Skip to main content
Top
Published in: Annals of Surgical Oncology 9/2009

01-09-2009 | Gastrointestinal Oncology

Chemosensitivity and Survival in Gastric Cancer Patients with Microsatellite Instability

Authors: 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

Published in: Annals of Surgical Oncology | Issue 9/2009

Login to get access

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.
Literature
1.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
2.
go back to reference Tahara E. Genetic pathways of two types of gastric cancer. IARC Sci Publ. 2004;327–49. Tahara E. Genetic pathways of two types of gastric cancer. IARC Sci Publ. 2004;327–49.
3.
go back to reference 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 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
4.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
5.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
6.
go back to reference Wu CW, Chen GD, Jiang KC, et al. A genome-wide study of microsatellite instability in advanced gastric carcinoma. Cancer. 2001;92:92–101.PubMedCrossRef Wu CW, Chen GD, Jiang KC, et al. A genome-wide study of microsatellite instability in advanced gastric carcinoma. Cancer. 2001;92:92–101.PubMedCrossRef
7.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
8.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
9.
go back to reference 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 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
10.
go back to reference 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 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
11.
go back to reference 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 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
12.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
13.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
14.
go back to reference 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 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
15.
go back to reference 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 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
16.
go back to reference 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 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
17.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
18.
go back to reference 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 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
19.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
20.
go back to reference 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 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
21.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
22.
go back to reference 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 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
23.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
24.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
25.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
26.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
27.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
28.
go back to reference Oda S, Zhao Y, Maehara Y. Microsatellite instability in gastrointestinal tract cancers: a brief update. Surg Today. 2005;35:1005–15.PubMedCrossRef Oda S, Zhao Y, Maehara Y. Microsatellite instability in gastrointestinal tract cancers: a brief update. Surg Today. 2005;35:1005–15.PubMedCrossRef
29.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
30.
go back to reference Takeuchi H, Baba H, Inutsuka S, et al. Antitumor chemosensitivity differs between clinical sarcoma and adenocarcinoma tissues. Anticancer Res. 1994;14:169–71.PubMed Takeuchi H, Baba H, Inutsuka S, et al. Antitumor chemosensitivity differs between clinical sarcoma and adenocarcinoma tissues. Anticancer Res. 1994;14:169–71.PubMed
31.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
32.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
33.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
34.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
35.
go back to reference Benatti P, Gafa R, Barana D, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005;11:8332–40.PubMedCrossRef Benatti P, Gafa R, Barana D, et al. Microsatellite instability and colorectal cancer prognosis. Clin Cancer Res. 2005;11:8332–40.PubMedCrossRef
36.
go back to reference 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 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
37.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
38.
go back to reference 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 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
39.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
40.
go back to reference 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 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
41.
go back to reference 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.PubMedCrossRef 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.PubMedCrossRef
Metadata
Title
Chemosensitivity and Survival in Gastric Cancer Patients with Microsatellite Instability
Authors
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
Publication date
01-09-2009
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 9/2009
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-009-0580-8

Other articles of this Issue 9/2009

Annals of Surgical Oncology 9/2009 Go to the issue

Controversies in the Management of Hepatic Colorectal Metastases

Chemotherapy-Associated Hepatotoxicity: Do We Need to Be Concerned?