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Mei C, Wang T, Xu B, Wu S, Zhang X, Lv Y, Zhang Y, Liu Z, Gong W. Association of CCND1 rs9344 polymorphism with lung cancer susceptibility and clinical outcomes: a case-control study. BMC Pulm Med 2024; 24:167. [PMID: 38589850 PMCID: PMC11000398 DOI: 10.1186/s12890-024-02983-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2023] [Accepted: 03/26/2024] [Indexed: 04/10/2024] Open
Abstract
BACKGROUND Cyclin D1 (CCND1) plays a pivotal role in cancer susceptibility and the platinum-based chemotherapy response. This study aims to assess the relationship between a common polymorphism (rs9344 G > A) in CCND1 gene with cancer susceptibility, platinum-based chemotherapy response, toxicities and prognosis of patients with lung cancer. METHODS This study involved 498 lung cancer patients and 213 healthy controls. Among them, 467 patients received at least two cycles of platinum-based chemotherapy. Unconditional logistical regression analysis and meta-analysis were performed to evaluate the associations. RESULTS The lung adenocarcinoma risk was significantly higher in patients with AA than GG + GA genotype (adjusted OR = 1.755, 95%CI = 1.057-2.912, P = 0.030). CCND1 rs9344 was significantly correlated with platinum-based therapy response in patients receiving PP regimen (additive model: adjusted OR = 1.926, 95%CI = 1.029-3.605, P = 0.040; recessive model: adjusted OR = 11.340, 95%CI = 1.428-90.100, P = 0.022) and in the ADC subgroups (recessive model: adjusted OR = 3.345, 95%CI = 1.276-8.765, P = 0.014). Furthermore, an increased risk of overall toxicity was found in NSCLC patients (additive model: adjusted OR = 1.395, 95%CI = 1.025-1.897, P = 0.034; recessive model: adjusted OR = 1.852, 95%CI = 1.088-3.152, P = 0.023), especially ADC subgroups (additive model: adjusted OR = 1.547, 95%CI = 1.015-2.359, P = 0.043; recessive model: adjusted OR = 2.030, 95%CI = 1.017-4.052, P = 0.045). Additionally, CCND1 rs9344 was associated with an increased risk of gastrointestinal toxicity in non-smokers (recessive model: adjusted OR = 2.620, 95%CI = 1.083-6.336, P = 0.035). Non-significant differences were observed in the 5-year overall survival rate between CCND1 rs9344 genotypes. A meta-analysis of 5432 cases and 6452 control samples did not find a significant association between lung cancer risk and CCND1 rs9344 polymorphism. CONCLUSION This study suggests that in the Chinese population, CCND1 rs9344 could potentially serve as a candidate biomarker for cancer susceptibility and treatment outcomes in specific subgroups of patients.
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Affiliation(s)
- Chao Mei
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Tian Wang
- Department of General medicine, Huangshi Central Hospital, The Affifiliated Hospital of Hubei Polytechnic University, Huangshi, China
| | - Baoli Xu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Sanlan Wu
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xuelin Zhang
- People's Hospital Of Chong Qing Liang Jiang New Area, Chongqing, China
| | - Yongning Lv
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yu Zhang
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zhaoqian Liu
- Department of Clinical Pharmacology, Hunan Key Laboratory of Pharmacogenetics, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Weijing Gong
- Department of Pharmacy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
- Hubei Province Clinical Research Center for Precision Medicine for Critical Illness, Wuhan, China.
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Pandey A, Bahl C, Sharma S, Singh N, Behera D. Functional role of CyclinD1 polymorphism (G870A) in modifying susceptibility and overall survival of North Indian lung cancer patients. TUMORI JOURNAL 2018; 104:179-187. [PMID: 30086699 DOI: 10.1177/0300891617753477] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/10/2024]
Abstract
PURPOSE The purpose of this study was to investigate the potential role of the cyclin D1 gene G870A polymorphism in the likelihood of the development of lung cancer and the overall survival of lung cancer patients in the North Indian population. METHODS The study consisted of 353 lung cancer cases and 351 age- and gender-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPP) was done for the CCND1 gene. The association analysis was done using the multiple linear regression, and the survival analysis was done using the Kaplan-Meier and the Cox regression models. RESULTS The GA genotype was associated with an increased risk for overall lung cancer (odds ratio [OR] = 1.63; p = 0.01). Combined variant genotype showed a significant association for overall lung cancer (OR 1.50; p = 0.03). In addition, smokers with the carrier genotype of CCND1 were found to have a significantly higher risk for lung cancer (OR 1.57; p = 0.04). No significant correlation was observed between the overall survival of lung cancer patients and CCND1 polymorphism. However, on stratifying the subjects on the basis of histology, it was evident that small-cell lung cancer (SCLC) patients carrying the mutant (AA) genotype showed nearly a fivefold increased mortality rate compared to the wild (GG) genotype (p = 0.03). CONCLUSIONS Our results suggest that polymorphic CCND1 may increase the risk of lung cancer in smokers from North India, and it may be associated with the overall survival of SCLC patients.
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Affiliation(s)
- Ankita Pandey
- 1 Department of Biotechnology, Thapar University, Patiala, Punjab - India
| | - Charu Bahl
- 1 Department of Biotechnology, Thapar University, Patiala, Punjab - India
| | - Siddharth Sharma
- 1 Department of Biotechnology, Thapar University, Patiala, Punjab - India
| | - Navneet Singh
- 2 Department of Pulmonary Medicine, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh - India
| | - Digamber Behera
- 2 Department of Pulmonary Medicine, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh - India
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Pandey A, Bahl C, Sharma S, Singh N, Behera D. Functional Role of CyclinD1 Polymorphism (G870A) in Modifying Susceptibility and Overall Survival of North Indian Lung Cancer Patients. TUMORI JOURNAL 2017:tj5000707. [PMID: 29739297 DOI: 10.5301/tj.5000707] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023]
Abstract
Purpose The purpose of this study was to investigate the potential role of the cyclin D1 gene G870A polymorphism in the likelihood of the development of lung cancer and the overall survival of lung cancer patients in the North Indian population. Methods The study consisted of 353 lung cancer cases and 351 age- and gender-matched healthy controls. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLPP) was done for the CCND1 gene. The association analysis was done using the multiple linear regression, and the survival analysis was done using the Kaplan-Meier and the Cox regression models. Results The GA genotype was associated with an increased risk for overall lung cancer (odds ratio [OR] = 1.63; p = 0.01). Combined variant genotype showed a significant association for overall lung cancer (OR 1.50; p = 0.03). In addition, smokers with the carrier genotype of CCND1 were found to have a significantly higher risk for lung cancer (OR 1.57; p = 0.04). No significant correlation was observed between the overall survival of lung cancer patients and CCND1 polymorphism. However, on stratifying the subjects on the basis of histology, it was evident that small-cell lung cancer (SCLC) patients carrying the mutant (AA) genotype showed nearly a fivefold increased mortality rate compared to the wild (GG) genotype (p = 0.03). Conclusions Our results suggest that polymorphic CCND1 may increase the risk of lung cancer in smokers from North India, and it may be associated with the overall survival of SCLC patients.
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Affiliation(s)
- Ankita Pandey
- 1 Department of Biotechnology, Thapar University, Patiala, Punjab - India
| | - Charu Bahl
- 1 Department of Biotechnology, Thapar University, Patiala, Punjab - India
| | - Siddharth Sharma
- 1 Department of Biotechnology, Thapar University, Patiala, Punjab - India
| | - Navneet Singh
- 2 Department of Pulmonary Medicine, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh - India
| | - Digamber Behera
- 2 Department of Pulmonary Medicine, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh - India
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Aytekin T, Aytekin A, Maralcan G, Gokalp MA, Ozen D, Borazan E, Yilmaz L. A cyclin D1 (CCND1) gene polymorphism contributes to susceptibility to papillary thyroid cancer in the Turkish population. Asian Pac J Cancer Prev 2015; 15:7181-5. [PMID: 25227811 DOI: 10.7314/apjcp.2014.15.17.7181] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Cyclin D1 is an important positive regulator of the G1/S phase of the cell cycle. We investigated the association between the CCND1 G870A polymorphism and susceptibility to papillary thyroid cancer in Turkish people. This study covered 102 patients with papillary thyroid cancer and 174 healthy controls. CCND1 genotyping was determined by the PCR-RFLP method. We found that the A allele frequency was higher in the cases than in the controls (p=0.042). On stratification analysis, papillary thyroid cancer risk was significantly elevated in individuals older than 45 years with the A allele (OR=1.91, 95% CI, 1.09-3.35, p=0.024) and in females with the A allele (OR=1.73, 95% CI, 1.06-2.84, p=0.029), compared to the G allele. According to the subject age, there was an increased papillary thyroid cancer risk for the individuals older than 45 years with the AA genotype (OR=2.28, 95% CI, 1.02-5.13, p=0.046) compared to the AG+GG combined genotypes. In conclusion, it is suggested that the CCND1 G870A polymorphism may contribute to the susceptibility to papillary thyroid cancer, especially in those who were older subjects (45 ≤ years old) and female, in the Turkish population.
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Affiliation(s)
- Turkan Aytekin
- Department of Biology, Faculty of Arts and Sciences, University of Gaziantep, Gaziantep, Turkey E-mail :
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Qin LY, Zhao LG, Chen X, Li P, Yang Z, Mo WN. The CCND1 G870A gene polymorphism and brain tumor risk: a meta-analysis. Asian Pac J Cancer Prev 2015; 15:3607-12. [PMID: 24870765 DOI: 10.7314/apjcp.2014.15.8.3607] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND In recent years, numerous studies have been performed to investigate the CCND1 G870A gene polymorphism impact on brain tumors susceptibility. Unfortunately, the results of previous studies were inconsistent. Therefore, we performed a meta-analysis to derive a more precise estimation of any association. MATERIALS AND METHODS We conducted a search in PubMed, Embase and CNKI covering all published papers up to November, 2013. Odds ratios (ORs) and their 95% confidence intervals (95%CIs) were applied to assess associations. RESULTS A total of 6 publications including 9 case-control studies met the inclusion criteria. The pooled ORs for the total included studies showed significant association among comparison A vs G (OR= 1.246, 95%CI= 1.092-1.423, p= 0.001), homozygote comparison AA vs GG (OR= 1.566, 95%CI= 1.194-2.054, p= 0.001), heterozygote comparison AG vs GG (OR= 1.290, 95%CI= 0.934-1.782, p= 0.122), dominant model AA/GA vs GG (OR= 1.381, 95%CI= 1.048-1.821, p= 0.022) and recessive model AA vs GA/GG (OR= 1.323, 95%CI= 1.057- 1.657, p= 0.015) especially in glioma. CONCLUSIONS CCND1 G870A polymorphism may increase brain tumor risk, especially for gliomas. However, more primary large scale and well-designed studies are still required to evaluate the interaction of CCND1 G870A polymorphism with brain tumor risk.
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Affiliation(s)
- Ling-Yan Qin
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning, China E-mail :
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Verim A, Ozkan N, Turan S, Korkmaz G, Cacina C, Yaylim I, Isbir T. Association of the Cylin D1 G870A polymorphism with laryngeal cancer: are they really related? Asian Pac J Cancer Prev 2014; 14:7629-34. [PMID: 24460344 DOI: 10.7314/apjcp.2013.14.12.7629] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Cylin D1(CCDN1) is an important regulator of the cell cycle whose alterations are thought to be involved in cancer development. There have been many studies indicating CCDN1 amplification or over- expression in a variety of cancer types. In addition to gene amplification, the G870A polymorphism may be related with altered CCDN1 activity, and therefore with cancer development. This hypothesis has been tested in different cancer types but results have been contradictory. We therefore aimed to investigate any relationship between CCDN1 A870G genotypes and laryngeal squamous cell cancer development and progression. MATERIALS AND METHODS A total of 68 Turkish patients with primary laryngeal squamous cell cancer and 133 healthy controls were enrolled. Polymerase chain reaction-restriction fragment length polymorphism analysis was used to determine the CCDN1 genotypes. RESULTS No significant association was detected between CCDN1 genotypes and laryngeal squamous cell cancer (LxSCCa) development. Similarly CCDN1 genotypes were not related to clinical parameters of Lx SCCa. However, there was a very significant association between CCDN1 G allele and presence of perineural invasion (p= 0.003; OR: 1.464; CI% 1.073-1.999). CCDN1 G allele frequency was significantly higher in the individuals with perineural invasion (85.7%) when compared to those without (58.5%). The 2 patients who died of disease were both found to possess the GG genotype. CONCLUSIONS These results pose a controversy in suggesting a protective role of the G allele against LxSCCa development and support the association of CCDN1 gene GG genotype with mortality in patients with LxSCCa.
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Affiliation(s)
- Aysegul Verim
- Department of Otorhinolaryngology/Head and Neck Surgery, Haydarpasa Numune Education and Research Hospital, Istanbul, Turkey E-mail : aysegulverim@ hotmail.com
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Qin LY, Zhao LG, Chen X, Yang Z, Mo WN. The CCND1 G870A Gene Polymorphism and Leukemia or Non-Hodgkin Lymphoma Risk: a Meta-analysis. Asian Pac J Cancer Prev 2014; 15:6923-8. [DOI: 10.7314/apjcp.2014.15.16.6923] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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Zeybek U, Yaylim I, Ozkan NE, Korkmaz G, Turan S, Kafadar D, Cacina C, Kafadar AM. Cyclin D1 gene G870A variants and primary brain tumors. Asian Pac J Cancer Prev 2014; 14:4101-6. [PMID: 23991960 DOI: 10.7314/apjcp.2013.14.7.4101] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Alterations of cyclin D1, one of the main regulators of the cell cycle, are known to be involved in various cancers. The CCDN1 G870A polymorphism causes production of a truncated variant with a shorter half-life and thus thought to impact the regulatory effect of CCDN1. The aim of the present study was to contribute to existing results to help to determine the prognostic value of this specific gene variant and evaluate the role of CCDN1 G870A polymorphism in brain cancer susceptibility. A Turkish study group including 99 patients with primary brain tumors and 155 healthy controls were examined. Genotypes were determined by polymerase chain reaction-restriction fragment length polymorphism analysis. The CCDN1 genotype frequencies in meningioma, glioma and control cases were not significantly different (p>0.05). No significant association was detected according to clinical parameters or tumor characteristics; however, a higher frequency of AG genotype was recorded within patients with astrocytic or oligoastrocytic tumors. A significant association between AG genotype and gliobilastoma multiforme (GBM) was recorded within the patients with glial tumors (p value=0.048 OR: 1.87 CI% 1.010-3.463). According to tumor characteristics, no statistically significant difference was detected within astrocytic, oligoasltrocytic tumors and oligodentrioglias. However, patients with astrocytic astrocytic or oligoastrocytic tumors showed a higher frequency of AG genotype (50%) when compared to those with oligodendrioglial tumors (27.3%). Our results indicate a possible relation between GBM formation and CCDN1 genotype.
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Affiliation(s)
- Umit Zeybek
- Department of Molecular Medicine, Institute of Experimental Medicine, Cerrahpasa Medical Faculty, Istanbul University, Istanbul, Turkey.
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Azad AK, Qiu X, Boyd K, Kuang Q, Emami M, Perera N, Palepu P, Patel D, Chen Z, Cheng D, Feld R, Leighl NB, Shepherd FA, Tsao MS, Xu W, Liu G, Cuffe S. A genetic sequence variant (GSV) at susceptibility loci of 5p15.33 (TERT-CLPTM1L) is associated with survival outcome in locally advanced and metastatic non-small-cell lung cancer (NSCLC). Lung Cancer 2014; 84:289-94. [PMID: 24679952 DOI: 10.1016/j.lungcan.2014.03.008] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2013] [Revised: 02/13/2014] [Accepted: 03/03/2014] [Indexed: 01/10/2023]
Abstract
INTRODUCTION Lung cancer is a leading cause of cancer-related mortality in North America. In addition to tobacco smoking, inherited genetic factors can also influence the development of lung cancer. These genetic factors may lead to biologically distinct subsets of cancers that have different outcomes. We evaluated whether genetic sequence variants (GSVs) associated with lung cancer risk are associated with overall survival (OS) and progression-free survival (PFS) in stage-III-IV non-small-cell lung cancer (NSCLC) patients. METHODS A total of 20 candidate GSVs in 12 genes previously reported to be associated with lung cancer risk were genotyped in 564 patients with stage-III or IV NSCLC. Multivariate Cox proportional hazard models adjusted for potential clinical prognostic factors were generated for OS and PFS. RESULTS After taking into account multiple comparisons, one GSV remained significant: rs4975616 on chromosome 5p15.33, located near the TERT-CLPTM1L gene. The adjusted hazard ratio (aHR) for OS was 0.75 (0.69-0.91), p = 0.002; for PFS aHR was 0.74 (0.62-0.89), p < 0.001 for each protective variant allele. Results were similar in both Stage III (OS: aHR = 0.70; PFS: aHR = 0.71) and Stage IV patients (OS: aHR = 0.81; PFS: aHR = 0.77). CONCLUSION A GSV on 5p15.33 is not only a risk factor for lung cancer but may also be associated with survival in patients with late stage NSCLC. If validated, GSVs may define subsets of patients with different risk and prognosis of NSCLC.
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Affiliation(s)
- Abul Kalam Azad
- Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Xin Qiu
- Department of Biostatistics, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Kevin Boyd
- Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Qin Kuang
- Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Marjan Emami
- Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Nicole Perera
- Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Prakruthi Palepu
- Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Devalben Patel
- Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Zhuo Chen
- Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Dangxiao Cheng
- Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Ronald Feld
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Natasha B Leighl
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Frances A Shepherd
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Ming-Sound Tsao
- Department of Pathology, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Wei Xu
- Department of Biostatistics, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
| | - Geoffrey Liu
- Ontario Cancer Institute, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada; Division of Medical Oncology and Hematology, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada; Division of Epidemiology, Dalla Lana School of Public Health, Toronto, Ontario, Canada.
| | - Sinead Cuffe
- Division of Medical Oncology and Hematology, Princess Margaret Cancer Center/University Health Network, University of Toronto, Toronto, Ontario, Canada
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Pérez-Morales R, Méndez-Ramírez I, Moreno-Macias H, Mendoza-Posadas AD, Martínez-Ramírez OC, Castro-Hernández C, Gonsebatt ME, Rubio J. Genetic Susceptibility to Lung Cancer Based on Candidate Genes in a Sample from the Mexican Mestizo Population: A Case–Control Study. Lung 2013; 192:167-73. [DOI: 10.1007/s00408-013-9536-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 11/11/2013] [Indexed: 01/10/2023]
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Zhou C, An H, Hu M, Liu Q, Geng P, Xu J, Sun B, Liu C. The cyclin D1 (CCND1) G870A polymorphism and lung cancer susceptibility: a meta-analysis. Tumour Biol 2013; 34:3831-7. [PMID: 23873109 DOI: 10.1007/s13277-013-0968-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2013] [Accepted: 06/24/2013] [Indexed: 01/10/2023] Open
Abstract
Several studies have investigated the association between Cyclin D1 (CCND1) G870A genetic polymorphism and lung cancer susceptibility, but the results were inconclusive. The aim of this meta-analysis was to summarize available evidence for such a relationship. The reviewers made use of MEDLINE, EMBASE, and BIOSIS databases. The relevant data were independently extracted by two reviewers. The odds ratio (OR) with 95% confidence interval (CI) was selected as the principal outcome measure. The heterogeneity test, the publication bias test, and the sensitivity analysis were performed. Overall, a total of 10 case-control studies were included. Our meta-analysis indicated that CCND1 G870A genetic polymorphism was a risk factor for lung cancer under homozygote model (OR = 1.18; 95% CI = 1.02, 1.37), recessive model (OR = 1.21; 95% CI = 1.03, 1.41), and allele model (OR = 1.11; 95% CI = 1.02, 1.21). In the subgroup analysis by source of ethnicity, a statistical increase of lung cancer risk was found among Asian groups for allele model (OR = 1.11; 95% CI = 1.01-1.22). The present meta-analysis suggests that CCND1 G870A polymorphism may be a risk factor for lung cancer. Besides, allele A may contribute to increased lung cancer risk.
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Affiliation(s)
- Changxi Zhou
- Nanlou Respiratory Diseases Department, PLA General Hospital, 28 Fuxing Road, Beijing, 100853, People's Republic of China
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CCND1 G870A polymorphism interaction with cigarette smoking increases lung cancer risk: meta-analyses based on 5008 cases and 5214 controls. Mol Biol Rep 2013; 40:4625-35. [PMID: 23653001 DOI: 10.1007/s11033-013-2556-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2012] [Accepted: 04/29/2013] [Indexed: 01/10/2023]
Abstract
Evidence indicates CCND1 G870A polymorphisms as a risk factor for a number of cancers. Increasing studies have been conducted on the association of CCND1 G870A polymorphism with lung cancer risk. However, the results were controversial. The aim of the present study was to derive a more precise estimation of the relationship. Meta-analyses examining the association between CCND1 G870A polymorphism and lung cancer were performed. Subgroup analyses regarding ethnicity, smoking status, histological types and source of controls were also implemented. All eligible studies for the period up to May 2012 were identified. The overall data from ten case-control studies including 5,008 cases and 5,214 controls indicated that variant A allele may have an association with increased lung cancer risk (AA vs GG: OR = 1.21; 95 % CI = 1.08-1.36, dominant model: OR = 1.09; 95 % CI = 1.00-1.19, recessive model: OR = 1.23; 95 % CI = 1.01-1.49). In the subgroup analysis by ethnicity, A allele may elevate lung cancer risk among Asians but not Caucasians or Mixed ethnicities. In smoking status subgroup, A allele was shown to associate with increased lung cancer risk among smokers but not non-smokers. In the subgroup analysis by histological types, increased cancer risks were shown in adenocarcinoma but not squamous cell carcinoma, under the homozygote comparison and recessive models. Collectively, the results of the present study suggest that CCND1 G870A polymorphism might be a low-penetrant risk factor for lung cancer, particularly among Asians and smokers. Moreover, homozygous AA alleles might have a correlation with increased lung adenocarcinoma susceptibility.
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Marshall AL, Christiani DC. Genetic susceptibility to lung cancer--light at the end of the tunnel? Carcinogenesis 2013; 34:487-502. [PMID: 23349013 PMCID: PMC3581605 DOI: 10.1093/carcin/bgt016] [Citation(s) in RCA: 65] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2012] [Revised: 12/30/2012] [Accepted: 01/17/2013] [Indexed: 01/10/2023] Open
Abstract
Lung cancer is one of the most common and deadliest cancers in the world. The major socio-environmental risk factor involved in the development of lung cancer is cigarette smoking. Additionally, there are multiple genetic factors, which may also play a role in lung cancer risk. Early work focused on the presence of relatively prevalent but low-penetrance alterations in candidate genes leading to increased risk of lung cancer. Development of new technologies such as genomic profiling and genome-wide association studies has been helpful in the detection of new genetic variants likely involved in lung cancer risk. In this review, we discuss the role of multiple genetic variants and review their putative role in the risk of lung cancer. Identifying genetic biomarkers and patterns of genetic risk may be useful in the earlier detection and treatment of lung cancer patients.
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Affiliation(s)
| | - David C. Christiani
- Department of Environmental Health, Harvard School of Public Health, Boston, MA 02115, USA
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Li Y, Zhang S, Geng JX, Yu Y. Effects of the cyclin D1 polymorphism on lung cancer risk--a meta-analysis. Asian Pac J Cancer Prev 2013; 13:2325-8. [PMID: 22901215 DOI: 10.7314/apjcp.2012.13.5.2325] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND Cyclin D1 (CCND1) is critical in the transition of the cell cycle from G1 to S phases and unbalanced cell cycle regulation is a hallmark of carcinogenesis. A number of studies conducted to assess the association between CCND1 G870A polymorphism and susceptibility to lung cancer have yielded inconsistent and inconclusive results. In the present study, the possible association above was assessed by a meta-analysis. METHODS Eligible articles were identified for the period up to November 2011. Pooled odds ratios (OR) with 95% confidence intervals (95%CI) were appropriately derived from fixed effects or random-effects models. Sensitivity analysis excluding studies whose genotype frequencies in controls significantly deviated from the Hardy-Weinberg equilibrium (HWE) was performed. RESULTS Ten case-control studies with a total of 10,548 subjects were eligible. At the overall analysis the CCND1 870A allele appeared to be associated with elevated lung cancer risk (for allele model, pooled OR=1.24, 95% CI: 1.08-1.44, P=0.004; for homozygous model, pooled OR=1.45, 95% CI: 1.14-1.84, P=0.003; for recessive model, pooled OR=1.29, 95% CI: 1.06-1.58, P=0.013; for dominant model, pooled OR=1.33, 95% CI: 1.08-1.65, P=0.009). Subgroup analyses by ethnicity and sensitivity analysis further pointed to associations, particularly in Asians. CONCLUSION This meta-analysis suggests that the A allele of CCND1 G870A polymorphism confers additional lung cancer risk.
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Affiliation(s)
- Yue Li
- Department of Medical Oncology, the Third Affiliated Hospital of Harbin Medical University, Harbin, China
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Chen X, Zhao T, Li L, Xu C, Zhang X, Tse V, Zhang T, Liu X, Lu F. CCND1 G870A Polymorphism with Altered Cyclin D1 Transcripts Expression Is Associated with the Risk of Glioma in a Chinese Population. DNA Cell Biol 2012; 31:1107-13. [DOI: 10.1089/dna.2011.1521] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Affiliation(s)
- Xiangmei Chen
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing, China
| | - Tianshu Zhao
- The Fourth Affiliated Hospital, Harbin Medical University, Heilongjiang Province, China
| | - Li Li
- The Fourth Affiliated Hospital, Harbin Medical University, Heilongjiang Province, China
| | - Chunhui Xu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing, China
| | - Xiaolei Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing, China
| | - Vincent Tse
- Department of Chemistry and Biochemistry, University of California-Los Angeles, Los Angeles, California
| | - Ting Zhang
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing, China
| | - Xiaoqian Liu
- The Fourth Affiliated Hospital, Harbin Medical University, Heilongjiang Province, China
| | - Fengmin Lu
- Department of Microbiology and Infectious Disease Center, School of Basic Medical Science, Peking University Health Science Center, Beijing, China
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Cyclin D1 G870A polymorphism and lung cancer risk: a meta-analysis. Tumour Biol 2012; 33:1467-76. [PMID: 22528945 DOI: 10.1007/s13277-012-0397-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2012] [Accepted: 04/02/2012] [Indexed: 01/10/2023] Open
Abstract
Many studies have investigated the association between Cyclin D1 (CCND1) G870A polymorphism and lung cancer risk, but the impact of CCND G870A polymorphism on lung cancer is unclear owing to the obvious inconsistence among those studies. This study aimed to quantify the strength of association between CCND1 G870A polymorphism and lung cancer risk. We searched the PubMed, Embase, and Wangfang databases for articles on studies relating the CCND1 G870A polymorphism to the risk of lung cancer in humans. We estimated summary odds ratios (ORs) with their confidence intervals (CIs) to assess the association. Meta-analyses of total studies showed that CCND1 G870A polymorphism was associated with lung cancer risk under three genetic models (OR(A versus G) = 1.13, 95 % CI 1.03-1.24; OR(AA versus GG) = 1.20, 95 % CI 1.07-1.35; OR(AA versus AG + GG) = 1.23, 95 % CI 1.02-1.50). Meta-analyses of studies with high quality showed that CCND1 G870A polymorphism was associated with lung cancer risk under two genetic models (OR(A versus G) = 1.08, 95 % CI 1.02-1.15; OR(AA versus GG) = 1.17, 95 % CI 1.04-1.32). Subgroup analyses by ethnicity and sensitivity analyses further identified the significant association above. No evidence of publication bias was observed. Meta-analyses of available data show a significant association between the CCND1 G870A polymorphism and lung cancer risk, and CCND1 G870A polymorphic variant A contributes to increased risk of lung cancer.
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Liu W, Zhu E, Wang R, Wang L, Gao L, Yang X, Liu T. Cyclin D1 gene polymorphism, A870G, is associated with an increased risk of salivary gland tumors in the Chinese population. Cancer Epidemiol 2011; 35:e12-7. [DOI: 10.1016/j.canep.2010.11.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2010] [Revised: 11/11/2010] [Accepted: 11/16/2010] [Indexed: 01/10/2023]
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Wang N, Qian X, Wang S, Gao H, Wang L, Huo Y, Zhang S. CCND1 rs9344 polymorphisms are associated with the genetic susceptibility to cervical cancer in Chinese population. Mol Carcinog 2011; 51:196-205. [PMID: 21594903 DOI: 10.1002/mc.20801] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2010] [Revised: 04/20/2011] [Accepted: 04/26/2011] [Indexed: 01/10/2023]
Abstract
Cyclin D1, with a common G/A polymorphism in rs9344, is an essential regulator of the G1 phase in cell cycles and plays an important role in several tumor types, and the homology of cyclin D1 with human papillomavirus (HPV)-16 E7 brought our attention to CCND1 gene in cervical cancer. A total of 738 native Chinese subjects consist of 327 cases and 411 controls were enrolled in this study. CCND1 genotyping was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and partially verified by sequencing of genomic DNA and cDNA. The transcription of cyclin D1 mRNA isoforms was analyzed by quantitative PCR; expression of protein isoforms by immunohistochemistry and Western blotting. We observed that the AA genotype had decreased risk of developing cervical cancer (odds ratio [OR] = 0.332; 95% confidence interval [CI] = 0.113-0.978; P = 0.045). The two mRNA isoforms were both transcripted from A and G allele. Transcript b decreased in squamous cell carcinoma of the uterine cervix (SCCUC) group (P = 0.004), especially poorly differentiated group (P = 0.004), and in G allele group of normal subjects (P = 0.001). In immunohistochemistry analysis, cyclins D1, D1a, and D1b failed to correlate with cervical cancer (P = 0.808, 0.445, and 0.095). However, cyclin D1b was downregulated in SCCUC group analyzed by Western blotting (P = 0.039). This study indicates that CCND1 rs9344 polymorphisms confer host susceptibility to cervical cancer. A allele possesses a relative protective effect probably through the cyclin D1b's inhibition on HPV carcinogenesis.
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Affiliation(s)
- Ning Wang
- Department of Obstetrics and Gynecology, Shengjing Hospital of China Medical University, Shenyang, China
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19
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Kim DH, Park SE, Kim M, Ji YI, Kang MY, Jung EH, Ko E, Kim Y, Kim S, Shim YM, Park J. A functional single nucleotide polymorphism at the promoter region of cyclin A2 is associated with increased risk of colon, liver, and lung cancers. Cancer 2011; 117:4080-91. [DOI: 10.1002/cncr.25930] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2010] [Revised: 11/13/2010] [Accepted: 12/08/2010] [Indexed: 01/10/2023]
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20
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Pabalan N, Bapat B, Sung L, Jarjanazi H, Francisco-Pabalan O, Ozcelik H. Cyclin D1 Pro241Pro (CCND1-G870A) polymorphism is associated with increased cancer risk in human populations: a meta-analysis. Cancer Epidemiol Biomarkers Prev 2008; 17:2773-81. [PMID: 18843022 DOI: 10.1158/1055-9965.epi-08-0169] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
The G870A polymorphism in the CCND1 gene may influence cancer risk. However, data from published studies with individual low statistical power have been controversial. To evaluate whether combined evidence shows an association between this polymorphism and cancer, we considered all available studies in a meta-analysis. Sixty studies were combined representing data for 18,411 cases and 22,209 controls. In our meta-analysis, we investigated overall sample and two ethnic populations (Caucasians and Asians) as well as nine cancer subtypes. Individuals who are homozygous for A allele (AA) were found to be associated with significantly increased cancer risk in overall sample [odds ratio (OR), 1.23; 95% confidence interval (95% CI), 1.13-1.33; P <or= 0.0001], Caucasians (OR, 1.16; 95% CI, 1.07-1.26; P=0.0002), and Asians (OR, 1.26; 95% CI, 1.14-1.39; P <or= 0.001). Among the nine cancer subtypes investigated, modestly significant risk (ORs, 1.08 to 1.51; P=0.02 to 0.04) was detected in breast, colorectal, head and neck, and other cancers. Highly significant and increased risk was found to be associated with genitourinary (OR, 1.51; 95% CI, 1.20-1.89; P=0.0004) and blood-related cancers (OR, 1.62; 95% CI, 1.28-2.05; P <or= 0.0001). Individuals who are heterozygous for AG were found to be at increased risk in overall, ethnic groups, as well as breast and colorectal cancers. Significant dominant effects seem to prevail in the majority of the categories investigated, where some recessive effects were also detected. Overall, the risk effects associated with this polymorphism were small; however, due its common occurrence, it affects a large portion of the human population (AA, 25%; AG, 50%). Although the independent small risk associated with CCND1-A870G polymorphism is not clinically useful, its interaction with other genetic variants and environmental factors has been shown to be associated with further increase in cancer risk (OR, 1.6-7.1). In conclusion, our study strongly supports the increased cancer risk associated with CCND1-A870G polymorphism in the human population.
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Affiliation(s)
- Noel Pabalan
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, 60 Murray Street, Room L6-304, Box 29, Toronto, Ontario, Canada M5T 3L9
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22
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Hung RJ, Boffetta P, Canzian F, Moullan N, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Chabrier A, Landi S, Gemignani F, Hall J, Brennan P. Sequence variants in cell cycle control pathway, X-ray exposure, and lung cancer risk: a multicenter case-control study in Central Europe. Cancer Res 2007; 66:8280-6. [PMID: 16912209 DOI: 10.1158/0008-5472.can-05-3099] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Exposure to ionizing radiation (IR) results in various types of DNA damage and is a suspected cause of lung cancer. An essential cellular machinery against DNA damage is cell cycle control, which is regulated by several genes, including TP53, CCND1, and CDKN2A. Therefore, we hypothesized that the genetic variants in these three genes influence the predisposition of lung cancer (i.e., CCND1 G870A, CDKN2A Ala(148)Thr, TP53 Arg(72)Pro, and 16-bp repeat in intron 3) and that the effect of X-ray on lung cancer risk can be modified by the presence of these genetic variations. The study was conducted in 15 centers in 6 countries of Central Europe between 1998 and 2002. A total of 2,238 cases and 2,289 controls were recruited and provided DNA samples. Cases with positive family history were analyzed separately. The joint effect of X-ray and previous risk genotypes was assessed, and modification by sequence variants on X-ray dose-response relationship with lung cancer risk was evaluated. We found an overall effect of TP53 intron 3 16-bp repeats [odds ratio (OR), 1.99; 95% confidence interval (95% CI), 1.27-3.13], which was stronger among cases with family history of lung cancer (OR, 2.98; 95% CI, 1.29-6.87). In addition, our results suggested an interaction that was greater than multiplicativity between TP53 intron 3 16-bp repeats and multiple X-ray exposures (interaction OR, 5.69; 95% CI, 1.33-24.3). We did not observe a main effect of CCND1 G870A polymorphism; however, the dose-response relationship between lung cancer risk and X-ray exposures was modified by CCND1 genotype with no risk from X-ray exposures among subjects who carried G/G genotype, intermediate risk [trend OR for X-ray, 1.16; 95% CI, 1.05-1.27) among subjects with G/A genotype, and highest risk [trend OR for X-ray, 1.29; 95% CI, 1.12-1.49) among subjects with A/A genotype. Sequence variants in cell cycle control pathway may increase the risk of lung cancer and modify the risk conferred by multiple X-ray exposures. However, a definite conclusion can only be drawn on replication by different studies among individuals who are highly exposed to IR.
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Sobti RC, Kaur P, Kaur S, Singh J, Janmeja AK, Jindal SK, Kishan J, Raimondi S. Effects of cyclin D1 (CCND1) polymorphism on susceptibility to lung cancer in a North Indian population. ACTA ACUST UNITED AC 2006; 170:108-14. [PMID: 17011980 DOI: 10.1016/j.cancergencyto.2006.05.017] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2005] [Revised: 05/10/2006] [Accepted: 05/15/2006] [Indexed: 01/14/2023]
Abstract
Cyclin D1 is involved in normal regulation of the cell cycle and plays an important role in the transition from G1 to S phase of the cell cycle. The CCND1 gene has a G-->A polymorphism in exon 4 that increases the frequency of alternate splicing. We analyzed the potential role of CCND1 gene polymorphisms in lung cancer patients (n = 151) and in a matched control population (n = 151). DNA was isolated from blood samples, and exon 4 of CCND1 was amplified by polymerase chain reaction. After digestion with MspI, common CCND1 polymorphic alleles were analyzed by means of agarose gel electrophoresis. The data obtained were analyzed using multiple logistic regression. After adjustment for age, sex, and smoking status, the AG genotype was associated with an increased risk for overall lung cancer (odds ratio OR = 1.7, 95% confidence interval CI = 0.92-3.14). No association was found between AA genotype and risk of lung cancer. In smokers, the combined AG+AA genotypes of CCND1 were found to be significant (OR = 1.9, 95% CI = 1.03-3.71, P = 0.03). No positive association was found between CCND1 genotypes in nonsmokers. The results suggest that the CCND1 A870G gene polymorphisms may increase the risk of lung cancer in smokers from north India.
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Affiliation(s)
- R C Sobti
- Department of Biotechnology, Panjab University, Chandigarh, India.
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24
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Gautschi O, Ratschiller D, Gugger M, Betticher DC, Heighway J. Cyclin D1 in non-small cell lung cancer: a key driver of malignant transformation. Lung Cancer 2006; 55:1-14. [PMID: 17070615 DOI: 10.1016/j.lungcan.2006.09.024] [Citation(s) in RCA: 191] [Impact Index Per Article: 10.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2006] [Revised: 09/25/2006] [Accepted: 09/26/2006] [Indexed: 01/10/2023]
Abstract
PURPOSE To review the evidence implicating the deregulation of cyclin D1 in the pathogenesis of non-small cell lung cancer (NSCLC), and to discuss the opportunities for targeted clinical intervention. METHODS Data published until June 2006 are summarized, and previously unpublished results from our own research are included. RESULTS In normal cells, cyclin D1 complexes with and activates cyclin-dependent kinases (CDK) and acts as a transcriptional regulator. The protein is frequently overexpressed in a wide range of cancers, sometimes coincident with CCND1 (cyclin D1) gene amplification (5-20% of tumours). A low level of somatic mutations have been seen in certain tumours. CCND1 is amplified in NSCLC and cyclin D1 is frequently overexpressed in tumours and pre-invasive bronchial lesions, generally from one parental allele. Mutation analyses revealed a frequent CCND1 gene polymorphism (A870G) that modulates alternative splicing and allows expression of an alternative cyclin D1 transcript (transcript cyclin D1b). The encoded cyclin D1b protein lacks a specific phosphorylation site required for nuclear export. Genotype has been correlated with the risk and/or severity of disease or drug response across a range of malignancies, including lung cancer. Together, these findings suggest a strong pathological role for cyclin D1 deregulation in bronchial neoplasia. CONCLUSION Current data indicate that cyclin D1 overexpression is not a consequence of, but rather a pivotal element in the process of malignant transformation in the lung and other tissues. This understanding may open new avenues for lung cancer diagnosis, treatment and prevention.
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Affiliation(s)
- Oliver Gautschi
- University of California Davis Cancer Center, Sacramento 95817, USA, and Clinic of Medical Oncology, University Hospital Bern, Bern, Switzerland.
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Hockley SL, Arlt VM, Brewer D, Giddings I, Phillips DH. Time- and concentration-dependent changes in gene expression induced by benzo(a)pyrene in two human cell lines, MCF-7 and HepG2. BMC Genomics 2006; 7:260. [PMID: 17042939 PMCID: PMC1621085 DOI: 10.1186/1471-2164-7-260] [Citation(s) in RCA: 89] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2006] [Accepted: 10/16/2006] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND The multi-step process of carcinogenesis can be more fully understood by characterizing gene expression changes induced in cells by carcinogens. In this study, expression microarrays were used to monitor the activity of 18,224 cDNA clones in MCF-7 and HepG2 cells exposed to the carcinogen benzo(a)pyrene (BaP) or its non-carcinogenic isomer benzo(e)pyrene (BeP). Time and concentration gene expression effects of BaP exposure have been assessed and linked to other measures of cellular stress to aid in the identification of novel genes/pathways involved in the cellular response to genotoxic carcinogens. RESULTS BaP (0.25-5.0 muM; 6-48 h exposure) modulated 202 clones in MCF-7 cells and 127 in HepG2 cells, including 27 that were altered in both. In contrast, BeP did not induce consistent gene expression changes at the same concentrations. Significant time- and concentration-dependent responses to BaP were seen in both cell lines. Expression changes observed in both cell lines included genes involved in xenobiotic metabolism (e.g., CYP1B1, NQO1, MGST1, AKR1C1, AKR1C3,CPM), cell cycle regulation (e.g., CDKN1A), apoptosis/anti-apoptosis (e.g., BAX, IER3), chromatin assembly (e.g., histone genes), and oxidative stress response (e.g., TXNRD1). RTqPCR was used to validate microarray data. Phenotypic anchoring of the expression data to DNA adduct levels detected by 32P-postlabelling, cell cycle data and p53 protein expression identified a number of genes that are linked to these biological outcomes, thereby strengthening the identification of target genes. The overall response to BaP consisted of up-regulation of tumour suppressor genes and down-regulation of oncogenes promoting cell cycle arrest and apoptosis. Anti-apoptotic signalling that may increase cell survival and promote tumourigenesis was also evident. CONCLUSION This study has further characterised the gene expression response of human cells after genotoxic insult, induced after exposure to concentrations of BaP that result in minimal cytotoxicity. We have demonstrated that investigating the time and concentration effect of a carcinogen on gene expression related to other biological end-points gives greater insight into cellular responses to such compounds and strengthens the identification of target genes.
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Affiliation(s)
- Sarah L Hockley
- Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Cotswold Road, Sutton, Surrey SM2 5NG, UK
| | - Volker M Arlt
- Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Cotswold Road, Sutton, Surrey SM2 5NG, UK
| | - Daniel Brewer
- Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Cotswold Road, Sutton, Surrey SM2 5NG, UK
- Cancer Research UK DNA Microarray Facility, Institute of Cancer Research, Cotswold Road, Sutton, Surrey, SM2 5NG, UK
| | - Ian Giddings
- Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Cotswold Road, Sutton, Surrey SM2 5NG, UK
- Cancer Research UK DNA Microarray Facility, Institute of Cancer Research, Cotswold Road, Sutton, Surrey, SM2 5NG, UK
| | - David H Phillips
- Section of Molecular Carcinogenesis, Institute of Cancer Research, Brookes Lawley Building, Cotswold Road, Sutton, Surrey SM2 5NG, UK
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Schernhammer ES, Tranah GJ, Giovannucci E, Chan AT, Ma J, Colditz GA, Hunter DJ, Willett WC, Fuchs CS. Cyclin D1 A870G polymorphism and the risk of colorectal cancer and adenoma. Br J Cancer 2006; 94:928-34. [PMID: 16495921 PMCID: PMC2361367 DOI: 10.1038/sj.bjc.6603007] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Cyclin D1 (CCND1) plays a key role in cell cycle control, particularly in the transition from G1 to S phase, which is regulated by cyclin-dependent kinases. A common adenine to guanine polymorphism (A870G) in the CCND1 gene has been associated with a longer-life protein and an increased risk of colorectal cancer and adenoma in some studies. Among subjects with hereditary nonpolyposis colorectal cancer, the A870G polymorphism has also been associated with a younger age of onset of colorectal cancer. We analysed 181 colorectal cancer cases and 475 matched controls and 524 adenoma cases and 517 matched controls within women in the Nurses’ Health Study (NHS) cohort, 171 colorectal cancer cases and 347 matched controls and 372 adenoma cases and 712 matched controls nested within men in the Health Professionals’ Follow-Up Study (HPFS) cohort, and 258 colorectal cancer cases and 415 matched controls within men in the Physicians’ Health Study (PHS) cohort to assess the risk associated with the CCND1 A870G genotype. Moreover, we assessed whether CCND1 genotype modified the effect of a sporadic (nonsyndromic) family history of colorectal cancer as well as the effect of other dietary and lifestyle risk factors for colorectal cancer and adenoma. In all cohorts combined, the CCND1 polymorphism did not show statistically significant associations to risk of colorectal cancer (odds ratio (OR) for A allele carriers, 1.04; 95% confidence interval (95% CI), 0.82–1.32) or adenoma (OR, 0.96; 95% CI, 0.79–1.18). The CCND1 A870G genotype was associated with a modest, although nonsignificantly elevated risk of colorectal cancer (OR, 1.59; 95% CI, 0.98–2.57) in women. In contrast, the polymorphism was not associated with increased risk of adenoma in either men or women. Among participants with the A870G genotype, a family history of colorectal cancer conferred a substantially greater risk of colorectal cancer in the women (P for interaction=0.06) and adenoma in the men (P for interaction=0.02). Current postmenopausal hormone (PMH) use was associated with a significant reduction in the risk of colorectal cancer and adenoma among women with the A870G genotype, whereas there was no effect of PMH use among those with the GG genotype. The CCND1 polymorphism appeared to confer a modest elevation in the risk of colorectal cancer among women. Moreover, the A870G genotype may enhance the protective effect of postmenopausal oestrogen use on the development of colorectal neoplasia.
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Affiliation(s)
- E S Schernhammer
- Channing Laboratory, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, 181 Longwood Avenue, Boston, MA 02115, USA.
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Knudsen KE, Diehl JA, Haiman CA, Knudsen ES. Cyclin D1: polymorphism, aberrant splicing and cancer risk. Oncogene 2006; 25:1620-8. [PMID: 16550162 DOI: 10.1038/sj.onc.1209371] [Citation(s) in RCA: 286] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The cyclin D1 proto-oncogene exercises powerful control over the mechanisms that regulate the mitotic cell cycle, and excessive cyclin D1 expression and/or activity is common in human cancers. Although somatic mutations of the cyclin D1 locus are rarely observed, mounting evidence demonstrates that a specific polymorphism of cyclin D1 (G/A870) and a protein product of a potentially related alternate splicing event (cyclin D1b) may influence cancer risk and outcome. Herein, we review the epidemiological and functional literatures that link these alterations of cyclin D1 to human tumor development and progression.
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Affiliation(s)
- K E Knudsen
- Department of Cell Biology, University of Cincinnati, Cincinnati, OH 45267, USA.
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Habuchi T. Common genetic polymorphisms and prognosis of sporadic cancers: prostate cancer as a model. Future Oncol 2006; 2:233-45. [PMID: 16563092 DOI: 10.2217/14796694.2.2.233] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
To date, most molecular epidemiological studies on gene polymorphisms in cancer have focused on the risk of development and susceptibility to cancer. However, interindividual genetic variation may contribute greatly to the treatment outcome and prognosis of cancer by affecting the interaction between cancer cells and hormones, growth factors and factors influencing the tumor microenvironment. In prostate cancer, several recent molecular epidemiological studies suggested the possibility of predicting treatment outcome and prognosis using genetic polymorphisms. Candidate genes are hormone-related, oncogenes, tumor-suppressor and cell cycle-growth control-related genes, as well as genes related to immune response, inflammatory change, neovasculization, and the extracellular matrix, genes involved in drug and xenobiotic metabolism and genes involved in DNA repair and genome stability. There remain a huge number of candidate genes whose polymorphisms may affect the progression and treatment outcome of various kinds of cancer, including that of prostate cancer.
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Affiliation(s)
- Tomonori Habuchi
- Department of Urology, Akita University School of Medicine, 1-1-1 Hondo, Akita 010-8543, Japan.
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Jiang J, Wang J, Suzuki S, Gajalakshmi V, Kuriki K, Zhao Y, Nakamura S, Akasaka S, Ishikawa H, Tokudome S. Elevated risk of colorectal cancer associated with the AA genotype of the cyclin D1 A870G polymorphism in an Indian population. J Cancer Res Clin Oncol 2006; 132:193-199. [PMID: 16328437 DOI: 10.1007/s00432-005-0039-7] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2005] [Accepted: 08/30/2005] [Indexed: 01/10/2023]
Abstract
PURPOSE To investigate whether the common cyclin D1 (CCND1) A870G polymorphism is a risk factor for colorectal cancer (CRC) in an Indian population. METHODS In this study, 301 newly diagnosed CRC patients and 291 healthy control subjects were genotyped by the PCR-RFLP method. Genotype frequencies were compared between cases and controls, and the association of genotypes with CRC was studied. RESULTS The CCND1 870 A allele was more frequently observed in CRC patients than controls (0.63 vs. 0.56, P=0.01), and after adjustment for age, sex, smoking habits, family history, family income and the consumption of meat, fish, vegetables and fruit, an increased risk was observed for the AA genotype compared to the GG+AG genotype (OR=1.56; 95% CI: 1.10-2.21). The increased risk were also found for colon (OR=1.96; 95% CI: 1.08-3.57) and rectal cancer (OR=1.51; 95% CI: 1.04-2.19). No correlation was observed between genotypes and age of diagnosis of CRC (49.9, 48.7 and 49.4 years for the GG, AG and AA genotypes, respectively; P=0.84). Multivariate analysis also revealed a stronger positive association with the AA genotype among patients with high meat intake (OR=2.67; 95% CI: 1.29-5.51), and particularly significant inverse associations with the GG+AG genotypes were also found for those with high vegetable consumption (OR=0.46; 95% CI: 0.27-0.79 of 2-3 servings/day, and OR=0.31; 95% CI: 0.18-0.53 for >3 servings/day) and fish intake (OR=0.48; 95% CI: 0.28-0.82). CONCLUSION These data support the hypothesis that the CCND1 A870G polymorphism may increase the risk of CRC in our Indian population.
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Affiliation(s)
- Jing Jiang
- Department of Health Promotion and Preventive Medicine, Nagoya City University Graduate School of Medical Sciences, 467-8601 Nagoya, Japan
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Gautschi O, Hugli B, Ziegler A, Bigosch C, Bowers NL, Ratschiller D, Jermann M, Stahel RA, Heighway J, Betticher DC. Cyclin D1 (CCND1) A870G gene polymorphism modulates smoking-induced lung cancer risk and response to platinum-based chemotherapy in non-small cell lung cancer (NSCLC) patients. Lung Cancer 2006; 51:303-11. [PMID: 16406195 DOI: 10.1016/j.lungcan.2005.10.025] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2005] [Revised: 10/24/2005] [Accepted: 10/31/2005] [Indexed: 01/10/2023]
Abstract
PURPOSE The cyclin D1 (CCND1) A870G gene polymorphism is linked to the outcome in patients with resectable non-small cell lung cancer (NSCLC). Here, we investigated the impact of this polymorphism on smoking-induced cancer risk and clinical outcome in patients with NSCLC stages I-IV. METHODS CCND1 A870G genotype was determined by polymerase chain reaction (PCR) and restriction fragment length polymorphism analysis (RFLP) of DNA extracted from blood. The study included 244 NSCLC patients and 187 healthy control subjects. RESULTS Patient characteristics were: 70% male, 77% smokers, 43% adenocarcinoma, and 27% squamous cell carcinoma. Eighty-one percent of the patients had stages III-IV disease. Median age at diagnosis was 60 years and median survival was 13 months. Genotype frequencies of patients and controls both conformed to the Hardy Weinberg equilibrium. The GG genotype significantly correlated with a history of heavy smoking (>or=40 py, P=0.02), and patients with this genotype had a significantly higher cigarette consumption than patients with AA/AG genotypes (P=0.007). The GG genotype also significantly correlated with tumor response or stabilization after a platinum-based first-line chemotherapy (P=0.04). Survival analysis revealed no significant differences among the genotypes. CONCLUSION Evidence was obtained that the CCND1 A870G gene polymorphism modulates smoking-induced lung cancer risk. Further studies are required to explore the underlying molecular mechanisms and to test the value of this gene polymorphism as a predictor for platinum-sensitivity in NSCLC patients.
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Affiliation(s)
- Oliver Gautschi
- Clinic and Policlinic of Medical Oncology, University Hospital, Freiburgstrasse 100, 3010 Bern, Switzerland.
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Geddert H, Kiel S, Zotz RB, Zhang J, Willers R, Gabbert HE, Sarbia M. Polymorphism of p16 INK4A and cyclin D1 in adenocarcinomas of the upper gastrointestinal tract. J Cancer Res Clin Oncol 2005; 131:803-8. [PMID: 16163549 DOI: 10.1007/s00432-005-0021-4] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2005] [Accepted: 06/30/2005] [Indexed: 01/10/2023]
Abstract
PURPOSE We investigated the prevalence of single nucleotide polymorphisms in the p16 gene (C540G) and the cyclin D1 gene (G870A), both known to regulate function in G1 arrest and therefore, may play an important role in carcinogenesis. METHODS Using PCR based restriction fragment length polymorphism and single strand conformational polymorphism, we determined single nucleotide exchanges in the p16 and cyclin D1 genes among 56 esophageal adenocarcinomas (ADC) arising in Barrett's esophagus, 95 cardiac gastric ADC, and in 191 distal gastric ADC. The allelic frequencies were compared to a control group of 253 healthy blood donors. RESULTS The C/G genotype of p16 was identified in 10.4% of esophageal carcinomas, 13.3% of cardiac carcinomas, and in 14.1% of gastric carcinomas, compared to 17.4% in the healthy control group. All other cases showed the C/C wildtype, as no homozygous G/G nucleotide exchange was detected in the group of cancer patients or in the control group. In esophageal cancer, cyclin D1 G/G genotype was found 28.6%, A/G in 46.4%, and A/A in 25.0%. In cardiac carcinoma, frequency of cyclin D1 genotype was 27.4% for G/G, 57.9% for A/G, and 14.7% for AA. In distal gastric carcinoma, both homozygous genotypes (G/G and A/A) had a frequency of 15.2% each, while the heterozygous A/G genotype occurred in 69.6% of patients. The control group displayed 24.9% G/G, 53.8% A/G, and 21.3% A/A genotype. CONCLUSIONS Our results show that frequencies of p16 or cyclin D1 polymorphisms in gastric and esophageal ADC do not differ significantly from the healthy control group. Therefore, these polymorphisms are unlikely to be associated with risk of ADC of the upper gastrointestinal tract.
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Affiliation(s)
- Helene Geddert
- Institute of Pathology, Heinrich-Heine-University, Postfach 101007, 40001, Duesseldorf, Germany
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Rydzanicz M, Golusinski P, Mielcarek-Kuchta D, Golusinski W, Szyfter K. Cyclin D1 gene (CCND1) polymorphism and the risk of squamous cell carcinoma of the larynx. Eur Arch Otorhinolaryngol 2005; 263:43-8. [PMID: 16258756 DOI: 10.1007/s00405-005-0957-7] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2004] [Accepted: 02/09/2005] [Indexed: 01/10/2023]
Abstract
Cyclin D1 is one of the key proteins involved in cell cycle control, and it is believed that its overexpression may be connected with tumorigenesis. A reason for cyclin D1 deregulation may be connected to a common G870A polymorphism at codon 242 in exon 4 of the CCND1 gene. This single nucleotide substitution, localized in the conserved splice donor site between exon 4 and the intron 4 boundary, might modulate the frequency of alternative splicing. It has been postulated that the A allele results in a higher level of mRNA (transcript b) encoding a protein with an altered C-terminal domain. The influence of CCND1 G-->A polymorphism for the risk of cancer and the prognosis of patients with different types of solid tumors has already been suggested. This study was conducted to investigate the association between the cyclin D1 gene polymorphism and laryngeal cancer risk, as well as the clinical outcome. We also examined the relationship between genotype/allele distributions and the cyclin D1 expression profile. The genotyping study was done using the PCR-RFLP method in 63 patients with larynx cancer and 102 healthy controls. The heterozygotic genotype GA as well as a combination of GA and AA genotypes were associated with an increased risk of larynx cancer compared to the GG genotype (OR =3.02; P =0.004 and OR =2.52; P =0.013, respectively). The A allele frequency was higher in cancer cases (0.484) than in controls (0.416) that were connected with a slightly increased risk of cancer development (OR =1.34); however, the difference was not significant. The AA genotype was associated with an early cancer onset compared to the GG genotype (median age: 51.5 and 63.0 years, respectively). We also demonstrated that the AA genotype was associated with the occurrence of lymph node metastases (OR =3.26) and a higher level of cyclin D1 overexpression. These results suggest that the CCND1 A allele may be a genetic factor that modulates the risk of larynx cancer development, and it may also have an effect on tumor biology and disease prognosis.
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Affiliation(s)
- Malgorzata Rydzanicz
- Institute of Human Genetics, Polish Academy of Sciences, Ul. Strzeszyńska 32, 60-479 Poznan, Poland.
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Opinion of the Scientific Committee on a request from EFSA related to A Harmonised Approach for Risk Assessment of Substances Which are both Genotoxic and Carcinogenic. EFSA J 2005. [DOI: 10.2903/j.efsa.2005.282] [Citation(s) in RCA: 171] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
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Hou X, Wang S, Zhou Y, Xu Z, Zou Y, Zhu X, Han M, Pang T, Han ZC. Cyclin D1 Gene Polymorphism and Susceptibility to Childhood Acute Lymphoblastic Leukemia in a Chinese Population. Int J Hematol 2005; 82:206-9. [PMID: 16207592 DOI: 10.1532/ijh97.a10418] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Cyclin D1 is a key protein involved in cell cycle regulation. A common A870G single nucleotide polymorphism in exon 4 of the cyclin D1 gene (CCND1) has an effect on the transcription of 2 different cyclin D1 messenger RNAs. Correlation between genetic polymorphism of A870G of CCND1 and clinical outcome among patients with acute lymphoblastic leukemia (ALL) has been reported. However, the effect on ALL occurrence remains unclear. To examine the genotypic frequency of CCND1 polymorphism, we performed a case-control study in a Chinese population of 183 children with ALL and 190 healthy controls. The genetic frequency of CCND1 had a significant overall correlation in patients and controls. The AA genotype of CCND1 showed a tendency to increase ALL risk 3.2898-fold compared with the AG + GG genotype (P = .0207). Stratification of patients according to cell type, risk level, and chemotherapeutic response showed significance for the AA genotype in T-cell ALL, ALL with high risk, and no complete remission (P = .047, P = .011, and P = .007, respectively). No gene dosage effect was observed in this study. The results of the present study suggested that CCND1 genetic polymorphism may be related to the occurrence of ALL in a population of Chinese children.
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Affiliation(s)
- Xuwei Hou
- State Key Laboratory of Experimental Hematology, Institute of Hematology and Hospital of Blood Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, PR China
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Casson AG, Zheng Z, Evans SC, Geldenhuys L, van Zanten SV, Veugelers PJ, Porter GA, Guernsey DL. Cyclin D1 polymorphism (G870A) and risk for esophageal adenocarcinoma. Cancer 2005; 104:730-9. [PMID: 15971196 DOI: 10.1002/cncr.21229] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
BACKGROUND To investigate individual susceptibility to gastroesophageal reflux disease, Barrett esophagus, and esophageal adenocarcinoma, the authors studied the frequency of the common G870A polymorphism of CCND1, which encodes cyclin D1, a key cell cycle regulatory protein. METHODS The study population included 307 patients who were enrolled in a prospective case-control study to evaluate lifestyle risk factors and molecular alterations in gastroesophageal reflux disease (n = 126 patients), Barrett esophagus (n = 125 patients), and esophageal adenocarcinoma (n = 56 patients). A control group included 95 strictly asymptomatic individuals. Genomic DNA was extracted from cases and controls, and polymerase chain reaction was used to amplify exon 4 of CCND1. After digestion with BsrI, acrylamide gel electrophoresis was used to identify the wild type and common G870A polymorphic alleles. The frequency of alleles (G/G, G/A, A/A) was compared between cases and controls. Immunohistochemistry was used to study cyclin D1 distribution in among patients in the case group. RESULTS Compared with the asymptomatic control group, and adjusted for age and gender, increasing frequencies were seen for the A/A genotype in patients with gastroesophageal reflux disease (odds ratio [OR], 2.83; 95% confidence interval [95% CI], 1.09-7.34), Barrett esophagus (OR, 3.69; 95% CI, 1.46-9.29), and esophageal adenocarcinoma (OR, 5.99; 95% CI, 1.86-18.96). No association was seen between genotype and cyclin D1 overexpression. CONCLUSIONS The CCND1 A/A genotype was associated with increased risk for gastroesophageal reflux disease, Barrett esophagus, and esophageal adenocarcinoma. The contribution of this polymorphism to susceptibility of defined stages of progression to esophageal adenocarcinoma suggested potential application in endoscopic Barrett surveillance programs.
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Affiliation(s)
- Alan G Casson
- Department of Surgery, Division of Thoracic Surgery, Dalhousie University, Halifax, Nova Scotia, Canada.
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Jeon YT, Kim JW, Song JH, Park NH, Song YS, Kang SB, Lee HP. Cyclin D1 G870A polymorphism and squamous cell carcinoma of the uterine cervix in Korean women. Cancer Lett 2005; 223:259-63. [PMID: 15896460 DOI: 10.1016/j.canlet.2004.12.024] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2004] [Revised: 12/15/2004] [Accepted: 12/18/2004] [Indexed: 01/10/2023]
Abstract
Though many investigators have reported relationships between the CCND1 polymorphism and susceptibility to various carcinomas, to our knowledge, no report has been issued concerning its relationship with uterine cervical cancer. Thus, we undertook this study to investigate the association between CCND1 polymorphisms and susceptibility to cervical cancer in Korean women. This study was carried on 222 patients with squamous cell carcinoma of uterine cervix and on 314 normal controls. CCND1 genotyping was determined by polymerase chain reaction and restriction fragment length polymorphism. The allelic frequencies of the cases (A, 0.53; G, 0.47) were not significantly different from those of the controls (A, 0.49; G, 0.51) (P=0.238). Regression analysis after adjusting for age showed that the CCND1 G870A genotypes are not related to the risk of squamous cell carcinoma of the uterine cervix. Our findings suggest that the CCND1 polymorphism is not associated with an increased risk of squamous cell carcinoma of uterine cervix in Korean women.
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Affiliation(s)
- Yong-Tark Jeon
- Department of Obstetrics and Gynecology, College of Medicine, Seoul National University, 28 Yungun-Dong, Jongno-Gu, 110-744 Seoul, South Korea
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Kang S, Kim JW, Park NH, Song YS, Kang SB, Lee HP. Cyclin D1 polymorphism and the risk of endometrial cancer. Gynecol Oncol 2005; 97:431-5. [PMID: 15863141 DOI: 10.1016/j.ygyno.2005.01.023] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2004] [Revised: 01/13/2005] [Accepted: 01/18/2005] [Indexed: 01/10/2023]
Abstract
OBJECTIVES The common G to A single nucleotide polymorphism (G870A) in the splice donor region of exon 4 enhances alternate splicing, and produces a longer half-life cyclin D1 (CCND1). This study was aimed at investigating the possible association between the G870A polymorphism in CCND1 and the risk of endometrial cancer. METHODS We assessed the association between the CCND1 G870A polymorphism and the risk of endometrial cancer in a hospital-based case-control study among 231 Korean women (77 cases; 154 matched controls). Controls were matched to cases with respect to age, menopausal status, and hormone therapy status. RESULT The allele frequencies of the case subjects (A, 0.45; G, 0.55) were significantly different from those of control subjects (A, 0.58; G, 0.42) (P = 0.008). All case and control subjects were in Hardy-Weinberg equilibrium. The AA genotype was associated with a significantly elevated odds ratio (OR) of 3.18 [95% confidence interval (CI) 1.38-7.37, P = 0.007], and the AG genotype was associated with an OR of 1.38 (95% CI 0.65-2.89). When we combined the GG and AG genotypes as a reference genotype, we found that the OR for the AA genotype was 2.53 (95% CI 1.34-4.80, P = 0.004), supporting a recessive model for the A allele. Conditional logistic regression adjusted for various risk factors of endometrial cancer revealed positive associations between the AA genotype and an increased risk of endometrial cancer (OR 3.16, 95% CI 1.18-8.43, P = 0.022). However, no significant difference in endometrial cancer stage or grade was observed between the CCND1 genotypes. CONCLUSION Our data suggest that the CCND1 polymorphism is associated with an increased risk of endometrial cancer. To validate this association, a large-scale population-based study is needed.
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Affiliation(s)
- Sokbom Kang
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Seoul National University, 28 Yungun-Dong, Chongno-Ku, Seoul 110-744, South Korea
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Ceschi M, Sun CL, Van Den Berg D, Koh WP, Yu MC, Probst-Hensch N. The effect of cyclin D1 (CCND1) G870A-polymorphism on breast cancer risk is modified by oxidative stress among Chinese women in Singapore. Carcinogenesis 2005; 26:1457-64. [PMID: 15845652 DOI: 10.1093/carcin/bgi093] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
Cyclin D1 (CCND1), an intracellular cell-cycle regulatory protein with checkpoint function, can promote cell proliferation or induce growth arrest and apoptosis depending on the cellular context. We hypothesized that the direction of the association between the (CCND1) G870A-polymorphism and breast cancer risk may be modified by dietary and genetic factors influencing the oxidant-antioxidant balance, such as a dietary pattern with a high intake of n-6 fatty acids and a low intake of n-3 fatty acids, or a genetic profile that is deficient in glutathione S-transferases. We tested our hypothesis in a case-control study nested into the Singapore Chinese Health Study, a prospective investigation of diet and cancer in 63,000 Chinese men and women. Genomic DNA collected from 258 incident cases of breast cancer and 670 female cohort controls was examined for CCND1, GSTM1, GSTT1 and GSTP1 genes using fluorogenic 5'-nuclease assay. Unconditional logistic regression models were used to assess the effects with adjustment for potential confounders. All statistical tests were two-sided. The heterozygous CCND1 GA genotype significantly reduced the breast cancer risk in all subjects (OR=0.67, 95% CI 0.45-0.99) when compared with the GG genotype. The association was restricted to women with a high (above median value) intake level of n-6 fatty acids (OR=0.51, 95% CI 0.30-0.87), a low (below median value) intake level of the antagonistic marine n-3 fatty acids (OR=0.54, 95% CI 0.32-0.93) or a total lack of the antioxidative GSTM1 (OR=0.44, 95% CI 0.25-0.80) or GSTT1 genes (OR=0.46, 95% CI 0.24-0.87). The effects were consistently stronger in cases with advanced disease. The AA genotype did not affect breast cancer risk. The results of this study are compatible with the hypothesis that the oxidant-antioxidant balance in cells is an important determinant of the direction of the cyclin D1 effect, leading either to cell proliferation or cell death.
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Affiliation(s)
- Michela Ceschi
- Cancer Registry and Molecular Epidemiology, University Hospital, Vogelsangstrasse 10, 8091 Zurich, Switzerland
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Spitz MR, Wu X, Mills G. Integrative epidemiology: from risk assessment to outcome prediction. J Clin Oncol 2005; 23:267-75. [PMID: 15637390 DOI: 10.1200/jco.2005.05.122] [Citation(s) in RCA: 54] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
In this paper, we advance the concept of integrative epidemiology. Our unifying premise is that the same genes that are implicated in cancer risk may also be involved in a person's propensity to carcinogenic exposure and/or to modulation of therapeutic outcome. In the coming years, molecular epidemiology will play an increasingly prominent role in early detection of cancer and in identifying genetically high-risk subgroups that might benefit disproportionately from more intensive screening or chemoprevention interventions. Molecular epidemiology is also integral to pharmacogenetic research, by constructing genetic profiles that could be used to individualize therapy and to understand the functional consequences of chemoprevention, chemotherapy, or radiotherapy response. At the level of risk assessment, the focus might be on germline polymorphisms in candidate genes; for early detection, epigenetic events in these same or other genes may be relevant; and tumor tissue expression levels, loss of heterozygosity, genomic amplification, rearrangements, or somatic mutations in the same classes of genes may determine outcome. We will provide examples of how changes in the function of a single gene can contribute to susceptibility to carcinogenic exposure, predisposition to cancer development, patient prognosis, and prediction of outcome.
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Affiliation(s)
- Margaret R Spitz
- Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Box 189, Houston, TX 77030, USA.
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Gao P, Zhou GY, Liu Y, Li JS, Zhen JH, Yuan YP. Alteration of cyclin D1 in gastric carcinoma and its clinicopathologic significance. World J Gastroenterol 2004; 10:2936-9. [PMID: 15378768 PMCID: PMC4576247 DOI: 10.3748/wjg.v10.i20.2936] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
AIM: To detect the genetic alteration and abnormal expression of cyclin D1 in gastric carcinoma and investigate its clinicopathologic significance in advanced gastric carcinoma.
METHODS: Proteins of cyclin D1 were detected by immunohistochemistry in 42 cases of advanced gastric carcinoma with their follow-up data available, 27 cases of early stage carcinoma, 21 cases of gastric adenoma, 22 cases of hyperplastic polyp and 20 cases of normal mucosa adjacent to adenocarcinomas. Genetic alteration of cyclin D1 was detected by Southern blot and expression of cyclin D1 mRNA was detected by PT-PCR in 42 cases of advanced gastric carcinoma.
RESULTS: Cyclin D1 protein was not expressed in normal mucosa, hyperplastic polyp and gastric adenoma, while it was only positively expressed in gastric carcinoma. The expression rate of cyclin D1 protein in early stage gastric carcinoma, advanced gastric carcinoma and lymph node metastasis was 48.1%, 47.4% and 50.0%, respectively. The amplification of cyclin D1 gene was detected in 16.6% of advanced gastric carcinomas. The overexpression of cyclin D1 mRNA was detected in 40.5% of the samples. There was no significant correlation between cyclin D1 protein expression and age, lymph-node metastasis and histological grading in patients with advanced gastric carcinoma (χ2 = 0.038,0.059,0.241, P > 0.05). Significant correlation was observed between the expression of cyclin D1 protein and the 5-year survival rate (χ2 = 3.92, P < 0.05).
CONCLUSION: Detection of cyclin D1 protein by immunohistochemistry may be useful in the diagnosis of early gastric carcinomas. Patients with positive expression of cyclin D1 protein tend to have a worse prognosis.
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Affiliation(s)
- Peng Gao
- Department of Pathology, School of Medicine, Shandong University, Jinan 250012, Shandong Province, China.
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Abstract
Although cigarette smoking is the dominant risk factor for several epithelial cancers, only a small fraction of individuals with tobacco exposure develop cancer. The underlying hypothesis is that genetic factors may render certain smokers more susceptible to cancer than others. Genetic alterations in critical regulatory pathways may predispose cells to carcinogenesis. These pathways include regulation of xenobiotic metabolism; control of genomic stability, including DNA repair mechanisms, cell-cycle checkpoints, apoptosis and telomere length; and control of microenvironmental factors, such as matrix metalloproteinases, inflammation and growth factors. In addition, epigenetic events, such as promoter hypermethylation and loss of imprinting, are also involved in carcinogenesis. In this review, we will summarize recent advances in genetic susceptibility to tobacco-related cancer. Emphasizing on risk assessment, we will describe how genetic variations in the above-mentioned genetic pathways modify the tobacco-related cancer risk. In addition, we will discuss how genetic variations may assist in predicting clinical outcome, such as the natural history of cancer and treatment response. The measurements of genetic susceptibility by both genotypic and phenotypic assays are covered in the text. Finally, we present a number of current concerns that need to be addressed as the exciting field of molecular cancer epidemiology advances rapidly.
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Affiliation(s)
- Xifeng Wu
- Department of Epidemiology, MD Anderson Cancer Center, Houston, TX 77030, USA.
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Wang C, Li Z, Fu M, Bouras T, Pestell RG. Signal transduction mediated by cyclin D1: from mitogens to cell proliferation: a molecular target with therapeutic potential. Cancer Treat Res 2004; 119:217-37. [PMID: 15164880 DOI: 10.1007/1-4020-7847-1_11] [Citation(s) in RCA: 63] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2023]
Affiliation(s)
- Chenguang Wang
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
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