Ron Firestein 1, 2, 3, *, Kaori Shima 2, Katsuhiko Nosho 2, Natsumi Irahara 2, Yoshifumi Baba 2, Emeric Bojarski 2, Edward L. Giovannucci 4, 5, Charles S. Fuchs 2, 4, and Shuji Ogino 1, 2, *
1 Dept. of Pathology, Brigham and Women's Hospital and
Harvard Medical School, Boston, MA, USA
2 Dept. Medical Oncology, Dana-Farber Cancer Institute
and Harvard Medical School, Boston, MA, USA
3 Broad Institute of Massachusetts Institute of Technology
and Harvard, Cambridge, MA, USA
4 Channing Laboratory, Dept. of Medicine, Brigham and
Women's Hospital and Harvard Medical School, Boston,
MA, USA
5 Departments of Epidemiology and Nutrition, Harvard
School of Public Health, Boston, MA, USA
email: Ron Firestein (firestein.ron@gene.com); Shuji Ogino (shuji_ogino@dfci.harvard.edu)
*Correspondence to Ron Firestein, Department of Pathology, Genentech, Inc., 1 DNA Way, South San Francisco, CA 94080 USA
*Correspondence to Shuji Ogino, Center for Molecular Oncologic Pathology, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Harvard Medical School, 44 Binney St., Room JF-215C, Boston, MA 02115 USA
WCH, CSF and SO are co-senior authors.
Ph: +1-617-632-3978; Fax: +1-617-582-8558
Funded by:
U.S. National Institute of Health; Grant Number: P01 CA87969,
P01 CA55075, P50 CA127003, R33 CA128625, K07 CA122826, K08 CA134836
Bennett Family Fund for Targeted Therapies Research
Entertainment Industry Foundation National Colorectal Cancer
Research Alliance
Japan Society for Promotion of Science
Keywords
colon cancer • CDK8 • prognosis • CTNNB1 • FASN
Alterations in the Wnt/b-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 b-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 two 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 b-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 b-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 b-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 b-catenin, and suggest that CDK8 may identify a subset of colon cancer patients with a poor prognosis.
Received: 10 July 2009; Revised: 28 August 2009; Accepted: 2 September 2009
1. Ron Firestein and William C. Hahn, "Revving the Throttle
on an Oncogene: CDK8 Takes the Driver Seat", Cancer Research, 69: (20),
7899-7901 (October 15, 2009).
http://cancerres.aacrjournals.org/cgi/content/full/69/20/7899
2. Moses O. Gold and Andrew P. Rice, "Targeting of CDK8 to a promoter-proximal RNA element demonstrates catalysis-dependent activation of gene expression". Nucleic Acid Research, 26: (16), 3784-3788 (1998).
1: CDK8 expression in 470 colorectal cancers in relation to beta-catenin
activation, other molecular alterations and patient survival.
Firestein R, Shima K, Nosho K, Irahara N, Baba Y, Bojarski E, Giovannucci
EL, Fuchs CS, Ogino S.
Int J Cancer. 2009 Sep 29. [Epub ahead of print]
PMID: 19790197 [PubMed - as supplied by publisher]
Related Articles
2: A cohort study of p27 localization in colon cancer, body mass
index, and patient survival.
Ogino S, Shima K, Nosho K, Irahara N, Baba Y, Wolpin BM, Giovannucci
EL, Meyerhardt JA, Fuchs CS.
Cancer Epidemiol Biomarkers Prev. 2009 Jun;18(6):1849-58.
PMID: 19505918 [PubMed - indexed for MEDLINE]
Related Articles
3: A cohort study of cyclin D1 expression and prognosis in 602 colon
cancer cases.
Ogino S, Nosho K, Irahara N, Kure S, Shima K, Baba Y, Toyoda S,
Chen L, Giovannucci EL, Meyerhardt JA, Fuchs CS.
Clin Cancer Res. 2009 Jul 1;15(13):4431-8. Epub 2009 Jun 23.
PMID: 19549773 [PubMed - indexed for MEDLINE]
Related Articles
4: A cohort study of STMN1 expression in colorectal cancer: body
mass index and prognosis.
Ogino S, Nosho K, Baba Y, Kure S, Shima K, Irahara N, Toyoda S,
Chen L, Kirkner GJ, Wolpin BM, Chan AT, Giovannucci EL, Fuchs CS.
Am J Gastroenterol. 2009 Aug;104(8):2047-56. Epub 2009 Jun 9.
PMID: 19513025 [PubMed - indexed for MEDLINE]
Related Articles
5: Colorectal cancer expression of peroxisome proliferator-activated
receptor gamma (PPARG, PPARgamma) is associated with good prognosis.
Ogino S, Shima K, Baba Y, Nosho K, Irahara N, Kure S, Chen L, Toyoda
S, Kirkner GJ, Wang YL, Giovannucci EL, Fuchs CS.
Gastroenterology. 2009 Apr;136(4):1242-50. Epub 2008 Dec 24.
PMID: 19186181 [PubMed - indexed for MEDLINE]
Related Articles
6: SIRT1 histone deacetylase expression is associated with microsatellite
instability and CpG island methylator phenotype in colorectal cancer.
Nosho K, Shima K, Irahara N, Kure S, Firestein R, Baba Y, Toyoda
S, Chen L, Hazra A, Giovannucci EL, Fuchs CS, Ogino S.
Mod Pathol. 2009 Jul;22(7):922-32. Epub 2009 May 8.
PMID: 19430421 [PubMed - indexed for MEDLINE]
Related Articles
7: JC virus T-antigen in colorectal cancer is associated with p53
expression and chromosomal instability, independent of CpG island methylator
phenotype.
Nosho K, Shima K, Kure S, Irahara N, Baba Y, Chen L, Kirkner GJ,
Fuchs CS, Ogino S.
Neoplasia. 2009 Jan;11(1):87-95.
PMID: 19107235 [PubMed - indexed for MEDLINE]
Related Articles Free article in PMC | at journal site
8: Relationship of CDX2 loss with molecular features and prognosis
in colorectal cancer.
Baba Y, Nosho K, Shima K, Freed E, Irahara N, Philips J, Meyerhardt
JA, Hornick JL, Shivdasani RA, Fuchs CS, Ogino S.
Clin Cancer Res. 2009 Jul 15;15(14):4665-73. Epub 2009 Jul 7.
PMID: 19584150 [PubMed - indexed for MEDLINE]
Related Articles
9: Fatty acid synthase overexpression in colorectal cancer is associated
with microsatellite instability, independent of CpG island methylator phenotype.
Ogino S, Kawasaki T, Ogawa A, Kirkner GJ, Loda M, Fuchs CS.
Hum Pathol. 2007 Jun;38(6):842-9. Epub 2007 Mar 12.
PMID: 17350669 [PubMed - indexed for MEDLINE]
Related Articles
10: Aurora-A expression is independently associated with chromosomal
instability in colorectal cancer.
Baba Y, Nosho K, Shima K, Irahara N, Kure S, Toyoda S, Kirkner GJ,
Goel A, Fuchs CS, Ogino S.
Neoplasia. 2009 May;11(5):418-25.
PMID: 19412426 [PubMed - indexed for MEDLINE]
Related Articles Free article in PMC | at journal site
11: A Prospective Cohort Study Shows Unique Epigenetic, Genetic,
and Prognostic Features of Synchronous Colorectal Cancers.
Nosho K, Kure S, Irahara N, Shima K, Baba Y, Spiegelman D, Meyerhardt
JA, Giovannucci EL, Fuchs CS, Ogino S.
Gastroenterology. 2009 Aug 14. [Epub ahead of print]
PMID: 19686742 [PubMed - as supplied by publisher]
Related Articles
12: DNMT3B expression might contribute to CpG island methylator
phenotype in colorectal cancer.
Nosho K, Shima K, Irahara N, Kure S, Baba Y, Kirkner GJ, Chen L,
Gokhale S, Hazra A, Spiegelman D, Giovannucci EL, Jaenisch R, Fuchs CS,
Ogino S.
Clin Cancer Res. 2009 Jun 1;15(11):3663-71. Epub 2009 May 26.
PMID: 19470733 [PubMed - indexed for MEDLINE]
Related Articles
13: p21 expression in colon cancer and modifying effects of patient
age and body mass index on prognosis.
Ogino S, Nosho K, Shima K, Baba Y, Irahara N, Kirkner GJ, Hazra
A, De Vivo I, Giovannucci EL, Meyerhardt JA, Fuchs CS.
Cancer Epidemiol Biomarkers Prev. 2009 Sep;18(9):2513-21. Epub 2009 Sep 1.
PMID: 19723919 [PubMed - in process]
Related Articles
14: CpG island methylator phenotype, microsatellite instability,
BRAF mutation and clinical outcome in colon cancer.
Ogino S, Nosho K, Kirkner GJ, Kawasaki T, Meyerhardt JA, Loda M,
Giovannucci EL, Fuchs CS.
Gut. 2009 Jan;58(1):90-6. Epub 2008 Oct 2.
PMID: 18832519 [PubMed - indexed for MEDLINE]
Related Articles
15: Cohort study of fatty acid synthase expression and patient survival
in colon cancer.
Ogino S, Nosho K, Meyerhardt JA, Kirkner GJ, Chan AT, Kawasaki T,
Giovannucci EL, Loda M, Fuchs CS.
J Clin Oncol. 2008 Dec 10;26(35):5713-20. Epub 2008 Oct 27.
PMID: 18955444 [PubMed - indexed for MEDLINE]
Related Articles
16: Vitamin D receptor expression is associated with PIK3CA and
KRAS mutations in colorectal cancer.
Kure S, Nosho K, Baba Y, Irahara N, Shima K, Ng K, Meyerhardt JA,
Giovannucci EL, Fuchs CS, Ogino S.
Cancer Epidemiol Biomarkers Prev. 2009 Oct;18(10):2765-72. Epub 2009 Sep 29.
PMID: 19789368 [PubMed - in process]
Related Articles
17: PIK3CA mutation is associated with poor prognosis among patients
with curatively resected colon cancer.
Ogino S, Nosho K, Kirkner GJ, Shima K, Irahara N, Kure S, Chan AT,
Engelman JA, Kraft P, Cantley LC, Giovannucci EL, Fuchs CS.
J Clin Oncol. 2009 Mar 20;27(9):1477-84. Epub 2009 Feb 23.
PMID: 19237633 [PubMed - indexed for MEDLINE]
Related Articles
18: Cyclooxygenase-2 expression is an independent predictor of poor
prognosis in colon cancer.
Ogino S, Kirkner GJ, Nosho K, Irahara N, Kure S, Shima K, Hazra
A, Chan AT, Dehari R, Giovannucci EL, Fuchs CS.
Clin Cancer Res. 2008 Dec 15;14(24):8221-7.
PMID: 19088039 [PubMed - indexed for MEDLINE]
Related Articles
19: Comprehensive biostatistical analysis of CpG island methylator
phenotype in colorectal cancer using a large population-based sample.
Nosho K, Irahara N, Shima K, Kure S, Kirkner GJ, Schernhammer ES,
Hazra A, Hunter DJ, Quackenbush J, Spiegelman D, Giovannucci EL, Fuchs
CS, Ogino S.
PLoS One. 2008;3(11):e3698. Epub 2008 Nov 12.
PMID: 19002263 [PubMed - indexed for MEDLINE]
Related Articles Free article in PMC | at journal site
20: Correlation of beta-catenin localization with cyclooxygenase-2
expression and CpG island methylator phenotype (CIMP) in colorectal cancer.
Kawasaki T, Nosho K, Ohnishi M, Suemoto Y, Kirkner GJ, Dehari R,
Meyerhardt JA, Fuchs CS, Ogino S.
Neoplasia. 2007 Jul;9(7):569-77.
PMID: 17710160 [PubMed - indexed for MEDLINE]
Related Articles Free article in PMC | at journal site
Links to Current
Research in Euchromatin:
Links to
Euchromatin Activator RNA Reviews:
Links to
Euchromatin Activator RNA Research:
Links to Ultrastructural
Probes of DNase I-Sensitive Sites:
Links to
RNA as a Therapeutic Agent:
Links to Hodgkin Lymphoma
Immuno-Pathology:
Links to Activated
T-Lymphocyte Immunotherapy:
Links to Medical
Systems Biology:
Links to Selective
Gene Transcription:
Links to RNA-Induced
Epigenetics:
Links to RNA-Induced
Embryogenesis:
Links to RNA and
Biological Causality:
Links to Reprogramming
and Neoplasia:
A Brief History of Activator RNA:
"Ultrastructural
Probes of Active DNA Sites, and the RNA Activators of DNA".
(PowerPoint Presentation).
Top of Page - Euchromatin
Network - Euchromatin
Research - Research
in Quantitative Radiology
For Further Information and Feedback:
Jeannette A. Hovsepian, M.D.
E-mail: frensasc@ix.netcom.com
Phone: +1 650 367 6483