 3
Number of Tables: 2

ISSN: 1015-2008 (Print)
eISSN: 1423-0291 (Online)

For additional information: https://www.karger.com/PAT

Abstract

Hypermethylation of CpG islands in the promoter region is associated with the silencing of a variety of tumor suppressor genes. DNA repair genes human Mut L homologue 1 (hMLH1) and O6-methylguanine-DNA methyltransferase (MGMT) have been shown to be hypermethylated in certain carcinomas. We studied DNA methylation of CpG islands in hMLH1 and MGMT in 50 gastric carcinomas and 10 intestinal metaplastic mucosa samples. We analyzed the methylation status of hMLH1 and MGMT using methylation-specific polymerase chain reaction and DNA sequencing analysis. We measured protein levels of hMLH1 using Western blot and immunohistochemical analysis. CpG island hypermethylation of hMLH1 and MGMT was detected in 11 (22%) and 8 (16%) of the 50 gastric tumors, respectively. Hypermethylation of the promoter was more common in intestinal-type gastric carcinomas than in poorly diffuse-type gastric carcinomas (p = 0.016 and 0.021, respectively; Fisher’s exact test). However, hMLH1 promoter hypermethylation did not coincide with MGMT promoter hypermethylation except in 1 patient. Hypermethylation of the hMLH1 promoter but not the MGMT promoter occurred in intestinal metaplastic mucosae. Immunohistochemical analysis revealed a corresponding reduction in hMLH1 protein expression in some of the intestinal metaplastic mucosae. Our results suggest that at least two types of promoter methylation participate in the development of gastric carcinoma. Tumor-specific promoter hypermethylation of hMLH1 may be an early event in carcinogenesis in the stomach.

© 2002 S. Karger AG, Basel


References

  1. 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, Baylin SB: Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. Proc Natl Acad Sci USA 1998;95:6870–6875.
  2. Leung SY, Yuen ST, Chung LP, Chu KM, Chan AS, Ho JC: hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability. Cancer Res 1999;59:159–164.
  3. 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, Meltzer SJ: Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. Cancer Res 1999;59:1090–1095.
  4. Pieper RO, Patel S, Ting SA, Futscher BW, Costello JF: Methylation of CpG island transcription factor binding sites is unnecessary for aberrant silencing of the human MGMT gene. J Biol Chem 1996;271:13916–13924.
  5. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG: Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 1999;59:793–797.
  6. Herfarth KK, Brent TP, Danam RP, Remack JS, Kodner IJ, Wells SA, Goodfellow PJ: A specific CpG methylation pattern of the MGMT promoter region associated with reduced MGMT expression in primary colorectal cancers. Mol Carcinog 1999;24:90–98.
  7. Oue N, Shigeishi H, Kuniyasu H, Yokozaki H, Kuraoka K, Ito R, Yasui W: Promoter hypermethylation of MGMT is associated with protein loss in gastric carcinoma. Int J Cancer 2001;93:805–809.
  8. Kuismanen SA, Holmberg MT, Salovaara R, Schweizer P, Aaltonen LA, de La Chapelle A, Nystrom-Lahti M, Peltomaki P: Epigenetic phenotypes distinguish microsatellite-stable and -unstable colorectal cancers. Proc Natl Acad Sci USA 1999;96:12661–12666.
  9. Toyota M, Ahuja N, Suzuki H, Itoh F, Ohe-Toyota M, Imai K, Baylin SB, Issa JP: Aberrant methylation in gastric cancer associated with the CpG island methylator phenotype. Cancer Res 1999;59:5438–5442.
  10. Endoh Y, Tamura G, Ajioka Y, Watanabe H, Motoyama T: Frequent hypermethylation of the hMLH1 gene promoter in differentiated-type tumors of the stomach with the gastric foveolar phenotype. Am J Pathol 2000;157:717–722.
    External Resources
  11. Lauren P: The two histological main types of gastric carcinoma. Diffuse and so-called intestinal type carcinoma: An attempt at histological classification. Acta Pathol Microbiol Scand 1965;64:31–49.
  12. Herman JG, Graff JR, Myohanen S, Nelkin BD, Baylin SB: Methylation-specific PCR: A novel PCR assay for methylation status of CpG islands. Proc Natl Acad Sci USA 1996;93:9821–9826.
  13. Oue N, Kuraoka K, Kuniyasu H, Yokozaki H, Wakikawa A, Matsusaki K, Yasui W: DNA methylation status of hMLH1, p16INK4a, and CDH1 is not associated with mRNA expression levels of DNA methyltransferase and DNA demethylase in gastric carcinomas. Oncol Rep 2001;8:1085–1089.
    External Resources
  14. Yasui W, Ayhan A, Kitadai Y, Nishimura K, Yokozaki H, Ito H, Tahara E: Increased expression of p34cdc2 and its kinase activity in human gastric and colonic carcinomas. Int J Cancer 1993;53:36–41.
  15. Yasui W, Ji ZQ, Kuniyasu H, Ayhan A, Yokozaki H, Ito H, Tahara E: Expression of transforming growth factor alpha in human tissues: Immunohistochemical study and Northern blot analysis. Virchows Arch A Pathol Anat Histopathol 1992;421:513–519.
  16. Whitehall VL, Walsh MD, Young J, Leggett BA, Jass JR: Methylation of O-6-methylguanine DNA methyltransferase characterizes a subset of colorectal cancer with low-level DNA microsatellite instability. Cancer Res 2001;61:827–830.
    External Resources
  17. Toyota M, Ohe-Toyota M, Ahuja N, Issa JP: Distinct genetic profiles in colorectal tumors with or without the CpG island methylator phenotype. Proc Natl Acad Sci USA 2000;97:710–715.
  18. Toyota M, Ahuja N, Ohe-Toyota M, Herman JG, Baylin SB, Issa JP: CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci USA 1999;96:8681–8686.
  19. Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN, Issa JP, Sidransky D, Baylin SB, Herman JG: Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 2000;60:2368–2371.
  20. Yokozaki H, Yasui W, Tahara E: Genetic and epigenetic changes in stomach cancer. Int Rev Cytol 2001;204:49–95.
  21. Aebi S, Kurdi-Haidar B, Gordon R, Cenni B, Zheng H, Fink D, Christen RD, Boland CR, Koi M, Fishel R, Howell SB: Loss of DNA mismatch repair in acquired resistance to cisplatin. Cancer Res 1996;56:3087–3090.
  22. de las Alas MM, Aebi S, Fink D, Howell SB, Los G: Loss of DNA mismatch repair: Effects on the rate of mutation to drug resistance. J Natl Cancer Inst 1997;89:1537–1541.
    External Resources
  23. Fink D, Nebel S, Norris PS, Baergen RN, Wilczynski SP, Costa MJ, Haas M, Cannistra SA, Howell SB: Enrichment for DNA mismatch repair-deficient cells during treatment with cisplatin. Int J Cancer 1998;77:741–746.
  24. Samimi G, Fink D, Varki NM, Husain A, Hoskins WJ, Alberts DS, Howell SB: Analysis of MLH1 and MSH2 expression in ovarian cancer before and after platinum drug-based chemotherapy. Clin Cancer Res 2000;6:1415–1421.
  25. Esteller M, Garcia-Foncillas J, Andion E, Goodman SN, Hidalgo OF, Vanaclocha V, Baylin SB, Herman JG: Inactivation of the DNA-repair gene MGMT and the clinical response of gliomas to alkylating agents. N Engl J Med 2000;343:1350–1354.
  26. Kawate H, Sakumi K, Tsuzuki T, Nakatsuru Y, Ishikawa T, Takahashi S, Takano H, Noda T, Sekiguchi M: Separation of killing and tumorigenic effects of an alkylating agent in mice defective in two of the DNA repair genes. Proc Natl Acad Sci USA 1998;95:5116–5120.
  27. Branch P, Aquilina G, Bignami M, Karran P: Defective mismatch binding and a mutator phenotype in cells tolerant to DNA damage. Nature 1993;362:652–654.
  28. Kat A, Thilly WG, Fang WH, Longley MJ, Li GM, Modrich P: An alkylation-tolerant, mutator human cell line is deficient in strand-specific mismatch repair. Proc Natl Acad Sci USA 1993;90:6424–6428.
    External Resources
  29. Leung WK, Kim JJ, Kim JG, Graham DY, Sepulveda AR: Microsatellite instability in gastric intestinal metaplasia in patients with and without gastric cancer. Am J Pathol 2000;156:537–543.
    External Resources
  30. Hamamoto T, Yokozaki H, Semba S, Yasui W, Yunotani S, Miyazaki K, Tahara E: Altered microsatellites in incomplete-type intestinal metaplasia adjacent to primary gastric cancers. J Clin Pathol 1997;50:841–846.
    External Resources
  31. Wheeler JM, Beck NE, Kim HC, Tomlinson IP, Mortensen NJ, Bodmer WF: Mechanisms of inactivation of mismatch repair genes in human colorectal cancer cell lines: The predominant role of hMLH1. Proc Natl Acad Sci USA 1999;96:10296–10301.
  32. Grady WM, Willis J, Guilford PJ, Dunbier AK, Toro TT, Lynch H, Wiesner G, Ferguson K, Eng C, Park JG, Kim SJ, Markowitz S: Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet 2000;26:16–17.

Article / Publication Details

First-Page Preview
Abstract of Original Paper

Published online: February 27, 2002
Issue release date: February 2002

Number of Print Pages: 7
Number of Figures: 3
Number of Tables: 2

ISSN: 1015-2008 (Print)
eISSN: 1423-0291 (Online)

For additional information: https://www.karger.com/PAT


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.