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Int J Cancer. 2017 Sep 1;141(5):967-976. doi: 10.1002/ijc.30796. Epub 2017 Jun 2.

CpG island methylator phenotype identifies high risk patients among microsatellite stable BRAF mutated colorectal cancers.

Vedeld HM1,2,3, Merok M1,3,4, Jeanmougin M1,2,3, Danielsen SA1,2,3, Honne H1,2,3, Presthus GK1,3,5, Svindland A6,7, Sjo OH2,4, Hektoen M1,2,3, Eknaes M1,2,3, Nesbakken A2,3,4, Lothe RA1,2,3,5, Lind GE1,2,3,5.

Author information

1
Department of Molecular Oncology, Institute for Cancer Research, Oslo University Hospital - Norwegian Radium Hospital, Oslo, Norway.
2
K.G. Jebsen Colorectal Cancer Research Centre, Oslo University Hospital, Oslo, Norway.
3
Centre for Cancer Biomedicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
4
Department of Gastrointestinal Surgery, Oslo University Hospital - Aker, Oslo, Norway.
5
Department of Biosciences, Faculty of Mathematics and Natural Sciences, University of Oslo, Oslo, Norway.
6
Department of Pathology, Oslo University Hospital, Oslo, Norway.
7
Faculty of Medicine, University of Oslo, Oslo, Norway.

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.

KEYWORDS:

Age of Onset; CIMP; Colon Cancer; DNA Methylation; Prognostic Factor

PMID:
28542846
PMCID:
PMC5518206
DOI:
10.1002/ijc.30796
[Indexed for MEDLINE]
Free PMC Article

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