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


METHODS
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 an independent predictor of prognosis in resected gastric cancer.
An
Changhyeok
C
Department of Pathology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030-4096.
Choi
In-Seon
IS
Yao
James C
JC
Worah
Samidha
S
Xie
Keping
K
Mansfield
Paul F
PF
Ajani
Jaffer A
JA
Rashid
Asif
A
Hamilton
Stanley R
SR
Wu
Tsung-Teh
TT
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D015820:Cadherins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D019942:Genes, p16 / Q000502:physiology*; D042822:Genomic Instability; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins; D010641:Phenotype; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D013274:Stomach Neoplasms / Q000208:ethnology / Q000235:genetics* / Q000401:mortality; D015996:Survival Rate
C079091:APBA1 protein, human; C491636:APBA2 protein, human; D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D002352:Carrier Proteins; D004273:DNA, Neoplasm; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1