A cohort study of cyclin D1 expression and prognosis in 602 colon cancer cases.

Abstract

PURPOSE:

Cyclin D1 and cyclin-dependent kinases (CDK) are commonly activated in colorectal cancer. The activity of cyclin D1 can be blocked by CDK inhibitors, including p27 (CDKN1B) and p21 (CDKN1A, which is induced by p53). However, prognostic significance of tumoral cyclin D1 remains uncertain, and no previous study has considered potential confounding effect of p53, p21, p27, and related molecular events [microsatellite instability (MSI), CpG island methylator phenotype, and LINE-1 hypomethylation].

EXPERIMENTAL DESIGN:

Among 602 colon cancer patients (stage I-IV) in two prospective cohort studies, cyclin D1 overexpression was detected in 330 (55%) tumors by immunohistochemistry. Cox proportional hazard models computed hazard ratios (HR) of colon cancer-specific and overall mortalities, adjusted for patient characteristics and tumoral molecular features, including p53, p21, p27, cyclooxygenase-2, fatty acid synthase, LINE-1 methylation, CpG island methylator phenotype, MSI, BMI, KRAS, and BRAF.

RESULTS:

Cyclin D1 overexpression was associated with a low cancer-specific mortality in Kaplan-Meier analysis (P = 0.006), and in both univariate Cox regression [unadjusted HR, 0.64; 95% confidence interval (CI), 0.47-0.88; P = 0.0063] and multivariate analyses (adjusted HR, 0.57; 95% CI, 0.39-0.84; P = 0.0048). Similar findings were observed for an overall mortality (adjusted HR, 0.74; 95% CI, 0.57-0.98; P = 0.036). Notably, the effect of cyclin D1 on survival might differ by MSI status (P(interaction) = 0.008). Compared with tumors that were both cyclin D1-negative and MSI-low/microsatellite stable, the presence of either cyclin D1 or MSI-high or both seemed to confer better clinical outcome (adjusted HR point estimates, 0.10-0.65).

CONCLUSIONS:

Cyclin D1 overexpression is associated with longer survival in colon cancer.

• Authors: Shuji Ogino, Katsuhiko Nosho, Natsumi Irahara, Shoko Kure, Kaori Shima, Yoshifumi Baba, Saori Toyoda, Li Chen, Edward L Giovannucci, Jeffrey A Meyerhardt, Charles S Fuchs
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 13 Pg. 4431-8 (Jul 01 2009) ISSN: 1557-3265 [Electronic] United States
• PMID: 19549773 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Topics

• Aged
• Carcinoma (diagnosis, genetics, mortality)
• Case-Control Studies
• Cohort Studies
• Colonic Neoplasms (diagnosis, genetics, mortality)
• Female
• Follow-Up Studies
• Gene Expression Profiling
• Gene Expression Regulation, Neoplastic
• Genes, bcl-1
• Humans
• Male
• Middle Aged
• Prognosis
• Survival Analysis