Prognostic value of CpG island methylator phenotype among colorectal cancer patients: a systematic review and meta-analysis.
BACKGROUND
Divergent findings regarding the prognostic value of CpG island methylator phenotype (CIMP) in colorectal cancer (CRC) patients exist in current literature. We aim to review data from published studies in order to examine the association between CIMP and CRC prognosis.


METHODS
A comprehensive search for studies reporting disease-free survival (DFS), overall survival (OS), or cancer-specific mortality of CRC patients stratified by CIMP is carried out. Study findings are summarized descriptively and quantitatively, using adjusted hazard ratios (HRs) as summary statistics.


RESULTS
Thirty-three studies reporting survival in 10 635 patients are included for review. Nineteen studies provide data suitable for meta-analysis. The definition of CIMP regarding gene panel, marker threshold, and laboratory method varies across studies. Pooled analysis shows that CIMP is significantly associated with shorter DFS (pooled HR estimate 1.45; 95% confidence interval (CI) 1.07-1.97, Q = 3.95, I(2) = 0%) and OS (pooled HR estimate 1.43; 95% CI 1.18-1.73, Q = 4.03, I(2) = 0%) among CRC patients irrespective of microsatellite instability (MSI) status. Subgroup analysis of microsatellite stable (MSS) CRC patients also shows significant association between shorter OS (pooled HR estimate 1.37; 95% CI 1.12-1.68, Q = 4.45, I(2) = 33%) and CIMP. Seven studies have explored CIMP's value as a predictive factor on stage II and III CRC patient's DFS after receiving adjuvant 5-fluorouracil (5-FU) therapy: of these, four studies showed that adjuvant chemotherapy conferred a DFS benefit among CIMP(+) patients, one concluded to the contrary, and two found no significant correlation. Insufficient data was present for statistical synthesis of CIMP's predictive value among CRC patients receiving adjuvant 5-FU therapy.


CONCLUSIONS
CIMP is independently associated with significantly worse prognosis in CRC patients. However, CIMP's value as a predictive factor in assessing whether adjuvant 5-FU therapy will confer additional survival benefit to CRC patients remained to be determined through future prospective randomized studies.
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore.
Y Y
YY
Juo
Department of Surgery, Medical College of Wisconsin, Milwaukee.
F M
FM
Johnston
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore.
D Y
DY
Zhang
Department of Internal Medicine, Danbury Hospital, Danbury.
H H
HH
Juo
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore.
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H
Wang
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore.
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EP
Pappou
Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore.
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T
Yu
Department of Oncology.
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H
Easwaran
Department of Oncology; Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, USA; Department of Sidney Kimmel Cancer Center, Baltimore USA.
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S
Baylin
Department of pathology, GROW School for Oncology and Developmental Biology, Maastricht University Medical Center, Maastricht, the Netherlands.
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van Engeland
Department of Surgery, Johns Hopkins University School of Medicine, Baltimore; Department of Oncology; Department of Sidney Kimmel Cancer Center, Baltimore USA; Department of Urology, Johns Hopkins University School of Medicine, Baltimore, USA. Electronic address: nahuja@jhmi.edu.
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N
Ahuja
D015179:Colorectal Neoplasms / Q000235:genetics* / Q000473:pathology; D018899:CpG Islands; D019175:DNA Methylation; D006801:Humans; D010641:Phenotype; D011379:Prognosis
CIMP; adjuvant chemotherapy; colorectal cancer; epigenetics; prognosis; tumor marker