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


METHODS
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.
Ogino
Shuji
S
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, USA. shuji_ogino@dfci.harvard.edu
Nosho
Katsuhiko
K
Irahara
Natsumi
N
Kure
Shoko
S
Shima
Kaori
K
Baba
Yoshifumi
Y
Toyoda
Saori
S
Chen
Li
L
Giovannucci
Edward L
EL
Meyerhardt
Jeffrey A
JA
Fuchs
Charles S
CS
D000368:Aged; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D016022:Case-Control Studies; D015331:Cohort Studies; D003110:Colonic Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000401:mortality; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D019940:Genes, bcl-1; D006801:Humans; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D016019:Survival Analysis