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Chemosensitivity and Survival in Gastric Cancer Patients with Microsatellite Instability

  • Gastrointestinal Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Introduction

Conflicting data exist regarding the relevance of high-frequency microsatellite instability (MSI-H) for predicting the prognosis and benefits of 5-fluorouracil (5-FU)-based chemotherapy. This study investigated the usefulness of MSI as either a prognostic indicator or predictor of distinct clinical attributes regarding the use of adjuvant chemotherapy with 5-FU and its analogues in gastric cancer.

Materials and methods

Data and tumor specimens were collected from 240 gastric cancer patients from 1993 to 2002. Five microsatellite loci were analyzed using a high-intensity microsatellite analysis reported previously. A Cox proportional hazard model was used to compare the clinical data and survival as well as any associations between MSI and 5-FU treatment status of patients with MSI or microsatellite stability (MSS) gastric cancers. A 3-(4,5-dimethyl-2-thiazolyl) -2,5-diphenyl-2H-tetrazolium bromide (MTT) assay was conducted in 168 cases to investigate chemosensitivity to 5-FU.

Results

This analysis identified 22 MSI-H (9.4%), 25 MSI-L (10.7%), and 193 MSS (79.9%) tumors. Gastric cancer with MSI-H tended to have increased likelihood to show higher age, antral location of the tumor, and lymph vessel involvement (P < 0.05). Univariate analyses failed to show any difference between the MSI-H and MSS/MSI-L groups with respect to overall survival. Furthermore, survival after the administration of 5-FU did not correlate with MSI status, and MSI was not associated with 5-FU sensitivity by MTT assay.

Conclusion

The results of this study indicate that MSI status has no clear influence on overall survival or response to 5-FU in gastric cancer.

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References

  1. Falchetti M, Saieva C, Lupi R, et al. Gastric cancer with high-level microsatellite instability: target gene mutations, clinicopathologic features, and long-term survival. Hum Pathol. 2008;39:925–32.

    Article  PubMed  CAS  Google Scholar 

  2. Tahara E. Genetic pathways of two types of gastric cancer. IARC Sci Publ. 2004;327–49.

  3. Kim JJ, Baek MJ, Kim L, et al. Accumulated frameshift mutations at coding nucleotide repeats during the progression of gastric carcinoma with microsatellite instability. Lab Invest. 1999;79:1113–20.

    PubMed  CAS  Google Scholar 

  4. Guo RJ, Wang Y, Kaneko E, et al. Analyses of mutation and loss of heterozygosity of coding sequences of the entire transforming growth factor beta type II receptor gene in sporadic human gastric cancer. Carcinogenesis. 1998;19:1539–44.

    Article  PubMed  CAS  Google Scholar 

  5. Lee HS, Choi SI, Lee HK, et al. Distinct clinical features and outcomes of gastric cancers with microsatellite instability. Mod Pathol. 2002;15:632–40.

    Article  PubMed  Google Scholar 

  6. Wu CW, Chen GD, Jiang KC, et al. A genome-wide study of microsatellite instability in advanced gastric carcinoma. Cancer. 2001;92:92–101.

    Article  PubMed  CAS  Google Scholar 

  7. Wu MS, Lee CW, Shun CT, et al. Distinct clinicopathologic and genetic profiles in sporadic gastric cancer with different mutator phenotypes. Genes Chromosomes Cancer. 2000;27:403–11.

    Article  PubMed  CAS  Google Scholar 

  8. Pinto M, Oliveira C, Machado JC, et al. MSI-L gastric carcinomas share the hMLH1 methylation status of MSI-H carcinomas but not their clinicopathological profile. Lab Invest. 2000;80:1915–23.

    Article  PubMed  CAS  Google Scholar 

  9. Kang GH, Shim YH, Ro JY. Correlation of methylation of the hMLH1 promoter with lack of expression of hMLH1 in sporadic gastric carcinomas with replication error. Lab Invest. 1999;79:903–9.

    PubMed  CAS  Google Scholar 

  10. Thibodeau SN, French AJ, Cunningham JM, et al. Microsatellite instability in colorectal cancer: different mutator phenotypes and the principal involvement of hMLH1. Cancer Res. 1998;58:1713–8.

    PubMed  CAS  Google Scholar 

  11. Cunningham JM, Christensen ER, Tester DJ, et al. Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. Cancer Res. 1998;58:3455–60.

    PubMed  CAS  Google Scholar 

  12. Oki E, Oda S, Maehara Y, Sugimachi K. Mutated gene-specific phenotypes of dinucleotide repeat instability in human colorectal carcinoma cell lines deficient in DNA mismatch repair. Oncogene. 1999;18:2143–7.

    Article  PubMed  CAS  Google Scholar 

  13. Bevilacqua RA, Simpson AJ. Methylation of the hMLH1 promoter but no hMLH1 mutations in sporadic gastric carcinomas with high-level microsatellite instability. Int J Cancer. 2000;87:200–3.

    Article  PubMed  CAS  Google Scholar 

  14. 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;59:159–64.

    PubMed  CAS  Google Scholar 

  15. Fleisher AS, Esteller M, Wang S, et al. Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. Cancer Res. 1999;59:1090–5.

    PubMed  CAS  Google Scholar 

  16. Nan HM, Song YJ, Yun HY, Park JS, Kim H. Effects of dietary intake and genetic factors on hypermethylation of the hMLH1 gene promoter in gastric cancer. World J Gastroenterol. 2005;11:3834–41.

    PubMed  CAS  Google Scholar 

  17. Sakata K, Tamura G, Endoh Y, Ohmura K, Ogata S, Motoyama T. Hypermethylation of the hMLH1 gene promoter in solitary and multiple gastric cancers with microsatellite instability. Br J Cancer. 2002;86:564–7.

    Article  PubMed  CAS  Google Scholar 

  18. Bacani J, Zwingerman R, Di Nicola N, et al. Tumor microsatellite instability in early onset gastric cancer. J Mol Diagn. 2005;7:465–77.

    PubMed  CAS  Google Scholar 

  19. Schneider BG, Bravo JC, Roa JC, et al. Microsatellite instability, prognosis and metastasis in gastric cancers from a low-risk population. Int J Cancer. 2000;89:444–52.

    Article  PubMed  CAS  Google Scholar 

  20. An C, Choi IS, Yao JC, et al. Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma. Clin Cancer Res. 2005;11:656–63.

    PubMed  CAS  Google Scholar 

  21. Beghelli S, de Manzoni G, Barbi S, et al. Microsatellite instability in gastric cancer is associated with better prognosis in only stage II cancers. Surgery. 2006;139:347–56.

    Article  PubMed  Google Scholar 

  22. Perez RO, Jacob CE, D’Ottaviano FL, et al. Microsatellite instability in solitary and sporadic gastric cancer. Rev Hosp Clin Fac Med Sao Paulo. 2004;59:279–85.

    PubMed  Google Scholar 

  23. Sakuramoto S, Sasako M, Yamaguchi T, et al. Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. N Engl J Med. 2007;357:1810–20.

    Article  PubMed  CAS  Google Scholar 

  24. Carethers JM, Smith EJ, Behling CA, et al. Use of 5-fluorouracil and survival in patients with microsatellite-unstable colorectal cancer. Gastroenterology. 2004;126:394–401.

    Article  PubMed  CAS  Google Scholar 

  25. Ribic CM, Sargent DJ, Moore MJ, et al. Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med. 2003;349:247–57.

    Article  PubMed  CAS  Google Scholar 

  26. Liang JT, Huang KC, Lai HS, et al. High-frequency microsatellite instability predicts better chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV sporadic colorectal cancer after palliative bowel resection. Int J Cancer. 2002;101:519–25.

    Article  PubMed  CAS  Google Scholar 

  27. Watanabe T, Wu TT, Catalano PJ, et al. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med. 2001;344:1196–206.

    Article  PubMed  CAS  Google Scholar 

  28. Oda S, Zhao Y, Maehara Y. Microsatellite instability in gastrointestinal tract cancers: a brief update. Surg Today. 2005;35:1005–15.

    Article  PubMed  Google Scholar 

  29. Oki E, Baba H, Tokunaga E, et al. Akt phosphorylation associates with LOH of PTEN and leads to chemoresistance for gastric cancer. Int J Cancer. 2005;117:376–80.

    Article  PubMed  CAS  Google Scholar 

  30. Takeuchi H, Baba H, Inutsuka S, et al. Antitumor chemosensitivity differs between clinical sarcoma and adenocarcinoma tissues. Anticancer Res. 1994;14:169–71.

    PubMed  CAS  Google Scholar 

  31. Oda S, Maehara Y, Ikeda Y, et al. Two modes of microsatellite instability in human cancer: differential connection of defective DNA mismatch repair to dinucleotide repeat instability. Nucleic Acids Res. 2005;33:1628–36.

    Article  PubMed  CAS  Google Scholar 

  32. Oda S, Oki E, Maehara Y, Sugimachi K. Precise assessment of microsatellite instability using high resolution fluorescent microsatellite analysis. Nucleic Acids Res. 1997;25:3415–20.

    Article  PubMed  CAS  Google Scholar 

  33. Sakurai M, Zhao Y, Oki E, Kakeji Y, Oda S, Maehara Y. High-resolution fluorescent analysis of microsatellite instability in gastric cancer. Eur J Gastroenterol Hepatol. 2007;19:701–9.

    Article  PubMed  Google Scholar 

  34. Tokunaga E, Oki E, Oda S, et al. Frequency of microsatellite instability inBreast cancer determined by high-resolution fluorescent microsatellite analysis. Oncology. 2000;59:44–9.

    Article  PubMed  CAS  Google Scholar 

  35. Benatti P, Gafa R, Barana D, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005;11:8332–40.

    Article  PubMed  CAS  Google Scholar 

  36. Mizoguchi M, Inamura T, Ikezaki K, et al. Patient survival and microsatellite instability in gliomas by high-resolution fluorescent analysis. Oncol Rep. 1999;6:791–5.

    PubMed  CAS  Google Scholar 

  37. Kobayashi K, Okamoto T, Takayama S, Akiyama M, Ohno T, Yamada H. Genetic instability in intestinal metaplasia is a frequent event leading to well-differentiated early adenocarcinoma of the stomach. Eur J Cancer. 2000;36:1113–9.

    Article  PubMed  CAS  Google Scholar 

  38. Wu MS, Lee CW, Shun CT, et al. Clinicopathological significance of altered loci of replication error and microsatellite instability-associated mutations in gastric cancer. Cancer Res. 1998;58:1494–7.

    PubMed  CAS  Google Scholar 

  39. Miyamoto N, Yamamoto H, Taniguchi H, et al. Differential expression of angiogenesis-related genes in human gastric cancers with and those without high-frequency microsatellite instability. Cancer Lett. 2007;254:42–53.

    Article  PubMed  CAS  Google Scholar 

  40. Hofler H, Langer R, Ott K, Keller G. Prediction of response to neoadjuvant chemotherapy in carcinomas of the upper gastrointestinal tract. Adv Exp Med Biol. 2006;587:115–20.

    PubMed  Google Scholar 

  41. Kinoshita T, Nashimoto A, Yamamura Y, et al. Feasibility study of adjuvant chemotherapy with S-1 (TS-1;tegafur, gimeracil, oteracil potassium) for gastric cancer. Gastric Cancer. 2004;7:104–9.

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Eiji Oki MD, PhD, Yoshihiro Kakeji MD, PhD, Yan Zhao MD, PhD, Rintaro Yoshida MD, Koji Ando MD, Takanobu Masuda MD, Kippei Ohgaki MD, PhD, Masaru Morita MD, PhD & Yoshihiko Maehara MD, PhD, FACS

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  1. Eiji Oki MD, PhD
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  2. Yoshihiro Kakeji MD, PhD
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  3. Yan Zhao MD, PhD
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  4. Rintaro Yoshida MD
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  5. Koji Ando MD
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  6. Takanobu Masuda MD
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  7. Kippei Ohgaki MD, PhD
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  8. Masaru Morita MD, PhD
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  9. Yoshihiko Maehara MD, PhD, FACS
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Correspondence to Eiji Oki MD, PhD.

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Oki, E., Kakeji, Y., Zhao, Y. et al. Chemosensitivity and Survival in Gastric Cancer Patients with Microsatellite Instability. Ann Surg Oncol 16, 2510–2515 (2009). https://doi.org/10.1245/s10434-009-0580-8

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  • DOI: https://doi.org/10.1245/s10434-009-0580-8

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