title: DNA methylation combinations in adjacent normal colon tissue predict cancer recurrence: evidence from a clinical cohort study.
abstract: Accumulating evidence has suggested the requirement for further stratification of patients in the same tumor stage according to molecular factors. We evaluate the combination of cancer stage and DNA methylation status as an indicator of the risk of recurrence and mortality among patients with colorectal cancer (CRC). A cohort study of 215 patients with CRC (mean age 64.32 years; 50.5% of men) from Tri-Service General Hospital in Taiwan examined the association between cancer stage and risk of CRC recurrence and mortality. A Cox proportional hazard model was used to analyze patient methylation status and clinical information at study entry, and their associations with CRC recurrence and mortality during follow-up. The advanced stage patients with p16, hMLH1, and MGMT methylation were associated with higher risk of CRC recurrence compared with the local stage patients with unmethylation status in tumor tissues, with adjusted hazard ratios (HRs) (95% confidence interval [CI]) of 9.64 (2.92-31.81), 8.29 (3.40-20.22), and 11.83 (3.49-40.12), respectively. When analyzing normal tissues, we observed similar risk of CRC recurrence with adjusted HRs (95% CI) of 10.85 (4.06-28.96), 9.04 (3.79-21.54), and 12.61 (4.90-32.44), respectively. For combined analyses, the risk of recurrence in the patients in advanced stage with DNA methylation in both normal and tumor tissues, compared with local stage with unmethylation, was increased with adjusted HR (95% CI) of 9.37 (3.36-26.09). In the advanced stage patients, methylation status and tissue subtype were associated with increased risk of 5-year cumulative CRC recurrence (p < 0.001). This study demonstrates that clustering DNA methylation status according to cancer stage and tissue subtype is critical for the assessment of risk of recurrence in CRC patients and also indicated an underlying mechanism.
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan (R.O.C.).
authors: Jen Chun
authors: JC
authors: Kuan
authors: Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan (R.O.C.).
authors: Chang Chieh
authors: CC
authors: Wu
authors: Department of Public Health, College of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan (R.O.C.).
authors: Chien An
authors: CA
authors: Sun
authors: School of Public Health, National Defense Medical Center, Taipei, Taiwan (R.O.C.).
authors: Chi Ming
authors: CM
authors: Chu
authors: School of Public Health, National Defense Medical Center, Taipei, Taiwan (R.O.C.).
authors: Fu Gong
authors: FG
authors: Lin
authors: Graduate Institute of Medical Sciences, National Defense Medical Center, Taipei, Taiwan (R.O.C.).
authors: Chih Hsiung
authors: CH
authors: Hsu
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan (R.O.C.).
authors: Po-Chieh
authors: PC
authors: Kan
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan (R.O.C.).
authors: Shih-Chieh
authors: SC
authors: Lin
authors: Department of Health Business Administration, Meiho University, Pingtung, Taiwan.
authors: Tsan
authors: T
authors: Yang
authors: Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan (R.O.C.); School of Public Health, National Defense Medical Center, Taipei, Taiwan (R.O.C.).
authors: Yu-Ching
authors: YC
authors: Chou
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D016022:Case-Control Studies; D003106:Colon / Q000378:metabolism*; D003110:Colonic Neoplasms / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D015254:DNA Modification Methylases / Q000235:genetics; D045643:DNA Repair Enzymes / Q000235:genetics; D005260:Female; D019942:Genes, p16; D006801:Humans; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D014408:Biomarkers, Tumor; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D025521:Tumor Suppressor Proteins; D015254:DNA Modification Methylases; C515491:MGMT protein, human; D000070957:MutL Protein Homolog 1; D045643:DNA Repair Enzymes