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A Cohort Study of Cyclin D1expression and Prognosis In Imaging, Diagnosis, Prognosis A Cohort Study of Cyclin D1 Expression and Prognosis in 602 Colon Cancer Cases Shuji Ogino,1, 2 , 3 Katsuhiko Nosho,1Natsumi Irahara,1Shoko Kure,1Kaori Shima,1Yo s hi f u m i B a b a , 1 SaoriToyoda,1Li Chen,2 Edward L. Giovannucci,3,4 Jeffrey A. Meyerhardt,1and Charles S. Fuchs1,4 Abstract Purpose: Cyclin D1 and cyclin-dependent kinases (CDK) are commonly activated in colorectal cancer. The activity of cyclin D1can 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-1hypomethylation]. Experimental Design: Among 602 colon cancer patients (stage I-IV) in two prospective cohort studies, cyclin D1overexpression 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-1methylation, CpG island methylator phenotype, MSI, BMI, KRAS,andBRAF. 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 D1on survival might differ by MSI status (Pinteraction = 0.008). Compared with tumors that were both cyclin D1^ negative and MSI-low/microsatellite stable, the presence of either cyclin D1or MSI-high or both seemed to confer better clinical outcome (adjusted HR point estimates, 0.10-0.65). Conclusions: Cyclin D1overexpression is associated with longer survival in colon cancer. Cyclin D1 (CCND1, the official gene symbol) plays a key role Authors’ Affiliations: 1Department of Medical Oncology, Dana-Farber Cancer in cell cycle control, particularly in the transition from G to S 2 1 Institute and Harvard Medical School; Department of Pathology, Brigham and phase, which is regulated by cyclin-dependent kinases (1). The Women’s Hospital, Boston and Harvard Medical School; 3Department of Epidemiology, Harvard School of Public Health; and 4Channing Laboratory, ability of cyclin D1 to drive the cell cycle forward can be Department of Medicine, Brigham and Women’s Hospital and Harvard Medical blocked by cyclin-dependent kinase (CDK) inhibitors, such as School, Boston, Massachusetts p27 (CDKN1B) and p21 (CDKN1A, which is induced by Received12/29/08;revised3/16/09;accepted4/7/09;publishedOnlineFirst 6/23/09. p53; ref. 1). Cyclin D1 overexpression occurs in one-third or Grant support: U.S. NIH P01 CA87969 (S. Hankinson), P01 CA55075 (W. more of colorectal cancers (2–20). Cyclin D1 activation by Willett), P50 CA127003 (C.S. Fuchs), K07 CA97992 (J.A. Meyerhardt), and K07 CA122826 (S. Ogino); the Bennett Family Fund; and the Entertainment APC mutation/WNT signaling seems to contribute to colon Industry Foundation National Colorectal Cancer Research Alliance. K. Nosho neoplasia initiation (21, 22). was supported by a fellowship grant from the Japan Society for Promotion of Despite a well-established role of cyclin D1 in cell cycle Science. The content is solely the responsibility of the authors and does not progression, previous data on cyclin D1 and clinical outcome necessarily represent the official views of National Cancer Institute or NIH. Funding agencies did not have any role in the design of the study; the in colon cancer have been conflicting (4–20). Although cyclin collection, analysis, or interpretation of the data; the decision to submit the D1 expression has been associated with poor prognosis in two manuscript for publication; or the writing of the manuscript. studies (4, 5), another study showed good prognosis The costs of publication of this article were defrayed in part by the payment of associated with cyclin D1 expression (6), and most page charges. This article must therefore be hereby marked advertisement in studies revealed no independent prognostic value of cyclin accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Note: Supplementary data for this article are available at Clinical Cancer D1 (7–20). However, most previous studies had limited Research Online (http://clincancerres.aacrjournals.org/). sample sizes, and only three studies (11, 15, 16) had sample Requests for reprints: ShujiOgino,CenterforMolecularOncologicPathology, sizes >170 (up to n = 363; ref. 16). In addition, cyclin D1 Dana-Farber Cancer Institute, Brigham and Women’s Hospital, Harvard Medical expression in colon cancer is related with microsatellite School, 44 Binney Street, Room JF-215C, Boston, MA 02115. Phone: 617-632- 3978; Fax: 617-582-8558; E-mail: [email protected]. instability (MSI), the CpG island methylator phenotype F 2009 American Association for Cancer Research. (CIMP), and BRAF mutation (23). Although these molecular doi:10.1158/1078-0432.CCR-08-3330 features have been associated with patient outcome (24–26), www.aacrjournals.org 4431 Clin Cancer Res 2009;15(13) July 1, 2009 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2009 American Association for Cancer Research. Imaging, Diagnosis, Prognosis underwent tumor resections (28). Tissue sections from all colon cancer Translational Relevance cases were reviewed and confirmed by a pathologist (S.O.). Tumor grade was categorized as high (V50% glandular area) or low (>50% Cyclin D1and cyclin-dependent kinase (CDK) activation glandular area). Based on availability of tissue samples, we included a has been shown to play an important role in carcinogenesis total of 602 stage I to IV colon cancer cases diagnosed up to 2002. There f in various organ systems including colon. CDK inhibitors were only 2.5% of Asians, Hispanics, and African Americans and the have been shown to be effective in cancer treatment.How- remaining 97.5% were non-Hispanic Caucasians. Written informed consent was obtained from all study subjects. This study was approved ever, the relation between cyclin D1expression in colon by the Human Subjects Committees at Brigham and Women’s Hospital cancer and patient survival has been controversial. We and the Harvard School of Public Health. have used the database of >600 colon cancer in two Measurement of mortality. Patients were observed until death or independent, prospective cohort studies, with available June 2006, whichever came first. Ascertainment of deaths included clinical information, adequate follow-up, and other reporting by the family or postal authorities. In addition, the names of important molecular events in colon cancers. To our persistent nonresponders were searched in the National Death Index. knowledge, this is the first large study to show influence The cause of death was assigned by physicians blinded to information of cyclin D1expression on clinical outcome independent of on life-style exposures and molecular changes in colon cancer. In rare related molecular events including p53, p21, p27, KRAS, patients who died as a result of colon cancer not previously reported, BRAF mutation, microsatellite instability, the CpG island we obtained medical records with permission from next of kin. More methylator phenotype, and LINE-1hypomethylation, all of than 98% of deaths in the cohorts were identified by these methods. DNA extraction, pyrosequencing of KRAS and BRAF,andMSI which are potential confounders. Thus, our findings are analysis. Genomic DNA from paraffin-embedded tissue was extracted, relevant to practice in oncology. and whole genome amplification was done (29). PCR and Pyrose- quencing targeted for KRAS codons 12 and 13 (29), and BRAF codon 600, were done (30). MSI status was determined using 10 microsatellite none of the previous studies (4–20) has considered con- markers (D2S123, D5S346, D17S250, BAT25, BAT26, BAT40, D18S55, founding or modifying effect of MSI, CIMP, and BRAF. D18S56, D18S67, and D18S487; ref. 31). MSI-high was defined as the In this study, using a large number (n = 602) of stage I to IV presence of instability in z30% of the markers, MSI-low as the presence colon cancers in two independent cohort studies, we have of instability in <30% of the markers, and microsatellite stability (MSS) examined the effect of cyclin D1 expression in colon cancer on as no unstable marker. patient survival. Because we concurrently assessed other related Real-time PCR (MethyLight) to determine CIMP status. Sodium molecular variables including p53, p21, p27, KRAS, BRAF, MSI, bisulfite treatment on tumor DNA and subsequent real-time PCR (MethyLight) assays were validated and done as previously described CIMP, and LINE-1 hypomethylation, we could evaluate the (32). We quantified promoter methylation in 8 CIMP-specific independent effect of cyclin D1 after controlling for these genes (CACNA1G, CDKN2A, CRABP1, IGF2, MLH1, NEUROG1, potential confounders. In particular, it is important to control RUNX3, and SOCS1; refs. 33–35). CIMP-high was defined as z6/ for the effect of MSI, CIMP, and LINE-1 hypomethylation 8 methylated promoters using the 8-marker CIMP panel, CIMP-low/0 because these molecular characteristics reflect genomic and as 0 to 5 methylated promoters, according to the previously established epigenomic status of cancer cells, and have been related with criteria (34). patient survival in colon cancer (24–27). Pyrosequencing to measure LINE-1 methylation. In order to accu- rately quantify relatively high LINE-1 methylation levels, we used Pyrosequencing as previously described (27). Materials and Methods Immunohistochemistry for cyclin D1, p53, p21, p27, cyclooxygenase-2 and fatty acid synthase. Tissue microarrays were constructed as Study population. We used the databases of two independent previously described (37).
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