CDK8 expression in 470 colorectal cancers in relation to β-catenin activation, other molecular alterations and patient survival

Autor: Ron Firestein, Emeric Bojarski, Katsuhiko Nosho, Natsumi Irahara, William C. Hahn, Shuji Ogino, Yoshifumi Baba, Edward Giovannucci, Kaori Shima, Charles S. Fuchs
Rok vydání: 2010
Předmět:
Proto-Oncogene Proteins B-raf
Cancer Research
Pathology
medicine.medical_specialty
Class I Phosphatidylinositol 3-Kinases
Colon
Colorectal cancer
Biology
medicine.disease_cause
Article
Cohort Studies
Immunoenzyme Techniques
Proto-Oncogene Proteins p21(ras)
Phosphatidylinositol 3-Kinases
Proto-Oncogene Proteins
medicine
Humans
Prospective Studies
RNA
Messenger
Prospective cohort study
Survival rate
beta Catenin
Aged
Oncogene
Reverse Transcriptase Polymerase Chain Reaction
Proportional hazards model
Microsatellite instability
Cancer
DNA Methylation
Cyclin-Dependent Kinase 8
Prognosis
medicine.disease
Fatty Acid Synthase
Type I
Survival Rate
Long Interspersed Nucleotide Elements
Oncology
Cyclooxygenase 2
Tissue Array Analysis
Case-Control Studies
Mutation
ras Proteins
Cancer research
Female
Microsatellite Instability
KRAS
Colorectal Neoplasms
Follow-Up Studies
Zdroj: International Journal of Cancer.
ISSN: 1097-0215
0020-7136
DOI: 10.1002/ijc.24908
Popis: 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 (p0.0001) 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.
Databáze: OpenAIRE
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