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CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer
  1. Shuji Ogino (shuji_ogino{at}dfci.harvard.edu)
  1. Dana-Farber Cancer Institute, United States
    1. Katsuhiko Nosho (katsuhiko_nosho{at}dfci.harvard.edu)
    1. Dana-Farber Cancer Institute, United States
      1. Gregory J Kirkner (gregory.kirkner{at}channing.harvard.edu)
      1. Brigham and Women's Hospital, United States
        1. Takako Kawasaki (takako_kawasaki{at}dfci.harvard.edu)
        1. Dana-Farber Cancer Institute, United States
          1. Jeffrey A Meyerhardt (jmeyerhardt{at}partners.org)
          1. Dana-Farber Cancer Institute, United States
            1. Massimo Loda (massimo_loda{at}dfci.harvard.edu)
            1. Dana-Farber Cancer Institute, Venezuela
              1. Edward L Giovannucci (egiovann{at}hsph.harvard.edu)
              1. Harvard School of Public Health, United States
                1. Charles S Fuchs (cfuchs{at}partners.org)
                1. Dana-Farber Cancer Institute, United States

                  Abstract

                  Background: The CpG island methylator phenotype (CIMP) characterized by widespread promoter methylation is associated with microsatellite instability (MSI) and BRAF mutation in colorectal cancer. The independent effect of CIMP, MSI and BRAF mutation on patient outcome remains uncertain.

                  Methods: Utilizing 649 colon cancers (stage I-IV) in two independent cohort studies, we quantified DNA methylation in 8 CIMP-specific promoters [CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3, and SOCS1], as well as MINT1, MINT31, p14, HIC1, IGFBP3, MGMT and WRN by MethyLight. We examined MSI, KRAS and BRAF status. Cox proportional hazard models computed hazard ratios (HRs) for colon cancer-specific and overall mortalities, adjusting for patient characteristics and tumoral molecular features.

                  Results: After adjustment for other predictors of patient survival, patients with CIMP-high cancers [126 (19%) tumors with >=6/8 methylated CIMP-specific promoters] experienced a significantly low colon cancer-specific mortality [multivariate HR 0.44, 95% confidence interval (CI) 0.22-0.88], whereas BRAF mutation was significantly associated with a high cancer-specific mortality (multivariate HR 1.97, 95% CI, 1.13-3.42). A trend toward a low cancer-specific mortality was observed for MSI-high tumors (multivariate HR 0.70, 95% CI, 0.36-1.37). In stratified analyses, CIMP-high tumors were associated with a significant reduction in colon cancer-specific mortality, regardless of both MSI and BRAF status. The relation between CIMP-high and lower mortality appeared to be consistent across all stages. KRAS mutation was unrelated to patient outcome.

                  Conclusion: CIMP-high appears to be an independent predictor of a low colon cancer-specific mortality, while BRAF mutation is associated with a high colon cancer-specific mortality.

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