CDK8 expression in 470 colorectal cancers in relation to beta-catenin activation, other molecular alterations and patient survival.
Alterations in the Wnt/beta-catenin pathway define a key event in the pathogenesis of colon cancer. We have recently shown that CDK8, the gene encoding a cyclin-dependent kinase (CDK) component of the Mediator complex, acts as a colon cancer oncogene that is necessary for beta-catenin activity. Here, we tested the hypothesis that colorectal cancers with CDK8 expression have distinct clinical, prognostic and molecular attributes. Among 470 colorectal cancers identified in 2 prospective cohort studies, CDK8 expression was detected in 329 (70%) tumors by immunohistochemistry. Cox proportional hazards model and backward stepwise elimination were used to compute hazard ratio (HR) of deaths according to CDK8 status, initially adjusted for various patient and molecular features, including beta-catenin, p53, p21, p27 (CDK inhibitors), cyclin D1, fatty acid synthase (FASN), cyclooxygenase-2 (COX-2), microsatellite instability (MSI), CpG island methylator phenotype (CIMP), LINE-1 methylation, and mutations in KRAS, BRAF and PIK3CA. CDK8 expression in colorectal cancer was independently associated with beta-catenin activation (p = 0.0002), female gender (p < 0.0001) and FASN overexpression (p = 0.0003). Among colon cancer patients, CDK8 expression significantly increased colon cancer-specific mortality in both univariate analysis [HR 1.70; 95% confidence interval (CI), 1.03-2.83; p = 0.039] and multivariate analysis (adjusted HR 2.05; 95% CI, 1.18-3.56; p = 0.011) that was adjusted for potential confounders including beta-catenin, COX-2, FASN, LINE-1 hypomethylation, CIMP and MSI. CDK8 expression was unrelated with clinical outcome among rectal cancer patients. These data support a potential link between CDK8 and beta-catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis.
Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, 44 Binney Street, Boston, MA 02115, USA.
Ron
R
Firestein
Kaori
K
Shima
Katsuhiko
K
Nosho
Natsumi
N
Irahara
Yoshifumi
Y
Baba
Emeric
E
Bojarski
Edward L
EL
Giovannucci
William C
WC
Hahn
Charles S
CS
Fuchs
Shuji
S
Ogino
D000368:Aged; D016022:Case-Control Studies; D058534:Class I Phosphatidylinositol 3-Kinases; D015331:Cohort Studies; D003106:Colon / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D056850:Cyclin-Dependent Kinase 8 / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019175:DNA Methylation; D054890:Fatty Acid Synthase, Type I / Q000378:metabolism; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D020084:Long Interspersed Nucleotide Elements; D053842:Microsatellite Instability; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011379:Prognosis; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras); D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D046888:Tissue Array Analysis; D051176:beta Catenin / Q000378:metabolism*; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism
C495270:CTNNB1 protein, human; C117307:KRAS protein, human; D011518:Proto-Oncogene Proteins; D012333:RNA, Messenger; D051176:beta Catenin; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C518729:FASN protein, human; D054890:Fatty Acid Synthase, Type I; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C095686:CDK8 protein, human; D056850:Cyclin-Dependent Kinase 8; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins