Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma

Changhyeok An, In Seon Choi, James C. Yao, Samidha Worah, Keping Xie, Paul F. Mansfield, Jaffer A. Ajani, Asif Rashid, Stanley R. Hamilton, Tsung Teh Wu

Research output: Contribution to journalArticle

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Abstract

Purpose: The influence of molecular characteristics in prognosis of gastric cancer remains unclear. The aim of this study was to evaluate the prognostic value of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in gastric cancer. Experimental Design: We studied the methylation profiles of tumor suppressor gene p16, DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using bisulfite/methylation-specific PCR, and MSI using five microsatellite markers in 83 resected gastric carcinomas. The CIMP and MSI status were compared with clinicopathologic features and overall survival. Results: Concordant methylation of multiple genes/loci (CIMP-high) was present in 31% of tumors and in 4% of non-neoplastic mucosa, CIMP-low in 55% and 17%, and CIMP-negative in 13% and 79%, respectively (P < 0.001). The prevalence of MSI-high, MSI-low, and MS-stable in tumor was 19%, 17%, and 64%, respectively. MSI status was closely associated with hMLH1 hypermethylation and CIMP status (P = 0.001). In univariate analysis, overall survival was predicted by pathologic stage (P < 0.0001), R0 resection (P = 0.0002), MINT31 methylation (P = 0.04), and CIMP-high status (P = 0.04). MSI status of tumor was not a significant predictor of prognosis. Although CIMP status seemed to be a prognostic predictor of gastric cancer, only pathologic stage remained a significant predictor of prognosis on multivariate analysis (P < 0.001). Conclusions: Our results indicate that there is an association between CIMP status and MSI status in gastric cancer. Concordant methylation of multiple genes/loci (CIMP-H) is associated with better survival but is not in independent predictor of prognosis in resected gastric cancer.

Original languageEnglish (US)
Pages (from-to)656-663
Number of pages8
JournalClinical Cancer Research
Volume11
Issue number2 I
StatePublished - Jan 15 2005
Externally publishedYes

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Microsatellite Instability
CpG Islands
Stomach
Carcinoma
Phenotype
Methylation
Stomach Neoplasms
Genes
Neoplasms
DNA Mismatch Repair
Tumor Suppressor Genes
Microsatellite Repeats
Mucous Membrane
Research Design
Multivariate Analysis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

An, C., Choi, I. S., Yao, J. C., Worah, S., Xie, K., Mansfield, P. F., ... Wu, T. T. (2005). Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma. Clinical Cancer Research, 11(2 I), 656-663.

Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma. / An, Changhyeok; Choi, In Seon; Yao, James C.; Worah, Samidha; Xie, Keping; Mansfield, Paul F.; Ajani, Jaffer A.; Rashid, Asif; Hamilton, Stanley R.; Wu, Tsung Teh.

In: Clinical Cancer Research, Vol. 11, No. 2 I, 15.01.2005, p. 656-663.

Research output: Contribution to journalArticle

An, C, Choi, IS, Yao, JC, Worah, S, Xie, K, Mansfield, PF, Ajani, JA, Rashid, A, Hamilton, SR & Wu, TT 2005, 'Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma', Clinical Cancer Research, vol. 11, no. 2 I, pp. 656-663.
An C, Choi IS, Yao JC, Worah S, Xie K, Mansfield PF et al. Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma. Clinical Cancer Research. 2005 Jan 15;11(2 I):656-663.
An, Changhyeok ; Choi, In Seon ; Yao, James C. ; Worah, Samidha ; Xie, Keping ; Mansfield, Paul F. ; Ajani, Jaffer A. ; Rashid, Asif ; Hamilton, Stanley R. ; Wu, Tsung Teh. / Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma. In: Clinical Cancer Research. 2005 ; Vol. 11, No. 2 I. pp. 656-663.
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abstract = "Purpose: The influence of molecular characteristics in prognosis of gastric cancer remains unclear. The aim of this study was to evaluate the prognostic value of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in gastric cancer. Experimental Design: We studied the methylation profiles of tumor suppressor gene p16, DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using bisulfite/methylation-specific PCR, and MSI using five microsatellite markers in 83 resected gastric carcinomas. The CIMP and MSI status were compared with clinicopathologic features and overall survival. Results: Concordant methylation of multiple genes/loci (CIMP-high) was present in 31{\%} of tumors and in 4{\%} of non-neoplastic mucosa, CIMP-low in 55{\%} and 17{\%}, and CIMP-negative in 13{\%} and 79{\%}, respectively (P < 0.001). The prevalence of MSI-high, MSI-low, and MS-stable in tumor was 19{\%}, 17{\%}, and 64{\%}, respectively. MSI status was closely associated with hMLH1 hypermethylation and CIMP status (P = 0.001). In univariate analysis, overall survival was predicted by pathologic stage (P < 0.0001), R0 resection (P = 0.0002), MINT31 methylation (P = 0.04), and CIMP-high status (P = 0.04). MSI status of tumor was not a significant predictor of prognosis. Although CIMP status seemed to be a prognostic predictor of gastric cancer, only pathologic stage remained a significant predictor of prognosis on multivariate analysis (P < 0.001). Conclusions: Our results indicate that there is an association between CIMP status and MSI status in gastric cancer. Concordant methylation of multiple genes/loci (CIMP-H) is associated with better survival but is not in independent predictor of prognosis in resected gastric cancer.",
author = "Changhyeok An and Choi, {In Seon} and Yao, {James C.} and Samidha Worah and Keping Xie and Mansfield, {Paul F.} and Ajani, {Jaffer A.} and Asif Rashid and Hamilton, {Stanley R.} and Wu, {Tsung Teh}",
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T1 - Prognostic significance of CpG island methylator phenotype and microsatellite instability in gastric carcinoma

AU - An, Changhyeok

AU - Choi, In Seon

AU - Yao, James C.

AU - Worah, Samidha

AU - Xie, Keping

AU - Mansfield, Paul F.

AU - Ajani, Jaffer A.

AU - Rashid, Asif

AU - Hamilton, Stanley R.

AU - Wu, Tsung Teh

PY - 2005/1/15

Y1 - 2005/1/15

N2 - Purpose: The influence of molecular characteristics in prognosis of gastric cancer remains unclear. The aim of this study was to evaluate the prognostic value of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in gastric cancer. Experimental Design: We studied the methylation profiles of tumor suppressor gene p16, DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using bisulfite/methylation-specific PCR, and MSI using five microsatellite markers in 83 resected gastric carcinomas. The CIMP and MSI status were compared with clinicopathologic features and overall survival. Results: Concordant methylation of multiple genes/loci (CIMP-high) was present in 31% of tumors and in 4% of non-neoplastic mucosa, CIMP-low in 55% and 17%, and CIMP-negative in 13% and 79%, respectively (P < 0.001). The prevalence of MSI-high, MSI-low, and MS-stable in tumor was 19%, 17%, and 64%, respectively. MSI status was closely associated with hMLH1 hypermethylation and CIMP status (P = 0.001). In univariate analysis, overall survival was predicted by pathologic stage (P < 0.0001), R0 resection (P = 0.0002), MINT31 methylation (P = 0.04), and CIMP-high status (P = 0.04). MSI status of tumor was not a significant predictor of prognosis. Although CIMP status seemed to be a prognostic predictor of gastric cancer, only pathologic stage remained a significant predictor of prognosis on multivariate analysis (P < 0.001). Conclusions: Our results indicate that there is an association between CIMP status and MSI status in gastric cancer. Concordant methylation of multiple genes/loci (CIMP-H) is associated with better survival but is not in independent predictor of prognosis in resected gastric cancer.

AB - Purpose: The influence of molecular characteristics in prognosis of gastric cancer remains unclear. The aim of this study was to evaluate the prognostic value of the CpG island methylator phenotype (CIMP) and microsatellite instability (MSI) in gastric cancer. Experimental Design: We studied the methylation profiles of tumor suppressor gene p16, DNA mismatch repair gene hMLH1, and four CpG islands (MINT1, MINT2, MINT25, and MINT31) using bisulfite/methylation-specific PCR, and MSI using five microsatellite markers in 83 resected gastric carcinomas. The CIMP and MSI status were compared with clinicopathologic features and overall survival. Results: Concordant methylation of multiple genes/loci (CIMP-high) was present in 31% of tumors and in 4% of non-neoplastic mucosa, CIMP-low in 55% and 17%, and CIMP-negative in 13% and 79%, respectively (P < 0.001). The prevalence of MSI-high, MSI-low, and MS-stable in tumor was 19%, 17%, and 64%, respectively. MSI status was closely associated with hMLH1 hypermethylation and CIMP status (P = 0.001). In univariate analysis, overall survival was predicted by pathologic stage (P < 0.0001), R0 resection (P = 0.0002), MINT31 methylation (P = 0.04), and CIMP-high status (P = 0.04). MSI status of tumor was not a significant predictor of prognosis. Although CIMP status seemed to be a prognostic predictor of gastric cancer, only pathologic stage remained a significant predictor of prognosis on multivariate analysis (P < 0.001). Conclusions: Our results indicate that there is an association between CIMP status and MSI status in gastric cancer. Concordant methylation of multiple genes/loci (CIMP-H) is associated with better survival but is not in independent predictor of prognosis in resected gastric cancer.

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