Get 20M+ Full-Text Papers For Less Than $1.50/day. Subscribe now for You or Your Team.

Learn More →

Association between DNA Methylation and Shortened Survival in Patients with Advanced Colorectal Cancer Treated with 5-Fluorouracil–Based Chemotherapy

Association between DNA Methylation and Shortened Survival in Patients with Advanced Colorectal... Purpose: There are no good genomic markers of survival in patients with advanced colorectal cancer. The CpG island methylator phenotype (CIMP) marks a distinctive pathway in colorectal cancer. We sought to determine the prognostic significance of CIMP in advanced colorectal cancer patients treated with 5-fluorouracil (5-FU) in an Eastern Cooperative Oncology Group clinical trial. Experimental Design: We studied 188 patients enrolled on protocol E2290, a five-arm trial comparing 5-FU, 5-FU in combination with N -phosphonoacetyl- l -aspartic acid, oral leucovorin, i.v. leucovorin, or IFNα-2a in patients with advanced colorectal cancer. Methylation of MINT1, MINT31, hMLH1, p14 ARF , and p16 INK4a in DNA extracted from formalin-fixed paraffin-embedded specimens was evaluated by combined bisulfite restriction analysis, and methylation of MINT2 was studied by methylation-specific PCR. Results: Methylation frequencies were 21% for MINT1 , 23% for MINT2 , 24% for MINT31 , 4% for hMLH1 , 11% for p14 ARF , and 17% for p16 INK4a . Methylation of MINT1, MINT31, p14 ARF , and p16 INK4a were correlated, as expected. There was no association between methylation and clinicopathologic factors or response to therapy. Methylation of MINT1, MINT31, p14 ARF , or p16 INK4a was associated individually with shortened overall survival. Hazard ratios were 1.51 ( P = 0.05) for MINT1 , 1.70 ( P = 0.006) for MINT31 , 2.22 ( P = 0.001) for p14 ARF , and 1.51 ( P = 0.05) for p16 INK4a . Concurrent methylation of two or more genes of the CIMP-associated subset ( MINT1, MINT31, p14 ARF and p16 INK4a ) defined a group of cases with markedly reduced overall survival and hazard ratio was 3.22 ( P < 0.0001 in multivariate analyses). Conclusions: CIMP is associated with poor survival in advanced colorectal cancer patients. prognosis DNA methylation/epigenetics Gastrointestinal cancers: colorectal http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Clinical Cancer Research American Association of Cancer Research

Association between DNA Methylation and Shortened Survival in Patients with Advanced Colorectal Cancer Treated with 5-Fluorouracil–Based Chemotherapy

Association between DNA Methylation and Shortened Survival in Patients with Advanced Colorectal Cancer Treated with 5-Fluorouracil–Based Chemotherapy

Clinical Cancer Research , Volume 13 (20): 6093 – Oct 15, 2007

Abstract

Purpose: There are no good genomic markers of survival in patients with advanced colorectal cancer. The CpG island methylator phenotype (CIMP) marks a distinctive pathway in colorectal cancer. We sought to determine the prognostic significance of CIMP in advanced colorectal cancer patients treated with 5-fluorouracil (5-FU) in an Eastern Cooperative Oncology Group clinical trial. Experimental Design: We studied 188 patients enrolled on protocol E2290, a five-arm trial comparing 5-FU, 5-FU in combination with N -phosphonoacetyl- l -aspartic acid, oral leucovorin, i.v. leucovorin, or IFNα-2a in patients with advanced colorectal cancer. Methylation of MINT1, MINT31, hMLH1, p14 ARF , and p16 INK4a in DNA extracted from formalin-fixed paraffin-embedded specimens was evaluated by combined bisulfite restriction analysis, and methylation of MINT2 was studied by methylation-specific PCR. Results: Methylation frequencies were 21% for MINT1 , 23% for MINT2 , 24% for MINT31 , 4% for hMLH1 , 11% for p14 ARF , and 17% for p16 INK4a . Methylation of MINT1, MINT31, p14 ARF , and p16 INK4a were correlated, as expected. There was no association between methylation and clinicopathologic factors or response to therapy. Methylation of MINT1, MINT31, p14 ARF , or p16 INK4a was associated individually with shortened overall survival. Hazard ratios were 1.51 ( P = 0.05) for MINT1 , 1.70 ( P = 0.006) for MINT31 , 2.22 ( P = 0.001) for p14 ARF , and 1.51 ( P = 0.05) for p16 INK4a . Concurrent methylation of two or more genes of the CIMP-associated subset ( MINT1, MINT31, p14 ARF and p16 INK4a ) defined a group of cases with markedly reduced overall survival and hazard ratio was 3.22 ( P < 0.0001 in multivariate analyses). Conclusions: CIMP is associated with poor survival in advanced colorectal cancer patients. prognosis DNA methylation/epigenetics Gastrointestinal cancers: colorectal

Loading next page...
 
/lp/american-association-of-cancer-research/association-between-dna-methylation-and-shortened-survival-in-patients-0IgUBk1QZ0

References

References for this paper are not available at this time. We will be adding them shortly, thank you for your patience.

Publisher
American Association of Cancer Research
Copyright
Copyright © 2010 American Association for Cancer Research
ISSN
1078-0432
eISSN
1557-3265
DOI
10.1158/1078-0432.CCR-07-1011
pmid
17947473
Publisher site
See Article on Publisher Site

Abstract

Purpose: There are no good genomic markers of survival in patients with advanced colorectal cancer. The CpG island methylator phenotype (CIMP) marks a distinctive pathway in colorectal cancer. We sought to determine the prognostic significance of CIMP in advanced colorectal cancer patients treated with 5-fluorouracil (5-FU) in an Eastern Cooperative Oncology Group clinical trial. Experimental Design: We studied 188 patients enrolled on protocol E2290, a five-arm trial comparing 5-FU, 5-FU in combination with N -phosphonoacetyl- l -aspartic acid, oral leucovorin, i.v. leucovorin, or IFNα-2a in patients with advanced colorectal cancer. Methylation of MINT1, MINT31, hMLH1, p14 ARF , and p16 INK4a in DNA extracted from formalin-fixed paraffin-embedded specimens was evaluated by combined bisulfite restriction analysis, and methylation of MINT2 was studied by methylation-specific PCR. Results: Methylation frequencies were 21% for MINT1 , 23% for MINT2 , 24% for MINT31 , 4% for hMLH1 , 11% for p14 ARF , and 17% for p16 INK4a . Methylation of MINT1, MINT31, p14 ARF , and p16 INK4a were correlated, as expected. There was no association between methylation and clinicopathologic factors or response to therapy. Methylation of MINT1, MINT31, p14 ARF , or p16 INK4a was associated individually with shortened overall survival. Hazard ratios were 1.51 ( P = 0.05) for MINT1 , 1.70 ( P = 0.006) for MINT31 , 2.22 ( P = 0.001) for p14 ARF , and 1.51 ( P = 0.05) for p16 INK4a . Concurrent methylation of two or more genes of the CIMP-associated subset ( MINT1, MINT31, p14 ARF and p16 INK4a ) defined a group of cases with markedly reduced overall survival and hazard ratio was 3.22 ( P < 0.0001 in multivariate analyses). Conclusions: CIMP is associated with poor survival in advanced colorectal cancer patients. prognosis DNA methylation/epigenetics Gastrointestinal cancers: colorectal

Journal

Clinical Cancer ResearchAmerican Association of Cancer Research

Published: Oct 15, 2007

There are no references for this article.