Skip to main content
NCBI home page
British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Feb;79(3-4):582–588. doi: 10.1038/sj.bjc.6690092

Microsatellite instability, Epstein–Barr virus, mutation of type II transforming growth factor β receptor and BAX in gastric carcinomas in Hong Kong Chinese

S Y Leung 1, S T Yuen 1, L P Chung 1, K M Chu 2, M P Wong 1, F J Branicki 2, J C I Ho 1
PMCID: PMC2362448  PMID: 10027334

Abstract

Microsatellite instability (MI), the phenotypic manifestation of mismatch repair failure, is found in a proportion of gastric carcinomas. Little is known of the links between MI and Epstein–Barr virus (EBV) status and clinicopathological elements. Examination of genes mutated through the MI mechanism could also be expected to reveal important information on the carcinogenic pathway. Seventy-nine gastric carcinomas (61 EBV negative, 18 EBV positive) from local Hong Kong Chinese population, an intermediate-incidence area, were examined. Eight microsatellite loci, inclusive of the A10 tract of type II transforming growth factor β receptor (TβR-II), were used to evaluate the MI status. MI in the BAX and insulin-like growth factor II receptor (IGF-IIR) genes were also examined. High-level MI (>40% unstable loci) was detected in ten cases (12.7%) and low-level MI (1–40% unstable loci) in three (3.8%). High-level MI was detected in two EBV-associated cases (11%) and the incidence was similar for the EBV-negative cases (13%). The high-level MIs were significantly associated with intestinal-type tumours (P = 0.03) and a more prominent lymphoid infiltrate (P = 0.04). Similar associations were noted in the EBV-positive carcinomas. The high-level MIs were more commonly located in the antrum, whereas the EBV-associated carcinomas were mostly located in body. Thirteen cardia cases were negative for both high-level MI and EBV. All patients aged below 55 were MI negative (P = 0.049). Of the high-level MIs, 80% had mutation in TβR-II, 40% in BAX and 0% in IGF-IIR. Of low-level MIs, 33% also had TβR-II mutation. These mutations were absent in the MI-negative cases. Of three lymphoepithelioma-like carcinomas, two cases were EBV positive and MI negative, one case was EBV negative but with high-level MI. In conclusion, high-level MIs were present regardless of the EBV status, and were found in a particular clinicopathological subset of gastric carcinoma patient. Inactivation of important growth regulatory genes observed in these carcinomas confirms the importance of MI in carcinogenesis. © 1999 Cancer Research Campaign

Keywords: microsatellite instability, gastric carcinoma, Hong Kong Chinese, Epstein–Barr virus, TβRII, BAX

Full Text

The Full Text of this article is available as a PDF (91.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aaltonen L. A., Peltomäki P., Leach F. S., Sistonen P., Pylkkänen L., Mecklin J. P., Järvinen H., Powell S. M., Jen J., Hamilton S. R. Clues to the pathogenesis of familial colorectal cancer. Science. 1993 May 7;260(5109):812–816. doi: 10.1126/science.8484121. [DOI] [PubMed] [Google Scholar]
  2. Akiyama Y., Nakasaki H., Nihei Z., Iwama T., Nomizu T., Utsunomiya J., Yuasa Y. Frequent microsatellite instabilities and analyses of the related genes in familial gastric cancers. Jpn J Cancer Res. 1996 Jun;87(6):595–601. doi: 10.1111/j.1349-7006.1996.tb00265.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Anagnostopoulos I., Hummel M. Epstein-Barr virus in tumours. Histopathology. 1996 Oct;29(4):297–315. doi: 10.1111/j.1365-2559.1996.tb01414.x. [DOI] [PubMed] [Google Scholar]
  4. Bocker T., Diermann J., Friedl W., Gebert J., Holinski-Feder E., Karner-Hanusch J., von Knebel-Doeberitz M., Koelble K., Moeslein G., Schackert H. K. Microsatellite instability analysis: a multicenter study for reliability and quality control. Cancer Res. 1997 Nov 1;57(21):4739–4743. [PubMed] [Google Scholar]
  5. Bronner C. E., Baker S. M., Morrison P. T., Warren G., Smith L. G., Lescoe M. K., Kane M., Earabino C., Lipford J., Lindblom A. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature. 1994 Mar 17;368(6468):258–261. doi: 10.1038/368258a0. [DOI] [PubMed] [Google Scholar]
  6. Chong J. M., Fukayama M., Hayashi Y., Takizawa T., Koike M., Konishi M., Kikuchi-Yanoshita R., Miyaki M. Microsatellite instability in the progression of gastric carcinoma. Cancer Res. 1994 Sep 1;54(17):4595–4597. [PubMed] [Google Scholar]
  7. Chung Y. J., Park S. W., Song J. M., Lee K. Y., Seo E. J., Choi S. W., Rhyu M. G. Evidence of genetic progression in human gastric carcinomas with microsatellite instability. Oncogene. 1997 Oct 2;15(14):1719–1726. doi: 10.1038/sj.onc.1201343. [DOI] [PubMed] [Google Scholar]
  8. Chung Y. J., Song J. M., Lee J. Y., Jung Y. T., Seo E. J., Choi S. W., Rhyu M. G. Microsatellite instability-associated mutations associate preferentially with the intestinal type of primary gastric carcinomas in a high-risk population. Cancer Res. 1996 Oct 15;56(20):4662–4665. [PubMed] [Google Scholar]
  9. Dietmaier W., Wallinger S., Bocker T., Kullmann F., Fishel R., Rüschoff J. Diagnostic microsatellite instability: definition and correlation with mismatch repair protein expression. Cancer Res. 1997 Nov 1;57(21):4749–4756. [PubMed] [Google Scholar]
  10. Fishel R., Lescoe M. K., Rao M. R., Copeland N. G., Jenkins N. A., Garber J., Kane M., Kolodner R. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell. 1993 Dec 3;75(5):1027–1038. doi: 10.1016/0092-8674(93)90546-3. [DOI] [PubMed] [Google Scholar]
  11. Hamilton-Dutoit S. J., Pallesen G. Detection of Epstein-Barr virus small RNAs in routine paraffin sections using non-isotopic RNA/RNA in situ hybridization. Histopathology. 1994 Aug;25(2):101–111. doi: 10.1111/j.1365-2559.1994.tb01565.x. [DOI] [PubMed] [Google Scholar]
  12. Han H. J., Yanagisawa A., Kato Y., Park J. G., Nakamura Y. Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res. 1993 Nov 1;53(21):5087–5089. [PubMed] [Google Scholar]
  13. Kehrl J. H. Transforming growth factor-beta: an important mediator of immunoregulation. Int J Cell Cloning. 1991 Sep;9(5):438–450. doi: 10.1002/stem.1991.5530090502. [DOI] [PubMed] [Google Scholar]
  14. Keller G., Grimm V., Vogelsang H., Bischoff P., Mueller J., Siewert J. R., Höfler H. Analysis for microsatellite instability and mutations of the DNA mismatch repair gene hMLH1 in familial gastric cancer. Int J Cancer. 1996 Nov 27;68(5):571–576. doi: 10.1002/(SICI)1097-0215(19961127)68:5<571::AID-IJC3>3.0.CO;2-W. [DOI] [PubMed] [Google Scholar]
  15. Kim H., Jen J., Vogelstein B., Hamilton S. R. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am J Pathol. 1994 Jul;145(1):148–156. [PMC free article] [PubMed] [Google Scholar]
  16. Lin J. T., Wu M. S., Shun C. T., Lee W. J., Wang J. T., Wang T. H., Sheu J. C. Microsatellite instability in gastric carcinoma with special references to histopathology and cancer stages. Eur J Cancer. 1995 Oct;31A(11):1879–1882. doi: 10.1016/0959-8049(95)00349-n. [DOI] [PubMed] [Google Scholar]
  17. Liu B., Farrington S. M., Petersen G. M., Hamilton S. R., Parsons R., Papadopoulos N., Fujiwara T., Jen J., Kinzler K. W., Wyllie A. H. Genetic instability occurs in the majority of young patients with colorectal cancer. Nat Med. 1995 Apr;1(4):348–352. doi: 10.1038/nm0495-348. [DOI] [PubMed] [Google Scholar]
  18. Liu B., Parsons R., Papadopoulos N., Nicolaides N. C., Lynch H. T., Watson P., Jass J. R., Dunlop M., Wyllie A., Peltomäki P. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med. 1996 Feb;2(2):169–174. doi: 10.1038/nm0296-169. [DOI] [PubMed] [Google Scholar]
  19. Markowitz S., Wang J., Myeroff L., Parsons R., Sun L., Lutterbaugh J., Fan R. S., Zborowska E., Kinzler K. W., Vogelstein B. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science. 1995 Jun 2;268(5215):1336–1338. doi: 10.1126/science.7761852. [DOI] [PubMed] [Google Scholar]
  20. Marra G., Boland C. R. Hereditary nonpolyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst. 1995 Aug 2;87(15):1114–1125. doi: 10.1093/jnci/87.15.1114. [DOI] [PubMed] [Google Scholar]
  21. Myeroff L. L., Parsons R., Kim S. J., Hedrick L., Cho K. R., Orth K., Mathis M., Kinzler K. W., Lutterbaugh J., Park K. A transforming growth factor beta receptor type II gene mutation common in colon and gastric but rare in endometrial cancers with microsatellite instability. Cancer Res. 1995 Dec 1;55(23):5545–5547. [PubMed] [Google Scholar]
  22. Nakamura S., Ueki T., Yao T., Ueyama T., Tsuneyoshi M. Epstein-Barr virus in gastric carcinoma with lymphoid stroma. Special reference to its detection by the polymerase chain reaction and in situ hybridization in 99 tumors, including a morphologic analysis. Cancer. 1994 May 1;73(9):2239–2249. doi: 10.1002/1097-0142(19940501)73:9<2239::aid-cncr2820730902>3.0.co;2-#. [DOI] [PubMed] [Google Scholar]
  23. Ohue M., Tomita N., Monden T., Miyoshi Y., Ohnishi T., Izawa H., Kawabata Y., Sasaki M., Sekimoto M., Nishisho I. Mutations of the transforming growth factor beta type II receptor gene and microsatellite instability in gastric cancer. Int J Cancer. 1996 Oct 9;68(2):203–206. doi: 10.1002/(SICI)1097-0215(19961009)68:2<203::AID-IJC11>3.0.CO;2-B. [DOI] [PubMed] [Google Scholar]
  24. Ott G., Kirchner T., Müller-Hermelink H. K. Monoclonal Epstein-Barr virus genomes but lack of EBV-related protein expression in different types of gastric carcinoma. Histopathology. 1994 Oct;25(4):323–329. doi: 10.1111/j.1365-2559.1994.tb01350.x. [DOI] [PubMed] [Google Scholar]
  25. Ottini L., Palli D., Falchetti M., D'Amico C., Amorosi A., Saieva C., Calzolari A., Cimoli F., Tatarelli C., De Marchis L. Microsatellite instability in gastric cancer is associated with tumor location and family history in a high-risk population from Tuscany. Cancer Res. 1997 Oct 15;57(20):4523–4529. [PubMed] [Google Scholar]
  26. Ouyang H., Shiwaku H. O., Hagiwara H., Miura K., Abe T., Kato Y., Ohtani H., Shiiba K., Souza R. F., Meltzer S. J. The insulin-like growth factor II receptor gene is mutated in genetically unstable cancers of the endometrium, stomach, and colorectum. Cancer Res. 1997 May 15;57(10):1851–1854. [PubMed] [Google Scholar]
  27. Papadopoulos N., Nicolaides N. C., Wei Y. F., Ruben S. M., Carter K. C., Rosen C. A., Haseltine W. A., Fleischmann R. D., Fraser C. M., Adams M. D. Mutation of a mutL homolog in hereditary colon cancer. Science. 1994 Mar 18;263(5153):1625–1629. doi: 10.1126/science.8128251. [DOI] [PubMed] [Google Scholar]
  28. Parkin D. M., Pisani P., Ferlay J. Estimates of the worldwide incidence of eighteen major cancers in 1985. Int J Cancer. 1993 Jun 19;54(4):594–606. doi: 10.1002/ijc.2910540413. [DOI] [PubMed] [Google Scholar]
  29. Parsons R., Myeroff L. L., Liu B., Willson J. K., Markowitz S. D., Kinzler K. W., Vogelstein B. Microsatellite instability and mutations of the transforming growth factor beta type II receptor gene in colorectal cancer. Cancer Res. 1995 Dec 1;55(23):5548–5550. [PubMed] [Google Scholar]
  30. Pisani P., Parkin D. M., Ferlay J. Estimates of the worldwide mortality from eighteen major cancers in 1985. Implications for prevention and projections of future burden. Int J Cancer. 1993 Dec 2;55(6):891–903. doi: 10.1002/ijc.2910550604. [DOI] [PubMed] [Google Scholar]
  31. Rampino N., Yamamoto H., Ionov Y., Li Y., Sawai H., Reed J. C., Perucho M. Somatic frameshift mutations in the BAX gene in colon cancers of the microsatellite mutator phenotype. Science. 1997 Feb 14;275(5302):967–969. doi: 10.1126/science.275.5302.967. [DOI] [PubMed] [Google Scholar]
  32. Renault B., Calistri D., Buonsanti G., Nanni O., Amadori D., Ranzani G. N. Microsatellite instability and mutations of p53 and TGF-beta RII genes in gastric cancer. Hum Genet. 1996 Nov;98(5):601–607. doi: 10.1007/s004390050267. [DOI] [PubMed] [Google Scholar]
  33. Rüschoff J., Dietmaier W., Lüttges J., Seitz G., Bocker T., Zirngibl H., Schlegel J., Schackert H. K., Jauch K. W., Hofstaedter F. Poorly differentiated colonic adenocarcinoma, medullary type: clinical, phenotypic, and molecular characteristics. Am J Pathol. 1997 May;150(5):1815–1825. [PMC free article] [PubMed] [Google Scholar]
  34. Schalling M., Ekman M., Kaaya E. E., Linde A., Biberfeld P. A role for a new herpes virus (KSHV) in different forms of Kaposi's sarcoma. Nat Med. 1995 Jul;1(7):707–708. doi: 10.1038/nm0795-707. [DOI] [PubMed] [Google Scholar]
  35. Shibata D., Weiss L. M. Epstein-Barr virus-associated gastric adenocarcinoma. Am J Pathol. 1992 Apr;140(4):769–774. [PMC free article] [PubMed] [Google Scholar]
  36. Shibata D., Weiss L. M., Hernandez A. M., Nathwani B. N., Bernstein L., Levine A. M. Epstein-Barr virus-associated non-Hodgkin's lymphoma in patients infected with the human immunodeficiency virus. Blood. 1993 Apr 15;81(8):2102–2109. [PubMed] [Google Scholar]
  37. Souza R. F., Appel R., Yin J., Wang S., Smolinski K. N., Abraham J. M., Zou T. T., Shi Y. Q., Lei J., Cottrell J. Microsatellite instability in the insulin-like growth factor II receptor gene in gastrointestinal tumours. Nat Genet. 1996 Nov;14(3):255–257. doi: 10.1038/ng1196-255. [DOI] [PubMed] [Google Scholar]
  38. Tokunaga M., Uemura Y., Tokudome T., Ishidate T., Masuda H., Okazaki E., Kaneko K., Naoe S., Ito M., Okamura A. Epstein-Barr virus related gastric cancer in Japan: a molecular patho-epidemiological study. Acta Pathol Jpn. 1993 Oct;43(10):574–581. doi: 10.1111/j.1440-1827.1993.tb03233.x. [DOI] [PubMed] [Google Scholar]
  39. Watanabe H., Enjoji M., Imai T. Gastric carcinoma with lymphoid stroma. Its morphologic characteristics and prognostic correlations. Cancer. 1976 Jul;38(1):232–243. doi: 10.1002/1097-0142(197607)38:1<232::aid-cncr2820380135>3.0.co;2-4. [DOI] [PubMed] [Google Scholar]
  40. Wojtowicz-Praga S. Reversal of tumor-induced immunosuppression: a new approach to cancer therapy. J Immunother. 1997 May;20(3):165–177. [PubMed] [Google Scholar]
  41. Yamamoto H., Sawai H., Perucho M. Frameshift somatic mutations in gastrointestinal cancer of the microsatellite mutator phenotype. Cancer Res. 1997 Oct 1;57(19):4420–4426. [PubMed] [Google Scholar]
  42. Yuen S. T., Chung L. P., Leung S. Y., Luk I. S., Chan S. Y., Ho J. In situ detection of Epstein-Barr virus in gastric and colorectal adenocarcinomas. Am J Surg Pathol. 1994 Nov;18(11):1158–1163. doi: 10.1097/00000478-199411000-00010. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES