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

Ron Firestein, Kaori Shima, Katsuhiko Nosho, Natsumi Irahara, Yoshifumi Baba, Emeric Bojarski, Edward L. Giovannucci, William C. Hahn, Charles S Fuchs, Shuji Ogino

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Abstract

Alterations in the Wnt/β-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 β-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 β-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 β-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 β-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 β-catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis.

Original languageEnglish
Pages (from-to)2863-2873
Number of pages11
JournalInternational Journal of Cancer
Volume126
Issue number12
DOIs
Publication statusPublished - 15 Jun 2010
Externally publishedYes

Keywords

  • CDK8
  • Colon cancer
  • CTNNB1
  • FASN
  • Prognosis

Cite this

Firestein, Ron ; Shima, Kaori ; Nosho, Katsuhiko ; Irahara, Natsumi ; Baba, Yoshifumi ; Bojarski, Emeric ; Giovannucci, Edward L. ; Hahn, William C. ; Fuchs, Charles S ; Ogino, Shuji. / CDK8 expression in 470 colorectal cancers in relation to β-catenin activation, other molecular alterations and patient survival. In: International Journal of Cancer. 2010 ; Vol. 126, No. 12. pp. 2863-2873.
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abstract = "Alterations in the Wnt/β-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 β-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 β-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 β-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 β-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 β-catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis.",
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author = "Ron Firestein and Kaori Shima and Katsuhiko Nosho and Natsumi Irahara and Yoshifumi Baba and Emeric Bojarski and Giovannucci, {Edward L.} and Hahn, {William C.} and Fuchs, {Charles S} and Shuji Ogino",
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Firestein, R, Shima, K, Nosho, K, Irahara, N, Baba, Y, Bojarski, E, Giovannucci, EL, Hahn, WC, Fuchs, CS & Ogino, S 2010, 'CDK8 expression in 470 colorectal cancers in relation to β-catenin activation, other molecular alterations and patient survival', International Journal of Cancer, vol. 126, no. 12, pp. 2863-2873. https://doi.org/10.1002/ijc.24908

CDK8 expression in 470 colorectal cancers in relation to β-catenin activation, other molecular alterations and patient survival. / Firestein, Ron; Shima, Kaori; Nosho, Katsuhiko; Irahara, Natsumi; Baba, Yoshifumi; Bojarski, Emeric; Giovannucci, Edward L.; Hahn, William C.; Fuchs, Charles S; Ogino, Shuji.

In: International Journal of Cancer, Vol. 126, No. 12, 15.06.2010, p. 2863-2873.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - CDK8 expression in 470 colorectal cancers in relation to β-catenin activation, other molecular alterations and patient survival

AU - Firestein, Ron

AU - Shima, Kaori

AU - Nosho, Katsuhiko

AU - Irahara, Natsumi

AU - Baba, Yoshifumi

AU - Bojarski, Emeric

AU - Giovannucci, Edward L.

AU - Hahn, William C.

AU - Fuchs, Charles S

AU - Ogino, Shuji

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AB - Alterations in the Wnt/β-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 β-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 β-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 β-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 β-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 β-catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis.

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KW - Colon cancer

KW - CTNNB1

KW - FASN

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