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CpG island methylator phenotype, microsatellite instability, BRAF mutation and clinical outcome in colon cancer
  1. Shuji Ogino1,2,3,
  2. Katsuhiko Nosho1,
  3. Gregory J Kirkner4,
  4. Takako Kawasaki1,
  5. Jeffrey A Meyerhardt1,
  6. Massimo Loda1,2,
  7. Edward L Giovannucci3,4,
  8. Charles S Fuchs1,4
  1. 1
    Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA
  2. 2
    Department of Pathology, Brigham and Women’s Hospital, Boston, and Harvard Medical School, Boston, Massachusetts, USA
  3. 3
    Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA
  4. 4
    Channing Laboratory, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
  1. Dr S Ogino, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical School, 44 Binney Street, Room JF-215C, Boston, MA 02115 USA; shuji_ogino{at}dfci.harvard.edu

Abstract

Background: The CpG island methylator phenotype (CIMP), characterised 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 prognosis remains uncertain.

Methods: Utilising 649 colon cancers (stage I–IV) in two independent cohort studies, we quantified DNA methylation in eight CIMP-specific promoters (CACNA1G, CDKN2A (p16), CRABP1, IGF2, MLH1, NEUROG1, RUNX3 and SOCS1) as well as CHFR, HIC1, IGFBP3, MGMT, MINT1, MINT31, p14, and WRN by using MethyLight technology. 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%) tumours 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 to 0.88), whereas the BRAF mutation was significantly associated with a high cancer-specific mortality (multivariate HR 1.97, 95% CI 1.13 to 3.42). A trend toward a low cancer-specific mortality was observed for MSI-high tumours (multivariate HR 0.70, 95% CI 0.36 to 1.37). In stratified analyses, CIMP-high tumours 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 prognostic significance.

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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Footnotes

  • Funding: This work was supported by The U.S. National Institute of Health grants P01 CA87969, P01 CA55075, P50 CA127003, and K07 CA122826 (to SO), the Bennett Family Fund for Targeted Therapies Research, and the Entertainment Industry Foundation National Colorectal Cancer Research Alliance. KN was supported by a fellowship grant from the Japan Society for the Promotion of Science.

  • Competing interests: None.

  • Ethics approval: This study was approved by the Human Subjects Committees at Brigham and Women’s Hospital and Harvard School of Public Health, on 30 October 2002 and 25 November 2002.

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