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In this study, we sought to determine the prognostic significance of DNA methylation, both in univariate analysis and in concert with other clinicopathologic factors known to influence outcome. <\/jats:p><jats:p> Patients and Methods: Fresh tissue (625 cancers) was obtained from 605 individuals (age range, 29 to 99 years) undergoing curative surgery for colorectal cancer at one institution during a period of 8 years. Clinicopathologic details were recorded for all tumors, including stage, grade, type, vascular space invasion, and clinical follow-up to 5 years. Microsatellite status was assessed using standard markers. Methylation of p16 and hMLH1 promoters was determined by methylation-specific polymerase chain reaction (PCR), whereas methylation at methylated-in-tumor loci (MINT)1, MINT2, MINT12, and MINT31 loci were assessed by bisulfite-PCR. <\/jats:p><jats:p> Results: Patients with microsatellite unstable tumors (12%) had better disease-specific survival than those with microsatellite stable (MSS) tumors (univariate analysis: hazard ratio [HR], 0.53; 95% CI, 0.27 to 1.0). Overall survival of individuals with MSS tumors was influenced by three independently significant factors: tumor stage (HR, 7.3; 95% CI, 5.1 to 10.4), heavy tumor methylation (HR, 2.1; 95% CI, 1.1 to 4.0), and vascular space invasion (HR, 1.9; 95% CI, 1.3 to 2.9). In MSS tumors, methylation at any single site was not independently predictive of survival. Neither methylation nor microsatellite status predicted a favorable response to chemotherapy. <\/jats:p><jats:p> Conclusion: DNA methylation is associated with a worse outcome in colorectal cancer, but this adverse prognostic influence is lost in those methylated tumors showing MSI. The mechanisms of these events warrant additional investigation. <\/jats:p>","DOI":"10.1200\/jco.2003.03.123","type":"journal-article","created":{"date-parts":[[2003,10,10]],"date-time":"2003-10-10T09:18:24Z","timestamp":1065777504000},"page":"3729-3736","source":"Crossref","is-referenced-by-count":157,"title":["Adverse Prognostic Effect of Methylation in Colorectal Cancer Is Reversed by Microsatellite Instability"],"prefix":"10.1200","volume":"21","author":[{"given":"Robyn Lynne","family":"Ward","sequence":"first","affiliation":[{"name":"From the Departments of Medical Oncology and Colorectal Surgery, St Vincent\u2019s Hospital, Darlinghurst; and the Schools of Medicine and Medical Sciences, University of New South Wales, Sydney, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kay","family":"Cheong","sequence":"additional","affiliation":[{"name":"From the Departments of Medical Oncology and Colorectal Surgery, St Vincent\u2019s Hospital, Darlinghurst; and the Schools of Medicine and Medical Sciences, University of New South Wales, Sydney, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su-Lyn","family":"Ku","sequence":"additional","affiliation":[{"name":"From the Departments of Medical Oncology and Colorectal Surgery, St Vincent\u2019s Hospital, Darlinghurst; and the Schools of Medicine and Medical Sciences, University of New South Wales, Sydney, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Meagher","sequence":"additional","affiliation":[{"name":"From the Departments of Medical Oncology and Colorectal Surgery, St Vincent\u2019s Hospital, Darlinghurst; and the Schools of Medicine and Medical Sciences, University of New South Wales, Sydney, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence","family":"O\u2019Connor","sequence":"additional","affiliation":[{"name":"From the Departments of Medical Oncology and Colorectal Surgery, St Vincent\u2019s Hospital, Darlinghurst; and the Schools of Medicine and Medical Sciences, University of New South Wales, Sydney, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas John","family":"Hawkins","sequence":"additional","affiliation":[{"name":"From the Departments of Medical Oncology and Colorectal Surgery, St Vincent\u2019s Hospital, Darlinghurst; and the Schools of Medicine and Medical Sciences, University of New South Wales, Sydney, Australia."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"233","reference":[{"key":"R2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-0142(20000401)88:7<1739::AID-CNCR30>3.0.CO;2-T"},{"key":"R3","doi-asserted-by":"publisher","DOI":"10.1002\/ssu.2980100105"},{"key":"R4","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(19930901)72:5<1536::AID-CNCR2820720508>3.0.CO;2-U"},{"key":"R5","doi-asserted-by":"publisher","DOI":"10.1007\/BF02234727"},{"key":"R6","doi-asserted-by":"publisher","DOI":"10.1054\/bjoc.2001.1964"},{"key":"R7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199407283310401"},{"key":"R8","doi-asserted-by":"publisher","DOI":"10.1002\/ijc.2910590606"},{"key":"R9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1699-0463.1995.tb01112.x"},{"key":"R10","unstructured":"Augenlicht LH, Wadler S, Corner G, et al: Low-level c-myc amplification in human colonic carcinoma cell lines and tumors: A frequent, p53-independent mutation associated with improved outcome in a randomized multi-institutional trial. 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