PURPOSE: The CpG island methylator phenotype (CIMP) is observed in approximately 30% of colorectal cancer (CRC) cases and is characterized by the concurrent methylation of multiple CpG islands in tumor DNA. This phenotype (CIMP+) is more frequently observed in tumors with proximal location, microsatellite instability, and normal p53. Because it has previously been observed that each of these features is associated with a good survival benefit from 5-fluorouracil (5-FU)-based adjuvant chemotherapy, we investigated in the present study whether CIMP+ has independent predictive value. EXPERIMENTAL DESIGN: CIMP+ status was evaluated in 103 stage III CRCs from patients treated with surgery alone and for an additional 103 cases from patients treated with surgery and adjuvant 5-FU-based chemotherapy. The two cohorts were randomly pair-matched for age, sex, and tumor site, and the median length of follow-up time was 39 months. RESULTS: CIMP+ status predicted survival benefit from 5-FU treatment independently of microsatellite instability and p53 mutation status (relative risk = 0.22; 95% confidence interval, 0.06-0.84; P = 0.027). Unmeasured, high-risk confounding factors could only account for this association if they were unequally distributed between the two patient cohorts by a factor of at least 2-fold. CONCLUSIONS: CIMP+ has independent predictive significance for the survival benefit from 5-FU chemotherapy in CRC. This molecular marker should be incorporated into prospective clinical trials of fluorouracil-based therapies to confirm its clinical value.
PURPOSE: The CpG island methylator phenotype (CIMP) is observed in approximately 30% of colorectal cancer (CRC) cases and is characterized by the concurrent methylation of multiple CpG islands in tumor DNA. This phenotype (CIMP+) is more frequently observed in tumors with proximal location, microsatellite instability, and normal p53. Because it has previously been observed that each of these features is associated with a good survival benefit from 5-fluorouracil (5-FU)-based adjuvant chemotherapy, we investigated in the present study whether CIMP+ has independent predictive value. EXPERIMENTAL DESIGN:CIMP+ status was evaluated in 103 stage III CRCs from patients treated with surgery alone and for an additional 103 cases from patients treated with surgery and adjuvant 5-FU-based chemotherapy. The two cohorts were randomly pair-matched for age, sex, and tumor site, and the median length of follow-up time was 39 months. RESULTS:CIMP+ status predicted survival benefit from 5-FU treatment independently of microsatellite instability and p53 mutation status (relative risk = 0.22; 95% confidence interval, 0.06-0.84; P = 0.027). Unmeasured, high-risk confounding factors could only account for this association if they were unequally distributed between the two patient cohorts by a factor of at least 2-fold. CONCLUSIONS:CIMP+ has independent predictive significance for the survival benefit from 5-FU chemotherapy in CRC. This molecular marker should be incorporated into prospective clinical trials of fluorouracil-based therapies to confirm its clinical value.
Authors: Rodrigo Jover; Thuy-Phuong Nguyen; Lucía Pérez-Carbonell; Pedro Zapater; Artemio Payá; Cristina Alenda; Estefanía Rojas; Joaquín Cubiella; Francesc Balaguer; Juan D Morillas; Juan Clofent; Luis Bujanda; Josep M Reñé; Xavier Bessa; Rosa M Xicola; David Nicolás-Pérez; Antoni Castells; Montserrat Andreu; Xavier Llor; C Richard Boland; Ajay Goel Journal: Gastroenterology Date: 2010-12-24 Impact factor: 22.682
Authors: Noriko Tanaka; Curtis Huttenhower; Katsuhiko Nosho; Yoshifumi Baba; Kaori Shima; John Quackenbush; Kevin M Haigis; Edward Giovannucci; Charles S Fuchs; Shuji Ogino Journal: Am J Pathol Date: 2010-10-29 Impact factor: 4.307
Authors: Tamara L Znajda; Shinichi Hayashi; Peter J Horton; John B Martinie; Prosanto Chaudhury; Victoria A Marcus; Jeremy R Jass; Peter Metrakos Journal: J Gastrointest Surg Date: 2006-04 Impact factor: 3.452