Advertisement

Gastric Cancer

, Volume 8, Issue 4, pp 238–244 | Cite as

Differences in genomic instability between intestinal- and diffuse-type gastric cancer

  • Matti Vauhkonen
  • Hanna Vauhkonen
  • Antti Sajantila
  • Pentti Sipponen
Original article

Abstract

Background

Microsatellite instability (MSI) and loss of heterozygosity (LOH) are lesions in the genome found with different frequencies in gastric carcinomas (GCAs). Despite a great body of studies, no systematic approach to the detailed classification of MSI and LOH in the two major types of GCA has been published.

Methods

Thirty-seven advanced GCAs, 25 intestinal-type (IGCAs) and 12 diffuse-type (DGCAs), were assayed with 15 autosomal tetranucleotide markers on 14 chromosomal arms. The observed frequencies and types of microsatellite alterations allowed stratification into subgroups, i.e., high- and low-grade MSI (MSI-H, MSI-L) or microsatellite-stable (MSS), and high- or low-grade, or non-detectable LOH (LOH-H, LOH-L, LOH-N).

Results

Collectively, the markers detected MSI-H tumors with sensitivity equal to that of BAT-26 (a single marker highly specific for MSI-H). Likewise, the markers detected LOH at chromosomal arms 5q, 18q, and 21q with a sensitivity equal to markers used previously. Seven (19%) MSI-H and six (16%) LOH-H tumors were found, with a significant association (P = 0.027) with IGCA: 92% of MSI-H and LOH-H occurred in IGCA patients only. Conversely, in DGCA, a significantly higher prevalence of a stable (LOH-N/MSS) phenotype was found as compared with IGCA (75.1% vs 28.0%; P = 0.035). The MSI-L phenotype was found in 57.9% of non-MSI-H IGCA tumors and was associated significantly (P = 0.015) with LOH-H.

Conclusion

A clear difference in genomic instability between IGCA and DGCA was found. In IGCA, the MSI and LOH pathways were more commonly involved, whereas in DGCA, a stable phenotype was predominant. As a novel finding, MSI-L as a true phenomenon and its association with LOH was observed in IGCA.

Key words

Stomach cancer Microsatellite instability Loss of heterozygosity Genomic instability 

References

  1. 1.
    Laurén, P 1965The two histologic main types of gastric carcinoma: diffuse and the so-called intestinal type carcinoma. An attempt at a histoclinical classificationActa Pathol Microbiol Scand643149PubMedGoogle Scholar
  2. 2.
    Watanabe, H, Jass, JR, Sobin, LH 1989Histological typing of esophageal and gastric tumorsWorld Health Organization International histological classification of the tumors2nd ed.Springer-VerlagBerlin206Google Scholar
  3. 3.
    Ming, SC 1998Cellular and molecular pathology of gastric carcinoma and precursor lesions: a critical reviewGastric Cancer13150CrossRefPubMedGoogle Scholar
  4. 4.
    Fuchs, CS, Mayer, RJ 1995Gastric carcinomaNew Engl J Med3333241PubMedGoogle Scholar
  5. 5.
    Sipponen, P, Marshall, BJ 2000Gastritis and gastric cancer in Western countriesGastroenterol Clin North Am2957992CrossRefPubMedGoogle Scholar
  6. 6.
    Tahara, E 2004Genetic pathways of two types of gastric cancerIARC Scientific Publications15732749PubMedGoogle Scholar
  7. 7.
    Kim, KM, Kwon, MS, Hong, SJ, Min, KO, Seo, EJ, Lee, KY,  et al. 2003Genetic classification of intestinal-type and diffuse-type gastric cancers based on chromosomal loss and microsatellite instabilityVirchows Arch443491500CrossRefPubMedGoogle Scholar
  8. 8.
    Ogata, SY, Tamura, G, Endoh, Y, Sakata, K, Ohmura, K, Motoyama, T 2001Microsatellite alterations and target gene mutations in the early stages of multiple gastric cancerJ Pathol19433440CrossRefPubMedGoogle Scholar
  9. 9.
    Halling, KC, Harper, J, Moskaluk, CA, Thibodeau, SN, Petroni, GR, Yustein, AS,  et al. 1999Origin of microsatellite instability in gastric cancerAm J Pathol15520511PubMedGoogle Scholar
  10. 10.
    Rhyu, MG, Park, WS, Meltzer, SJ 1994Microsatellite instability occurs frequently in human gastric carcinomaOncogene92932PubMedGoogle Scholar
  11. 11.
    Nishizuka, S, Tamura, G, Terashima, M, Satodate, R 1998Loss of heterozygosity during the development and progression of differentiated adenocarcinoma of the stomachJ Pathol1853843CrossRefPubMedGoogle Scholar
  12. 12.
    Choi, SW, Choi, JR, Chung, YJ, Kim, KM, Rhyu, MG 2000Prognostic implications of microsatellite genotypes in gastric carcinomaInt J Cancer8937883CrossRefPubMedGoogle Scholar
  13. 13.
    Sakakura, C, Mori, T, Sakabe, T, Ariyama, Y, Shinomiya, T, Date, K,  et al. 1999Gains, losses and amplifications of genomic materials in primary gastric cancers analysed by comparative genomic hybridizationGenes Chromosom Cancer24299305CrossRefPubMedGoogle Scholar
  14. 14.
    Varis, A, Wolf, M, Monni, O, Vakkari, ML, Kokkola, A, Moskaluk, C,  et al. 2002Targets of gene amplification and overexpression at 17q in gastric cancerCancer Res6226259PubMedGoogle Scholar
  15. 15.
    Boland, CR, Thibodeau, SN, Hamilton, SR, Sidransky, D, Eshleman, JR, Burt, RW,  et al. 1998A 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 cancerCancer Res58524857PubMedGoogle Scholar
  16. 16.
    Laiho, P, Launonen, V, Lahermo, P, Esteller, M, Guo, M, Herman, JG,  et al. 2002Low-level microsatellite instability in most colorectal carcinomasCancer Res62116670PubMedGoogle Scholar
  17. 17.
    Halford, S, Sasieni, P, Rowan, A, Wasan, H, Bodmer, W, Talbot, I,  et al. 2002Low-level microsatellite instability occurs in most colorectal cancers and is a nonrandomly distributed quantitative traitCancer Res62537PubMedGoogle Scholar
  18. 18.
    Halford, SER, Sawyer, EJ, Lambros, MB, Gorman, P, Macdonald, ND, Talbot, IC,  et al. 2003MSI-low, a real phenomenon which varies in frequency among cancer typesJ Pathol20138994CrossRefPubMedGoogle Scholar
  19. 19.
    Sieben, NLG, ter Haar, NT, Cornelisse, CJ, Fleuren, GJ, Cleton-Jansen, AM 2000PCR artefacts in LOH and MSI analysis of microdissected tumor cellsHum Pathol3114149CrossRefPubMedGoogle Scholar
  20. 20.
    Thiagalingam, S, Foy, RL, Cheng, KH, Lee, HJ, Thiagalingam, A, Ponte, JF 2002Loss of heterozygosity as a predictor to map tumor suppressor genes in cancer: molecular basis of its occurrenceCurr Opin Oncol146572CrossRefPubMedGoogle Scholar
  21. 21.
    Fleischer, AS, Esteller, M, Wang, S, Tamura, G, Suzuki, H, Ying, J,  et al. 1999Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instabilityCancer Res5910905Google Scholar
  22. 22.
    Leung, SY, Yuen, ST, Chung, LP, Chu, KM, Chan, ASY, Ho, JCI 1999hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instabilityCancer Res5915964PubMedGoogle Scholar
  23. 23.
    Duval, A, Reperant, M, Compoint, A, Seruca, R, Ranzani, GN, Iacopetta, B,  et al. 2002Target gene mutation profile differs between gastrointestinal and endometrial tumors with mismatch repair deficiencyCancer Res62160912PubMedGoogle Scholar
  24. 24.
    Thiagalingam, S, Laken, S, Willson, JKV, Markowitz, SD, Kinzler, KW, Vogelstein, B,  et al. 2001Mechanisms underlying losses of heterozygosity in human colorectal cancersProc Natl Acad Sci USA982698702CrossRefPubMedGoogle Scholar
  25. 25.
    Lengauer, C, Kinzler, KW, Vogelstein, B 1998Genetic instabilities in human cancersNature3966439CrossRefPubMedGoogle Scholar
  26. 26.
    Tamura, G, Sakata, K, Nishizuka, S, Maesawa, C, Suzuki, Y, Terashima, M,  et al. 1996Allelotype of adenoma and differentiated adenocarcinoma of the stomachJ Pathol1803717CrossRefPubMedGoogle Scholar
  27. 27.
    Choi, SW, Park, SW, Lee, KY, Kim, KM, Chung, YJ, Rhyu, MG 1998Fractional allelic loss in gastric carcinoma correlates with growth patternsOncogene1726559CrossRefPubMedGoogle Scholar
  28. 28.
    Hiyama, T, Tanaka, S, Yoshihara, M, Sasao, S, Kose, K, Shima, H,  et al. 2004Chromosomal and microsatellite instability in sporadic gastric cancerJ Gastroenterol Hepatol1975660CrossRefPubMedGoogle Scholar
  29. 29.
    Hiyama, T, Tanaka, S, Yoshihara, M, Sasao, S, Kose, K, Shima, H,  et al. 2004Chromosomal and microsatellite instability in sporadic gastric cancer. J Gastroenterol Hepatol an alternative genetic pathway to human colorectal cancerCarcinogenesis258416Google Scholar
  30. 30.
    Goel, A, Arnold, CN, Niedzwiecki, D, Chang, DK, Ricciardello, L, Carethers, JM,  et al. 2003Characterisation of sporadic colon cancer by patterns of genomic instabilityCancer Res63160814PubMedGoogle Scholar
  31. 31.
    Vauhkonen, H, Hedman, M, Vauhkonen, M, Kataja, M, Sipponen, P, Sajantila, A 2004Evaluation of gastrointestinal cancer tissues as a source of genetic information for forensic investigations by using STRsForensic Sci Int13915967CrossRefPubMedGoogle Scholar
  32. 32.
    Hoang, JM, Cottu, PH, Thuille, B, Salmon, RJ, Thomas, G, Hamelin, R 1997BAT-26, an indicator of the replication error phenotype in colorectal cancers and cell linesCancer Res573003PubMedGoogle Scholar
  33. 33.
    McKie, AB, Filipe, MI, Lemoine, NR 1993Abnormalities affecting the APC and MCC tumor suppressor gene loci on chromosome 5q occur frequently in gastric cancer but not in pancreatic cancerInt J Cancer55598603PubMedGoogle Scholar
  34. 34.
    Fang, DC, Jass, JR, Wang, DX 1998Loss of heterozygosity and loss of expression of the DCC gene in gastric cancerJ Clin Pathol515936PubMedCrossRefGoogle Scholar
  35. 35.
    Carvalho, R, Kayademir, T, Soares, P, Canedo, P, Sousa, S, Oliveira, C,  et al. 2002Loss of heterozygosity and promoter methylation, but not mutation, may underlie loss of TFF1 in gastric carcinomaLab Invest82131926PubMedGoogle Scholar
  36. 36.
    Habano, W, Sugai, T, Nakamura, SI, Uesugi, N, Yoshida, T, Sasou, S 2000Microsatellite instability and mutation of mitochondrial and nuclear DNA in gastric carcinomaGastroenterology11883541CrossRefPubMedGoogle Scholar
  37. 37.
    Buonsanti, G, Calistri, D, Padovan, L, Luinetti, O, Fiocca, R, Solcia, E,  et al. 1997Microsatellite instability in intestinal- and diffuse-type gastric carcinomaJ Pathol18216773CrossRefPubMedGoogle Scholar
  38. 38.
    Hayden, JD, Cawkwell, L, Dixon, MF, Pardal, F, Murgatroyd, H, Gray, S,  et al. 2000A comparison of microsatellite instability in early onset gastric carcinomas from relatively low and high incidence European populationsInt J Cancer8518991CrossRefPubMedGoogle Scholar
  39. 39.
    Toyota, M, Ahuja, N, Suzuki, H, Itoh, F, Ohe-Toyota, M, Imai, K,  et al. 1999Aberrant methylation in gastric cancer associated with the CpG island methylator phenotypeCancer Res59543842PubMedGoogle Scholar
  40. 40.
    Ottini, L, Palli, D, Falchetti, M, D'Amico, C, Amorosi, A, Saieva, C,  et al. 1997Microsatellite instability in gastric cancer is associated with tumor location and family history in high-risk population from TuscanyCancer Res5745239PubMedGoogle Scholar
  41. 41.
    Grogg, KL, Lohse, CM, Pankratz, VS, Halling, KC, Smyrk, TC 2003Lymphocyte-rich gastric cancer: associations with Epstein-Barr virus, microsatellite instability, histology, and survivalMod Pathol1664151CrossRefPubMedGoogle Scholar
  42. 42.
    Yamamoto, H, Perez-Piteira, J, Yoshida, T, Terada, M, Itoh, F, Imai, K,  et al. 1999Gastric cancers of the microsatellite mutator phenotype display characteristic genetic and clinical featuresGastroenterology116134857CrossRefPubMedGoogle Scholar
  43. 43.
    Oliveira, C, Seruca, R, Seixas, M, Sobrinho-Simões, M 1998The clinocopathological features of gastric carcinomas with microsatellite instability may be mediated by mutations of different target genes. A study of the TGFßRII, IGFII, and BAX genesAm J Pathol15312119PubMedGoogle Scholar

Copyright information

© International and Japanese Gastric Cancer Association 2005

Authors and Affiliations

  • Matti Vauhkonen
    • 1
  • Hanna Vauhkonen
    • 2
    • 3
  • Antti Sajantila
    • 2
  • Pentti Sipponen
    • 3
  1. 1.Department of Medicine, HUCHJorvi HospitalEspooFinland
  2. 2.Department of Forensic MedicineUniversity of HelsinkiHelsinkiFinland
  3. 3.Department of Pathology, HUSLABJorvi HospitalEspooFinland

Personalised recommendations