Significance Of Cyclin D1 Overexpression Research Articles

Significance of cyclin D1 overexpression for the diagnosis of mantle cell lymphoma: a clinicopathologic comparison of cyclin D1-positive MCL and cyclin D1-negative MCL-like B-cell lymphoma

AbstractMantle cell lymphoma (MCL) is a distinct clinicopathologic entity of non-Hodgkin’s lymphoma, characterized by a monotonous proliferation of small to medium-sized lymphocytes with co-expression of CD5 and CD20, an aggressive and incurable clinical course, and frequent t(11;14)(q13;q32) translocation. We examined 151 cases of lymphoma with MCL morphology from a viewpoint of cyclin D1 overexpression, which is now easily detectable by immunohistochemistry. 128 cases (85%) showed positive nuclear staining for cyclin D1, while the remaining 23 (15%) were negative. Except for cyclin D1 immunohistochemistry, current diagnostic methods, including morphological and phenotypical examinations, could not make this distinction. Although both the cyclin D1-positive and -negative groups were characterized by male predominance, advanced stages of the disease, frequent extranodal involvement, and low CD23 reactivity, the cyclin D1-positive group showed a higher age distribution (P = .04), larger cell size (P = .02), higher mitotic index (P = .01), more frequent gastrointestinal involvement (P = .05), higher international prognostic index score (P = .05), and lower p27KIP1 expression (P < .0001). Of particular interest is that cyclin D1-positive MCL showed significantly worse survival than cyclin D1-negative lymphoma (5-year survival: 30% versus 86%, P = .0002), which was confirmed by multivariate analysis to be independent of other risk factors. These data suggest that cyclin D1-positive and -negative groups may represent different entities and that the former closely fits the characteristics of classical, typical MCL. We therefore propose that cyclin D1-positivity should be included as one of the standard criteria for MCL, and that innovative therapies for this incurable disease should be explored on the basis of the new criteria. (Blood. 2000;95:2253-2261

Prognostic Significance of Cyclin D1 Over-expression in Colorectal Cancer: An Experience from Madinah, Saudi Arabia.

Background and study aim: Cyclin D1 is a key regulatory protein in the cell cycle and is over-expressed in many tumors, including endometrial, thyroid, urothelial, breast, brain gliomas, and esophageal cancers. The main aim of the present study is to examine the expression pattern of cyclin D1 and its correlation with the different clinicopathological features in patients with colorectal camcer (CRC) from the Madinah region of Saudi Arabia. Patients and methods:The archival tumor blocks were analyzed using immunohistochemistry for Cyclin D1 over-expression in 324 CRC patients diagnosed from January 2006 to December 2017, at the Department of Pathology, King Fahad Hospital, Madinah, Saudi Arabia.Results: Cyclin D1 over-expression was absent in normal mucosa, while 15% cases of adenoma showed its over-expression. In CRC, Cyclin D1 was expressed at high levels in 24.1% of case. No significant correlation was observed between Cyclin D1 over-expression and age, gender, tumor size, type and location. However, Cyclin D1 over-expression exhibited a significant correlation with tumor differentiation (p=0.04), lymph node involvement (p=0.001), lymphovascular invasion (p=0.001), distant metastasis (p=0.006) and AJCC staging (p=0.001). The Kaplan-Meir analysis revealed a shorter period of survival with Cyclin D1 over-expression (p=0.000). The Cox-regression model analysis showed that Cyclin D1 over-expression was an independent prognostic marker in CRC (p=0.000). Conclusion: Cyclin D1 over-expression increases during normal-adenoma-carcinoma sequence. The significant association observed between Cyclin D1 over-expression, advanced tumor stage and short survival period clearly suggest the role of Cyclin D1 in the carcinogenesis and progression of CRC.

Significance of cyclin D1 overexpression in progression and radio-resistance of pediatric ependymomas.

Due to the limited efficacy of chemotherapy, the applications of adjuvant irradiation play an important role for ependymoma treatment. However, in the young ages, the resistance of residual and recurrent tumor, and long-term intellectual sequelae remain the major obstacles of radiotherapy. Understanding the mechanism of therapeutic failure caused by radio-resistance is, therefore, crucial in ependymoma treatment. Here we retrospectively analyze clinic-pathological factors in 82 cases of ependymoma less than 20 years old and identify radio-resistant genes through gene expression microarray followed by qRT-PCR validation and immunohistochemistry staining. Thirty-one out of 82 (37.8%) patients are under 3-year-old. The 10 years PFS and OS are 38% and 60%. Gross-total resection is the single significant prognostic factor for longer 10 years PFS and OS in the multivariant analysis (p<0.05). According to the microarray analysis, CCND1 is up-regulated in supratentorial and infratentorial ependymomas and is associated with DNA repair. We demonstrated that 24 primary and 16 recurrent ependymomas were up-regulated, and 5 out of 7 paired samples exhibited higher CCND1 expression in recurrent tumors. We also found RAD51, another DNA repair gene, was up-regulated in supratentorial and infratentorial ependymomas. Knocking down CCND1 reduced cell proliferation and repressed several genes associated with S-phase and DNA repair. Homologous recombination activities of DNA repair were significantly decreased in CCND1-deficient cells while the level of γH2AX was increased after irradiation. In summary, these observations suggest a robust role of CCND1 in regulating cell proliferation and radio-resistance in ependymomas, providing a potential therapeutic target for pediatric ependymomas.

Cyclin D1 Overexpression Is Associated with Poor Clinicopathological Outcome and Survival in Oral Squamous Cell Carcinoma in Asian Populations: Insights from a Meta-Analysis

BackgroundThe clinicopathological significance of cyclin D1 overexpression and prognosis of oral squamous cell carcinoma has not been fully quantified. We performed a comprehensive meta-analysis for evaluation of cyclin D1 overexpression in oral squamous cell carcinoma to determine the strength of this association.MethodsUsing both medical subheadings and free terms, we searched PubMed, Embase and the Institute for Scientific Information Web of Science for all eligible studies published before Nov. 2013. We retrieved 1674 citations, determining that 15 met the selection criteria. We used the odds ratio (OR) and hazard ratio (HR) as the common measures of association to quantitatively determine the correlation between cyclin D1 overexpression and outcomes of oral cancer. We performed a meta-analysis and heterogeneity, sensitivity, and subgroup analyses to clarify and validate the pooled results.ResultsThe pooled results provided compelling evidence that cyclin D1 overexpression was significantly correlated with increased tumor size (OR = 1.617, 95% confidence interval [CI] = 1.046–2.498, p = 0.031), lymphoid node metastasis (OR = 2.035, 95% CI = 1.572–2.635, p<0.001), tumor differentiation (OR = 1.976, 95% CI = 1.363–2.866, p<0.001), and advancement of clinical stages (OR = 1.516, 95% CI = 1.140–2.015, p = 0.004), and adversely influenced overall survival of OSCC patients (HR = 1.897, 95% CI = 1.577–2.282, p<0.001). The strength of association varied in different oral cavity subsites.ConclusionOur findings indicated that cyclin D1 expression correlates with detrimental clinicopathological outcome and poor prognosis in oral squamous cell carcinoma. Our results may be useful in the management of oral cancer.

Significance of Cyclin D1 Overexpression and Amplification in Ductal Hyperplasia, Carcinoma in situ and Invasive Carcinoma in Egyptian Female Breast

Significance of Cyclin D1 Overexpression and Amplification in Ductal Hyperplasia, Carcinoma in situ and Invasive Carcinoma in Egyptian Female Breast

CCND1 amplification and cyclin D1 expression in breast cancer and their relation with proteomic subgroups and patient outcome

Despite strong evidence regarding the role of CCND1 amplification and protein overexpression in breast carcinoma, the associations between CCND1 amplification/cyclin D1 overexpression and clinicopathological variables and clinical outcome remain controversial. (1) to correlate cyclin D1 expression with gene amplification; (2) to analyse the correlations between CCND1 amplification and overexpression with clinicopathological features and patients' outcome in invasive breast cancer; (3) to define the prevalence and clinical significance of cyclin D1 overexpression and CCND1 amplification in ER positive breast carcinomas (4) to define the prevalence of cyclin D1 overexpression and CCND1 amplification in breast cancers with basal-like immunophenotype. CCND1 amplification and protein expression were assessed on a tissue microarray containing 880 unselected invasive breast cancer cases, by means of chromogenic in situ hybridisation using the Spotlight CCND1 amplification probe and immunohistochemistry, using the rabbit monoclonal antibody SP4. A total of 59/613 tumours (9.6%) showed CCND1 amplification and 224/514 (43.6%) showed strong cyclin D1 expression. A strong positive correlation between CCND1 amplification and higher levels of cyclin D1 expression was found (P < 0.001). Basal-like cancers showed infrequent CCND1 amplification and cyclin D1 overexpression (P < 0.001). Both CCND1 amplification and cyclin D1 expression were associated with positive ER status. CCND1 gene amplification was an independent prognostic factor for patients with ER positive breast cancer. Our results demonstrate a strong correlation between CCND1 amplification and its protein expression in breast cancer. However, protein expression is more pervasive than gene amplification and associated with ER expression.

Prognostic significance of cyclin D1 overexpression in patients (pts) with primary breast cancer (BC)

Prognostic significance of cyclin D1 overexpression in patients (pts) with primary breast cancer (BC)

Prognostic significance of cyclin D1 overexpression in patients (pts) with primary breast cancer (BC)

9714 Background: Cyclin D1, a key cell cycle regulator, is overexpressed in approximately 50% of BCs. Previous studies yielded conflicting results on the prognostic importance of cyclin D1 in BC. In this study, we evaluated overexpression of cyclin D1 in primary BC to determine any relation to clinicopathologic factors and its impact on survival. Methods: Formalin fixed tissue samples from 119 pts diagnosed with primary BC in 1996 and 1997 were analyzed for cyclin D1 expression by immunohistochemistry (IHC). A scoring system based on intensity and proportion of staining cells was used to judge cyclin D1 overexpression. ER, PR, Her2-Neu, p53 and Ki-67 expression by IHC and nuclear grade (NG) and histologic grade were determined at the time of diagnosis. OS and DFS curves were estimated by the method of Kaplan-Meier using log rank statistics. Clinicopathologic variables were included in Cox proportional hazards model to determine significance. Results: Cyclin D1 overexpression was observed in 68 of the 119 pts (57%). There was a positive correlation between cyclin D1 overexpression and ER expression (p=0.005) and an inverse correlation between cyclin D1 overexpression and both TNM stage and tumor size (p=0.009 and 0.042). Median follow up was 57 months. In univariate analysis, younger age, nodal involvement and higher NG were associated with poorer DFS (p=0.016, 0.001 and 0.026) and OS (p<0.001, p=0.016 and 0.036). Cyclin D1 had no influence on DFS or OS regardless of the cut point used to define overexpression. Among the ER positive subgroup however, there was a trend for improved OS in pts with cyclin D1 negative tumors (p=0.08). In contrast, cyclin D1 expression did not influence OS in ER negative subset. When ER positive pts with ductal carcinoma histology were considered, cyclin D1 negativity was associated with a better prognosis (p=0.053). In multivariate analyses of DFS and OS, only the nodal status (p=0.031 and 0.023) and NG (p=0.029 and 0.039) remained statistically significant. Conclusions: Cyclin D1 overexpression is not an independent predictor of prognosis in BC. In ER positive subgroup however, there is a trend for improved survival in cyclin D1 negative pts. No significant financial relationships to disclose.

Immunohistochemical analysis of cyclin D1 and p53 in multiple myeloma: relationship to proliferative activity and prognostic significance.

Conflicting data are reported on the clinical significance of cyclin D1 deregulation in multiple myeloma. The aim of this study was to evaluate the incidence and prognostic significance of cyclin D1 expression and p53 mutations in multiple myeloma, as well as the relationship of their expression with selected clinical data, histological features, and proliferative activity of myeloma cells. We analyzed bone marrow biopsy specimens obtained from 59 patients with newly diagnosed multiple myeloma. Expression of cyclin D1 and p53 was analyzed using standard immunohistochemical method of B5-fixed and routinely processed paraffin-embedded bone marrow specimens. Cyclin D1 was overexpressed in 14/59 (27%) and p53 in 5/59 (8.5%) specimens. There was no significant correlation between cyclin D1 overexpression and age, gender, clinical stage (Durie-Salmon classification), extent of osteolytic lesions, type of monoclonal protein, hemoglobin concentration, platelet count, serum concentration of creatinine, calcium, C-reactive protein, and beta2-microglobulin. No association was observed between the expression of cyclin D1 and the extent of bone marrow infiltration, histological grade, proliferative activity index (measured with Ki-67 immunoreactivity) and response to therapy. No significant difference was observed regarding overall survival between cyclin D1 positive and cyclin D1 negative patients (29 vs 36 mo, p = 0.76). Results of this study did not revealed prognostic significance of cyclin D1 overexpression in multiple myeloma. Mutations of p53 gene are rare events in myeloma, suggesting their limited role in the pathogenesis of the disease.

Significance of Cyclin D1 Overexpression in Transitional Cell Carcinomas of the Urinary Bladder and its Correlation With Histopathologic Features

BACKGROUND. Genetic alterations leading to neoplastic transformation of the uroChyi Chia R. Lee, M.D. thelium are likely to involve the activation of oncogenes and loss of functional Shinji Yamamoto, M.D. tumor suppressor genes. Cyclin D1 has been implicated as a putative protooncoKeiichirou Morimura, M.D. gene whereas mutations of the p53 gene occur frequently in invasive transitional Hideki Wanibuchi, M.D. cell carcinomas (TCCs) of the urinary bladder. In this study, cyclin D1 overexNobuyasu Nishisaka, M.D. pression and nuclear accumulation of p53 were evaluated and the results correlated Shinichi Ikemoto, M.D. with histopathologic features. Tatsuya Nakatani, M.D. METHODS. TCCs of the urinary bladder from 161 surgical procedures were evaluSeiji Wada, M.D. ated for cyclin D1 overexpression and nuclear accumulation of p53. Results were Taketoshi Kishimoto, M.D. correlated with tumor grade, T classification, and papillary status. Topologic distriShoji Fukushima, M.D. butions of cyclin D1, p53, and proliferating cellular nuclear antigen (PCNA) were evaluated. Northern blot analysis was performed on selected specimens. 1 First Department of Pathology, Osaka City UniRESULTS. Overexpression of cyclin D1 was observed in 47% (24 of 51) of Grade 1 versity Medical School, Osaka, Japan. TCCs and 20% (13 of 65) of Grade 2 TCCs but in no Grade 3 TCCs. Approximately 34% (14 of 41) of Ta classified TCCs and 21% (13 of 63) of T1 classified TCCs 2 Department of Urology, Osaka City University Medical School, Osaka, Japan. were immunoreactive for cyclin D1 whereas none of the TCCs beyond T1 was immunoreactive. Overexpression of cyclin D1 was observed only in papillary type TCCs. Results of Northern blot analysis for cyclin D1 were comparable to those of immunohistochemistry. CONCLUSIONS. The observed significant relation between cyclin D1 overexpression and tumor grade/T classification suggests that cyclin D1 may be a useful biologic marker for biopsied materials or urine cytology specimens. The prognostic significance of cyclin D1 overexpression in TCCs remains to be determined. Cancer 1997; 79:780–9. q 1997 American Cancer Society.

Prognostic Significance of Cyclin D1 Overexpression in Non-Small Cell Lung Cancer

Background: The cyclin D1 gene is one of the most frequently amplified chromosomal regions(11q13) in human carcinomas. In laryngeal and head and neck carcinomas, its overexpression has been shown to be associated with advanced local invasion and presence of lymph node metastases. Cyclin D1 may therefore playa key role in cell growth regulation and tumorigenesis. Lung cancer is a worldwide problem and in many contries it is the most lethal malignancy. As relapse is frequent after resection of early stage non-small cell lung cancer, there is an urgent need to define prognostic factors. Purpose: This study was undertaken to evaluate the prognostic value of the cyclin D1, that is one the G1 cyclins which control cell cycle progression by allowing G1 to S phase transition, on the patients in radically resected non-small cell lung cancer. Method: Total 81 cases of formalin-fixed paraffin-embedded blocks from resected primary non-small cell lung cancer from January 1, 1983 to July 31, 1995 at Hanyang University Hospital were available for both clinical follow-up and immunohistochemical staining using monoclonal antibodies for cyclin D1. Results : The histologic classification of the tumor was based on WHO criteria, and the specimens included 45 squamous cell carcinomas, 25 adenocarcinomas and 11 large cell carcinomas. Cyclin D1 overexpression was noted in 26 cases of 81 cases tested (30.9%). Cyclin D1 expression was not significantly associated with cell types of the tumor, pathological staging and the size of the tumor. But cyclin D1 overexpression was significantly correlated with positive lymph node metastasis(p=0.035). The mean survival duration was months in cyclin D1 positive group and months in eyclin D1 negative group. There was a nearly significant difference in overall survival between cyclin D1 positive and negative groups(p=0.0515) in radically resected non-small cell lung cancer. Conclusion: Based on this study, cyelin D1 overexpression appears an important poor prognostic indicator in non-small cell lung cancer and may have diagnostic and prognostic importance in the treatment of resectable non-small cell lung cancer.

Significance of cyclin D1 overexpression in transitional cell carcinomas of the urinary bladder and its correlation with histopathologic features.

Genetic alterations leading to neoplastic transformation of the urothelium are likely to involve the activation of oncogenes and loss of functional tumor suppressor genes. Cyclin D1 has been implicated as a putative protooncogene whereas mutations of the p53 gene occur frequently in invasive transitional cell carcinomas (TCCs) of the urinary bladder. In this study, cyclin D1 overexpression and nuclear accumulation of p53 were evaluated and the results correlated with histopathologic features. TCCs of the urinary bladder from 161 surgical procedures were evaluated for cyclin D1 overexpression and nuclear accumulation of p53. Results were correlated with tumor grade, T classification, and papillary status. Topologic distributions of cyclin D1, p53, and proliferating cellular nuclear antigen (PCNA) were evaluated. Northern blot analysis was performed on selected specimens. Overexpression of cyclin D1 was observed in 47% (24 of 51) of Grade 1 TCCs and 20% (13 of 65) of Grade 2 TCCs but in no Grade 3 TCCs. Approximately 34% (14 of 41) of Ta classified TCCs and 21% (13 of 63) of T1 classified TCCs were immunoreactive for cyclin D1 whereas none of the TCCs beyond T1 was immunoreactive. Overexpression of cyclin D1 was observed only in papillary type TCCs. Results of Northern blot analysis for cyclin D1 were comparable to those of immunohistochemistry. The observed significant relation between cyclin D1 overexpression and tumor grade/T classification suggests that cyclin D1 may be a useful biologic marker for biopsied materials or urine cytology specimens. The prognostic significance of cyclin D1 overexpression in TCCs remains to be determined.

Significance of Cyclin D1 Overexpression in Transitional Cell Carcinomas of the Urinary Bladder and its Correlation with Histopathological Features

Significance of Cyclin D1 Overexpression in Transitional Cell Carcinomas of the Urinary Bladder and its Correlation with Histopathological Features

Significance of Cyclin D1 Overexpression and K-ras Point Mutations in Lung Tumors Induced by N-methyl-N-nitrosourethane in Hamsters.

Female Syrian golden hamsters were given a subcutaneous injection of 0.6 mg of N-methyl-N-nitrosourethane (MNUR) every 2 weeks for 8 weeks (a total of 5 doses) and then maintained without any treatment for the next 26 weeks. The MNUR-induced bronchiolo-alveolar cell tumors were all adenomas composed of basophilic or clear cells in a papillary growth pattern or papillary/solid tumors consisting of pleomorphic cells. Ultrastructurally, most of the tumor cells had the lamellar bodies characteristic of alveolar type II cells in their cytoplasm. Positive cyclin D1 immunostaining was associated with pleomorphic cell type adenomas, whereas no overexpression of p53 protein, hsp70 or mdm2 gene protein was detected in any of the tumors. The lung tumor samples were examined for the presence of mutations in the K-ras gene in codon 12, 13, and 61 by a non-isotopic method for selective oligonucleotide hybridization after PCR amplification of DNA from formalin fixed tissue embedded in paraffin. Lung tumors from 6 of 18 (33%) tumor bearers contained a point mutation in codon 13 or 61, 3 involving GGC→GAC transitions at the second base of codon 13 and 3 affecting the 61st codon, one CAA→CTA, and two CAA→CGA. No mutations were detected in codon 12. These findings indicate that, at least, a point mutation of the K-ras gene was related to the development of bronchiolo-alveolar cell adenomas induced by MNUR and may suggest that cyclin DI overexpression in pleomorphic cell type tumors plays a role in the process of malignant transformation.

Oncogenic Collaboration of the Cyclin D1 (PRAD1, bcl‐1) Gene with a Mutated p53 and an Activated ras Oncogene in Neoplastic Transformation

Cyclin D1 is one of the key regulators in G1 progression in the cell cycle and is also a candidate oncogene (termed PRAD1 or bcl‐1) in several types of human tumors. We report a collaboration of the cyclin D1 gene with ras and a mutated form of p53 (p53‐mt) in neoplastic transformation. Transfection of cyclin D1 alone or in combination with ras or with p53‐mt was not sufficient for focus formation of rat embryonic fibroblasts. However, focus formation induced by co‐transfection of ras and p53‐mt was enhanced in the presence of the cyclin D1‐expression plasmid. Co‐transfection of ras‐ and p53‐mt‐transformants with the cyclin D1‐expression plasmid resulted in reduced serum dependency in vitro, Furthermore, the transformants expressing exogenous cyclin D1 grew faster than those without the cyclin D1 plasmid when injected into nude mice. These observations strengthen the significance of cyclin D1 overexpression through gene rearrangement or gene amplification observed in human tumors as a step in multistep oncogenesis; deregulated expression of cyclin D1 may reduce the requirement for growth factors and may stimulate in vivo growth.