CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers. Issue 5 (2nd June 2017)

• Record Type: Journal Article
• Authors: Vedeld, Hege Marie; Merok, Marianne; Jeanmougin, Marine; Danielsen, Stine A.; Honne, Hilde; Presthus, Gro Kummeneje; Svindland, Aud; Sjo, Ole H.; Hektoen, Merete; Eknæs, Mette; Nesbakken, Arild; Lothe, Ragnhild A.; Lind, Guro E.
• Is Part Of: International journal of cancer. Volume 141:Issue 5(2017:Sep. 01)
• Page Start: 967
• Page End: 976
• Publication Date: 2017-06-02
• Subjects: Age of Onset -- CIMP -- Colon Cancer -- DNA Methylation -- Prognostic Factor; Cancer -- Periodicals; Cancer -- Prevention -- Periodicals; 616.994
• DOI: 10.1002/ijc.30796
• Languages: English
• ISSNs: 0020-7136

Abstract

Abstract : The prognostic value of CpG island methylator phenotype (CIMP) in colorectal cancer remains unsettled. We aimed to assess the prognostic value of this phenotype analyzing a total of 1126 tumor samples obtained from two Norwegian consecutive colorectal cancer series. CIMP status was determined by analyzing the 5‐markers CAGNA1G, IGF2, NEUROG1, RUNX3 and SOCS1 by quantitative methylation specific PCR (qMSP). The effect of CIMP on time to recurrence (TTR) and overall survival (OS) were determined by uni‐ and multivariate analyses. Subgroup analyses were conducted according to MSI and BRAF mutation status, disease stage, and also age at time of diagnosis (<60, 60‐74, ≥75 years). Patients with CIMP positive tumors demonstrated significantly shorter TTR and worse OS compared to those with CIMP negative tumors (multivariate hazard ratio [95% CI] 1.86 [1.31‐2.63] and 1.89 [1.34‐2.65], respectively). In stratified analyses, CIMP tumors showed significantly worse outcome among patients with microsatellite stable (MSS, P < 0.001), and MSS BRAF mutated tumors ( P < 0.001), a finding that persisted in patients with stage II, III or IV disease, and that remained significant in multivariate analysis ( P < 0.01). Consistent results were found for all three age groups. To conclude, CIMP is significantly associated with inferior outcome for colorectal cancer patients, and can stratify the poor prognostic patients with MSS BRAF mutated tumors. Abstract : What's new? As many as one‐fifth of colorectal cancers have a CpG island methylator phenotype (CIMP) involving widespread promoter DNA methylation. CIMP is associated with key factors related to disease outcome, including microsatellite instability and BRAF mutations. In this study, CIMP was found to be significantly associated with worse prognosis in colorectal cancer patients, particularly those with microsatellite stable (MSS) BRAF ‐mutated tumors. In stratified analyses, trends toward worse survival were identified for CIMP‐positive stage III and stage IV patients in the MSS BRAF ‐mutated group. The findings suggest that CIMP status should be included in prognostic analyses at time of diagnosis.