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Hypermethylation of the hMLH1 gene promoter is associated with microsatellite instability in early human gastric neoplasia

Oncogene volume 20, pages 329–335 (2001)Cite this article

Abstract

A significant portion of gastric cancers exhibit defective DNA mismatch repair, manifested as microsatellite instability (MSI). High-frequency MSI (MSI-H) is associated with hypermethylation of the human mut-L homologue 1 (hMLH1) mismatch repair gene promoter and diminished hMLH1 expression in advanced gastric cancers. However, the relationship between MSI and hMLH1 hypermethylation has not been studied in early gastric neoplasms. We therefore investigated hMLH1 hypermethylation, hMLH1 expression and MSI in a group of early gastric cancers and gastric adenomas. Sixty-four early gastric neoplasms were evaluated, comprising 28 adenomas, 18 mucosal carcinomas, and 18 carcinomas with superficial submucosal invasion but clear margins. MSI was evaluated using multiplex fluorescent PCR to amplify loci D2S123, D5S346, D17S250, BAT 25 and BAT 26. Methylation-specific PCR was performed to determine the methylation status of hMLH1. In two hypermethylated MSI-H cancers, hMLH1 protein expression was also evaluated by immunohistochemistry. Six of sixty-four early gastric lesions were MSI-H, comprising 1 adenoma, 4 mucosal carcinomas, and 1 carcinoma with superficial submucosal invasion. Two lesions (one adenoma and one mucosal carcinoma) demonstrated low-frequency MSI (MSI-L). The remaining 56 neoplasms were MSI-stable (MSI-S). Six of six MSI-H, one of two MSI-L, and none of thirty MSI-S lesions showed hMLH1 hypermethylation (P<0.001). Diminished hMLH1 protein expression was demonstrated by immunohistochemistry in two of two MSI-H hypermethylated lesions. hMLH1 promoter hypermethylation is significantly associated with MSI and diminished hMLH1 expression in early gastric neoplasms. MSI and hypermethylation-associated inactivation of hMLH1 are more prevalent in early gastric cancers than in gastric adenomas. Thus, hypermethylation-associated inactivation of the hMLH1 gene can occur early in gastric carcinogenesis.

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Abbreviations

Ab:

antibody

hMLH1:

human mut-L homologue 1

MMR:

mismatch repair

MSI:

microsatellite instability

MSP:

methylation-specific PCR

References

  • Aaltonen LA, Peltomaki P, Leach FS, Sistonen P, Pylkkanen L, Mecklin JP, Jarvinen H, Powell SM, Jen J, Hamilton SR, Petersen GM, Kinzler KW, Vogelstein G, de la Chapelle A. . 1993 Science 260: 812–816.

  • Akiyama Y, Nakasaki H, Nihei Z, Iwama T, Nomizu T, Utsunomiya J and Yuasa Y. . 1996 Jpn. J. Cancer Res. 87: 595–601.

  • Bankfalvi A, Navabi H, Bier B, Bocker W, Jasani B and Schmid KW. . (1994). J. Pathol. 174: 223–228.

  • Baylin SB and Herman JG. . 2000 Trends Genet. 16: 168–174.

  • Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, Meltzer SJ, Rodriguez-Bigas MA, Fodde R, Ranzani GN and Srivastava SA. . 1998 Cancer Res. 58: 5248–5257.

  • Claij N and te Riele H. . 1999 Exp. Cell. Res. 246: 1–10.

  • Correa P and Shiao YH. . 1994 Cancer Res. 54: 1941s–1943s.

  • Craanen ME, Dekker W, Blok P, Ferwerda J and Tytgat GN. . 1992 Am. J. Gastroenterol. 87: 572–579.

  • Cunningham JM, Christensen ER, Tester DJ, Kim CY, Roche PC, Burgart LJ and Thibodeau SN. . 1998 Cancer Res. 58: 3455–3460.

  • dos Santos NR, Seruca R, Constancia M, Seixas M and Sobrinho-Simoes M. . 1996 Gastroenterology 110: 38–44.

  • Driessen A, Ectors N, Van Cutsem E, Penninckx F, Filez L, Pittaluga S, Delabie J, De Wolf-Peeters C and Geboes K. . 1999 Gastroenterol. Clin. Biol. 23: 747–753.

  • Eckardt VF, Giessler W, Kanzler G, Remmele W and Bernhard G. . 1990 Gastroenterology 98: 708–714.

  • Esteller M, Levine R, Baylin SB, Ellenson LH and Herman JG. . 1998 Oncogene 17: 2413–2417.

  • Esteller M, Tortola S, Toyota M, Capella G, Peinado MA, Baylin SB and Herman JG. . 2000 Cancer Res. 60: 129–133.

  • Esteller M, Catasus L, Matias-Guiu X, Mutter GL, Prat J, Baylin SB and Herman JG. . 1999a Am. J. Pathol. 155: 1767–1772.

  • Esteller M, Hamilton SR, Burger PC, Baylin SB and Herman JG. . 1999b Cancer Res. 59: 793–797.

  • 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 Cancer Res. 59: 1090–1095.

  • Fukutomi H and Sakita T. . 1984 Jpn. J. Clin. Oncol. 14: 169–179.

  • Halling KC, Harper J, Moskaluk CA, Thibodeau SN, Petroni GR, Yustein AS, Tosi P, Minacci C, Roviello F, Piva P, Hamilton SR, Jackson CE and Powell SM. . 1999 Am. J. Pathol. 155: 205–211.

  • Han HJ, Yanagisawa A, Kato Y, Park JG and Nakamura Y. . 1993 Cancer Res. 53: 5087–5089.

  • 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 Proc. Natl. Acad. Sci. USA 95: 6870–6875.

  • Herman JG, Graff JR, Myohanen S, Nelkin BD and Baylin SB. . 1996 Proc. Natl. Acad. Sci. USA 93: 9821–9826.

  • Hoang JM, Cottu PH, Thuille B, Salmon RJ, Thomas G and Hamelin R. . 1997 Cancer Res. 57: 300–303.

  • Iino H, Jass JR, Simms LA, Young J, Leggett B, Ajioka Y and Watanabe H. . 1999 J. Clin. Pathol. 52: 5–9.

  • Ionov Y, Peinado MA, Malkhosyan S, Shibata D and Perucho M. . 1993 Nature 363: 558–561.

  • Isogaki J, Shinmura K, Yin W, Arai T, Koda K, Kimura T, Kino I and Sugimura H. . 1999 Cancer Detect. Prev. 23: 204–214.

  • Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, Jessup JM and Kolodner R. . 1997 Cancer Res. 57: 808–811.

  • Kang GH, Shim YH and Ro JY. . 1999 Lab. Invest. 79: 903–909.

  • Karran P and Hampson R. . 1996 Cancer Surv. 28: 69–85.

  • Keller G, Rudelius M, Vogelsang H, Grimm V, Wilhelm MG, Mueller J, Siewert JR and Hofler H. . 1998 Am. J. Pathol. 152: 1281–1289.

  • Kuipers EJ. . 1998 Aliment. Pharmacol. Ther. 12: Suppl 1, 25–36.

  • Leach FS, Polyak K, Burrell M, Johnson KA, Hill D, Dunlop MG, Wyllie AH, Peltomaki P, de la Chapelle A, Hamilton SR, Kinzler KW and Vogelstein B. . 1996 Cancer Res. 56: 235–240.

  • Leung SY, Yuen ST, Chung LP, Chu KM, Chan AS and Ho JC. . 1999 Cancer Res. 59: 159–164.

  • Orlow I, Lianes P, Lacombe L, Dalbagni G, Reuter VE and Cordon-Cardo C. . 1994 Cancer Res. 54: 2848–2851.

  • Ottini L, Palli D, Falchetti M, D'Amico C, Amorosi A, Saieva C, Calzolari A, Cimoli F, Tatarelli C, De Marchis L, Masala G, Mariani-Costantini R and Cama A. . 1997 Cancer Res. 57: 4523–4529.

  • Parkin DM, Pisani P and Ferlay J. . 1999 Int. J. Cancer 80: 827–841.

  • Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N and Sibley RK. . 1991 N. Engl. J. Med. 325: 1127–1131.

  • Rhyu MG, Park WS and Meltzer SJ. . 1994 Oncogene 9: 29–32.

  • Sasaki I, Yao T, Nawata H and Tsuneyoshi M. . 1999 Cancer 85: 1719–1729.

  • Savides C. . 1999). Tumors of the Stomach, 3rd edition Philadelphia: Lippincott Williams and Wilkins. Vol. 1 p.1500–1529.

  • Semba S, Yokozaki H, Yamamoto S, Yasui W and Tahara E. . 1996 Cancer 77: 1620–1627.

  • Suzuki H, Itoh F, Toyota M, Kikuchi T, Kakiuchi H, Hinoda Y and Imai K. . 1999 Int. J. Cancer 83: 309–313.

  • Suzuki H, Harpaz N, Tarmin L, Yin J, Jiang HY, Bell JD, Hontanosas M, Groisman GM, Abraham JM and Meltzer SJ. . 1994 Cancer Res 54: 4841–4844.

  • Tamura G. . 1996 Pathol. Int. 46: 834–841.

  • Thibodeau SN, Bren G and Schaid D. . 1993 Science 260: 816–819.

  • 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 Cancer Res. 56: 4836–4840.

  • Tomasulo J. . 1971 Cancer 27: 1346–1355.

  • Wu MS, Chen SY, Shun CT, Lee WJ, Wang HP, Wang TH, Chen CJ and Lin JT. . 1997 J. Gastroenterol. Hepatol. 12: 425–428.

  • Yin J, Kong D, Wang S, Zou TT, Souza RF, Smolinski KN, Lynch PM, Hamilton SR, Sugimura H, Powell SM, Young J, Abraham JM and Meltzer SJ. . 1997 Hum. Mutat. 10: 474–478.

  • Zhou XP, Hoang JM, Li YJ, Seruca R, Carneiro F, Sobrinho-Simoes M, Lothe RA, Gleeson CM, Russell SE, Muzeau F, Flejou JF, Hoang-Xuan K, Lidereau R, Thomas G and Hamelin R. . 1998 Genes Chromosomes Cancer 21: 101–107.

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Acknowledgements

This work was partially supported by NIH grants CA85069, CA78843, DK 47717, and CA77057 (to SJ Meltzer), CA67497 (to SJ Meltzer and KT Wilson), DK53620 (to SP James, SJ Meltzer and KT Wilson), K08-DK02469 (to KT Wilson), DK09886-01 (to AS Fleisher), and the Office of Medical Research, Department of Veterans Affairs (SJ Meltzer and KT Wilson). JG Herman receives research funding and is entitled to sales royalties from INTERGEN, which is developing products related to research described in this paper. The terms of this arrangement have been reviewed and approved by The Johns Hopkins University in accordance with its conflict of interest policies. M Esteller is a recipient of a Spanish Ministerio de Educacion y Cultura Award.

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Author notes

  1. A Steven Fleisher and Manel Esteller: AS Fleisher and M Esteller contributed equally to this work

Authors and Affiliations

  1. Department of Medicine, Gastroenterology Division, University of Maryland School of Medicine and Baltimore VA Hospital, Baltimore, 21201, Maryland, MD, USA

    A Steven Fleisher, Jing Yin, Tong-Tong Zou, John M Abraham, Dehe Kong, Stephen P James, Keith T Wilson & Stephen J Meltzer

  2. Greenebaum Cancer Center, University of Maryland School of Medicine and Baltimore VA Hospital, Baltimore, 21201, Maryland, MD, USA

    Keith T Wilson & Stephen J Meltzer

  3. Program in Genetics, University of Maryland School of Medicine and Baltimore VA Hospital, Baltimore, 21201, Maryland, MD, USA

    Asma Rashid & O Colin Stine

  4. Department of Pathology, University of Maryland School of Medicine and Baltimore VA Hospital, Baltimore, 21201, Maryland, MD, USA

    Dehe Kong & Stephen J Meltzer

  5. The Johns Hopkins Oncology Center, Baltimore, 21231, Maryland, MD, USA

    Manel Esteller & James G Herman

  6. Department of Pathology, Yamagata University School of Medicine, Yamagata, 990, Japan

    Gen Tamura

  7. Department of Microbiology and Molecular Genetics, University of California, Irvine, California, USA

    Satoshi Nishizuka

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  1. A Steven Fleisher
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Fleisher, A., Esteller, M., Tamura, G. et al. Hypermethylation of the hMLH1 gene promoter is associated with microsatellite instability in early human gastric neoplasia. Oncogene 20, 329–335 (2001). https://doi.org/10.1038/sj.onc.1204104

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