Association of Cyclin D1 Variants with Head and Neck Cancer Susceptibility: Evidence from a Meta-analysis

Whether cyclin D1 (CCND1) gene variants increase susceptibility to head and neck cancer (HNC) isundetermined. Therefore, we performed the present meta-analysis to systematically assess any possibleassociation between CCND1 variants (G870A and G1722C) and HNC risk. Seventeen studies for CCND1 G870Aand three studies for CCND1 G1722C were included. Overall, CCND1 polymorphisms (G870A and G1722C)had no association with increased HNC risk (p>0.05). In the subgroup analysis by smoking status, significantlyincreased HNC risk was found among smokers under allele contrast, homozygous comparison and recessivemodels (p<0.05), smoking carriers of A allele and AA genotype appearing at elevated risk. In conclusion, whilethere was overall a lack of any association between CCND1 polymorphisms (G870A and G1722C) and HNCrisk, smokers carrying the A allele and AA genotype of the CCND1 G870A polymorphism may be susceptibleto HNC development.     

Cyclin D1 (CCND1) G870A polymorphisms and cervical cancer susceptibility: a Meta-analysis based on Ten case–control studies

Many studies have evaluated the association between cyclin D1 (CCND1) G870A polymorphism and cervical cancer susceptibility. However, these studies showed inconsistent results. The aim of this study was to derive a more precise estimation of this association. We searched PubMed and Embase for related studies that had been published in English, and ten case–control studies with a total of 2,864 cases and 3,898 controls were finally identified to be eligible studies in the meta-analysis. The association was assessed by summarizing the odds ratios (ORs) with the corresponding 95 % confidence intervals (CIs). Overall, there was no significant association between cyclin D1 (CCND1) G870A polymorphism and cervical cancer risk (for the allele model A vs. G: OR?=?1.02, 95 % CI 0.88–1.19, p?=?0.76; for the co-dominant model AA vs. GG: OR?=?1.03, 95 % CI 0.75–1.41, p?=?0.85; for the dominant model AA?+?GA vs. GG: OR?=?1.00, 95 % CI 0.78–1.28, p?=?0.99; for the recessive comparison AA vs. GA?+?GG: OR?=?1.06, 95 % CI 0.85–1.32, p?=?0.62). In subgroup analysis by ethnicity, no significant difference was found in both Asians and Caucasians. In summary, the present meta-analysis provides evidence that genotypes for the cyclin D1 (CCND1) G870A polymorphism may be not associated with genetic susceptibility of cervical cancer.     

Expression and subcellular localization of cyclin D1 protein in epithelial ovarian tumour cells

The expression of cyclin D1 protein in tumour sections from 81 patients with epithelial ovarian cancer was analysed using immunohistochemistry. The tumours that overexpressed cyclin D1 in more than 10% of neoplastic cells were considered positive. Thus overexpression of cyclin D1 was observed in 72/81 (89%) of the cases examined. Protein was detected in both the nucleus and the cytoplasm in 24/81 (30%) and localized exclusively in the cytoplasm in 48/81 (59%) of the tumours. Cyclin D1 was overexpressed in both borderline and invasive tumours. There was no association between protein overexpression and tumour stage and differentiation. Furthermore, no correlation between cyclin D1 expression and clinical outcome was observed. However, in tumours overexpressing cyclin D1 (n = 72), the proportion displaying exclusively cytoplasmic localization of protein was higher in those with serous compared with non-serous histology (P = 0.004, odds ratio 4.8, 95% confidence interval 1.4-19.1). Western analysis using a monoclonal antibody to cyclin D1 identified a 36 kDa protein in homogenates from seven tumours displaying cytoplasmic only and one tumour demonstrating both nuclear and cytoplasmic immunostaining. Using restriction fragment length polymorphism polymerase chain reaction and PCR-multiplex analysis, amplification of the cyclin D1 gene (CCND1 was detected in 1/29 of the tumours demonstrating overexpression of cyclin D1 protein. We conclude that deregulation of CCND1 expression leading to both cytoplasmic and nuclear protein localization is a frequent event in ovarian cancer and occurs mainly in the absence of gene amplification.     

Contribution of cyclin d1 (CCND1) and E-cadherin (CDH1) polymorphisms to familial and sporadic colorectal cancer

The molecular basis for most non-HNPCC familial colorectal cancer cases is unknown, but there is increasing evidence that common genetic variants may play a role. We investigated the contribution of polymorphisms in two genes implicated in the pathogenesis of colorectal cancer, cyclin D1 (CCND1) and E-cadherin (CDH1), to familial and sporadic forms of the disease. The CCND1 870A/G polymorphism is thought to affect the expression of CCND1 through mRNA splicing and has been reported to modify the penetrance of HNPCC. Inactivation of E-cadherin is common in colorectal cancer, and truncating germline mutations have been reported to confer susceptibility to colorectal as well as diffuse gastric cancer. The -160A/C CDH1 polymorphism appears to affect expression of CDH1 and may therefore also confer an increased risk. We found a significantly higher frequency of CCND1 870A allele in 206 familial cases compared to 171 controls (P=0.03). Odds ratios in heterozygotes and homozygotes were 1.7 (95% CI: 1.0-2.66) and 1.8 (95% CI: 1.0-3.3) respectively. The difference was accounted for by an over-representation of A allele in non-HNPCC familial cases (P=0.007). Over-representation of the CCND1 A allele was also seen in sporadic colorectal cancer cases compared to controls but this did not attain statistical significance (P=0.08). No significant differences between the frequency of CDH1 -160A/C genotypes in familial, sporadic colorectal cancer cases and controls were seen, although a possible association between the low expressing A allele and right-sided tumours was detected in familial cases.     

Distribution of <Emphasis Type="Italic">CCND1</Emphasis> A870G Polymorphism in Patients with Advanced Uterine Cervical Carcinoma

We examined the distribution of the CCND1 A870G (rs9344) polymorphic variant in patients with cervical cancer (n = 129) and healthy individuals (n = 288) in a sample of a Polish cohort. We showed that patients with advanced cervical cancer bearing the CCND1 A/A and A/G genotypes displayed a 1.811-fold increased risk of cervical cancer (95% CI = 1.150–2.852, p = 0.0098). We also found a significantly higher frequency of the CCND1 870A allele in patients with cancer than in controls, p = 0.0116. Our investigation confirmed that the CCND1 870A gene variant may be a genetic risk factor in the incidence of advanced cervical cancer.     

Association of cyclin D1 gene polymorphisms with risk of esophageal squamous cell carcinoma in Kashmir Valley: a high risk area

Investigation of potential association of SNPs (G870A, rs9344; G1722C, rs678653) of cyclin D1 gene (CCND1) with susceptibility to esophageal squamous cell carcinoma (ESCC) in Kashmir valley (India). The study included 302 subjects comprising 151 ESCC cases and 151 controls. PCR‐RFLP and direct sequencing were employed for genotyping. The G870A polymorphism, the individuals carrying GA + AA genotype was having 2.80‐fold increased risk for development of ESCC (OR 2.8, 95% CI = 1.77–4.4; P = 0.0001) compared to GG genotype. Further a significantly higher risk was observed in individuals who consume >3 cups per day of salted tea (OR = 5.1; 95% CI = 1.6–16.7; P = 0.0016) and had smoking habits (OR = 6.3; 95% CI = 2.9–13.9; P = 0.0005). We also demonstrate for the first time in CCND1 1722 locus, the CC genotype was strongly associated with increased risk of developing ESCC (OR = 2.58; 95% CI = 1.61–4.15; P = 0.0001). In addition, the frequency of polymorphic C allele was also found to be higher in cases (OR = 1.92; 95% CI = 1.37–2.69; P = 0.0002). There appears to be an influence of CCND1 G870A/G1772C genotypes on genetic susceptibility to ESCC. Mol. Carcinog. ©2011 Wiley‐Liss, Inc.     

CYP2D6 and CYP2E1 Gene Polymorphisms and their Association with Cervical Cancer Susceptibility: A Hospital Based Case-Control Study from South-Western Maharashtra

Background: In last few years several studies all over the world discovered the genetic polymorphisms in different cytochrome P450 genes associated with risk of various cancers, but contradictory outcomes were evidenced in case of cervical cancer risk.  In this case-control study we aimed to see whether the polymorphism of CYP2D6 or CYP2E1 genes may or may not be associated with cervical cancer risk in women of rural Maharashtra. Methods: In this case-control study, the association of CYP2D6 and CYP2E1 gene polymorphism with cervical cancer risk was studied by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The study was conducted with 350 clinically confirmed cervical cancer patients and 350 healthy women in a population of South-Western Maharashtra. The Odds ratio (OR) with 95% confidence interval and p-value were evaluated, where p ≤0.005 was considered as statistically significant. Results: After the analysis of SNP (rs389209) of CYP2D6 and SNPs (rs2031920, rs6413432, rs6413420) of CYP2E1, we noticed that variant allele A of CYP2E1*6 showed significant increase in cervical cancer cases (OR=4.81; 95% CI: 1.57- 14.77; p=0.005). The genotypic distribution of heterozygote G/A genotype of CYP2D6*4 showed negative association with cervical cancer development when age of cancer occurrence (OR=0.41; 95% CI: 0.27- 0.61; p<0.0001) and tobacco history (OR=0.35; 95% CI: 0.20- 0.59; p=0.0001) was considered. Conclusion: The findings from this study supported that rs6413432 SNP of CYP2E1*6 increased cervical cancer risk in the studied rural women population.     

<Emphasis Type="Italic">CCND1</Emphasis> amplification and cyclin D1 expression in breast cancer and their relation with proteomic subgroups and patient outcome

INTRODUCTION: 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. AIMS OF THE STUDY: (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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSION: 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.     

Effects of the cyclin D1 polymorphism on lung cancer risk--a meta-analysis

Background: Cyclin D1 (CCND1) is critical in the transition of the cell cycle from G1 to S phases andunbalanced cell cycle regulation is a hallmark of carcinogenesis. A number of studies conducted to assess theassociation between CCND1 G870A polymorphism and susceptibility to lung cancer have yielded inconsistentand 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) with95% 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 theHardy-Weinberg equilibrium (HWE) was performed. Results: Ten case-control studies with a total of 10,548subjects were eligible. At the overall analysis the CCND1 870A allele appeared to be associated with elevatedlung 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 ethnicityand sensitivity analysis further pointed to associations, particularly in Asians. Conclusion: This meta-analysissuggests that the A allele of CCND1 G870A polymorphism confers additional lung cancer risk.     

CCND1基因G870A位点多态性与宫颈癌易感性的Meta分析

目的:运用Meta分析方法研究CCND1基因G870A位点多态性与宫颈癌易感性的发生风险。方法:检索PubMed和CNKI数据库中有关CCND1基因G870A位点多态性与宫颈癌易感性的相关性研究,根据纳入标准提取文献数据,应用STATA 11.0软件以OR值和95%可信区间为效应指标,进行Meta统计分析,并对发表偏倚及检测敏感性进行检测。结果:纳入9篇对照研究,共计2638例宫颈癌患者和3651例健康对照人群,Meta分析结果显示,总人群中,CCND1基因G870A位点多态性与宫颈癌风险之间没有显著关联(GA vs GG:OR=1.07,95%CI=0.86-1.34,P=0.53,I2=57.6%;AA vs GG:OR=1.09,95%CI=0.79-1.51,P=0.59,I2=75.0%;(GA+AA) vs GG:OR=1.08,95%CI=0.86-1.36,P=0.49,I2=64.6%;AA vs (GG+GA):OR=1.07,95%CI=0.83-1.36,P=0.61,I2=73.3%)。在针对种族和对照人群来源设计的亚组分析中,仍没有发现CCND1基因G870A位点多态性和宫颈癌的发生风险具有相关性。结论:CCND1基因G870A位点多态性可能与宫颈癌的发生无关。     

Cyclin D1 (CCND1) genotype is associated with tumour grade in sporadic pituitary adenomas.

The cyclin D1 (CCND1) gene contains a frequent A/G polymorphism within the splice donor region of exon 4/intron 4. CCND1 genotype is associated with clinical outcome in a number of malignancies although prognostic significance varies with tumour type. We examined CCND1 allele frequencies and genotype distribution in 294 patients with sporadic pituitary adenomas of various histologies. CCND1 allele frequencies and distribution of genotypes were similar in the 294 cases compared with previously reported control populations. Analysis according to tumour subtype showed no statistical difference in allele frequencies compared with controls. However, CCND1 genotype distribution in the somatotrophinomas showed a significant difference compared with normal controls (P = 0.008). We next examined CCND1 allele frequencies and genotype distribution across the tumour grades. Within the total tumour cohort the CCND1 allele frequencies showed a significant inverse relationship across the tumour grades (P = 0.005). The CCND1 A allele progressively increased from grade 1 (0.37) through to grade 4 (0.62) tumours, whilst the CCND1 G allele frequency progressively decreased from grade 1 (0.63) through to grade 4 (0.38) tumours. Trend analysis of CCND1 genotypes showed a significant progressive increase in AA frequency from grade 1 (15%) through to grade 4 (46%) tumours (P = 0.005). The CCND1 GG genotype progressively decreased from grade 1 (41%) through to grade 4 (23%) tumours (P = 0.204). No statistical significance was observed between CCND1 AG genotype and tumour grades. While the functional significance of the observed segregation of the CCND1 A/G polymorphism and tumour grade is unclear, our data suggest that CCND1 allele frequencies and genotype distributions show significant differences between tumour grades in sporadic pituitary adenomas. Since CCND1 genotype may be determined by analysis of peripheral blood samples it may provide a useful predictive marker for those tumours likely to show invasive behaviour. This may be clinically useful in indicating which tumours should receive adjunctive treatment (e.g. radiotherapy) immediately after surgical resection.     

CCND1 polymorphisms (A870G and C1722G) modulate its protein expression and survival in oral carcinoma

Cyclin D1 is an essential regulator of the G1 phase of the cell cycle progression and plays an important role in the transition of the cell from the G1 phase to the S phase of the cell cycle. Overexpression of cyclin D1 is a frequently observed feature of human cancers of diverse histological origin. Recently, we have reported overexpression of cyclin D1 in oral carcinoma. However, the underlying mechanism leading to this aberrant expression remains poorly understood. In this study, we have investigated the role of CCND1 A870G and C1722G polymorphisms on cyclin D1 expression and prognosis in a relatively homogenous population of 178 oral squamous cell carcinoma patients by PCR-SSCP, RFLP, RT-PCR and immunohistochemical methods. Genotype frequencies of both the polymorphisms were conformed to Hardy-Weinberg equilibrium. CCND1 A870G (p=0.004) and C1722G (p=0.012) polymorphisms were significantly associated with cyclin D1 expression. Kaplan-Meier estimates revealed that CCND1 genotypes A870G 'GG' (p=0.012) and C1722G 'CC' (p=0.021) could predict the poor survival of the patients. In multivariate analysis, CCND1 A870G genotype combination (p=0.024, HR - 1.74 (1.08-2.81)) and cyclin D1 expression (p=0.025, HR - 1.72 (1.07-2.77)) were independent predictors of survival in this patient cohort. Our results thus demonstrate, CCND1 polymorphisms stand-in as cis-acting regulatory elements modulating its expression and cyclin D1 genotype and phenotype could provide valuable additional information regarding prognosis of oral cancer patients.     

Association of cyclin D1 polymorphism with increased susceptibility to oral squamous cell carcinoma

We have examined the association of the CCND1 A/G870 polymorphism with susceptibility and outcome in 174 German patients with oral SCC (OSCC). The CCND1 G870 allele frequency was increased in cases (G870=0.65) when compared to controls (n=155, G870=0.54) and the distribution of CCND1 genotypes were significantly different (p=0.014). Using logistic regression, correcting for age, gender and tobacco consumption, an increased frequency of the CCND1 GG870 genotype was observed in the OSCC cases (p=0.025, OR 3.37, 95% CI 1.61-9.80). No significant associations were observed between CCND1 A/G870 and tumour histological factors. Our data suggests that the CCND1 GG870 genotype is associated with increased susceptibility to OSCC. The involvement of cyclin D1 polymorphism in mechanisms of SCC development may differ in the different sub-sites of the head and neck.     

A Cyclin D1 (CCND1) Gene Polymorphism Contributes to Susceptibility to Papillary Thyroid Cancer in the Turkish Population

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 genotypingwas 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.     

Polymorphisms in TP53 (rs1042522), p16 (rs11515 and rs3088440) and NQO1 (rs1800566) Genes in Thai Cervical Cancer Patients with HPV 16 Infection

The risk of cervical cancer development in women infected with HPV varies in relation to the individual host’sgenetic makeup. Many studies on polymorphisms as genetic factors have been aimed at analyzing associations withcervical cancer. In this study, single nucleotide polymorphisms (SNPs) in 3 genes were investigated in relation tocervical cancer progression in HPV16 infected women with lesions. Two thousand cervical specimens were typedby PCR sequencing methods for TP53 (rs1042522), p16 (rs11515 and rs3088440) and NQO1 (rs1800566). Ninetytwo HPV16 positive cases and thirty two normal cases were randomly selected. Analysis of TP53 (rs1042522)showed a significantly higher frequency in cancer samples (OR=1.22, 95%CI=1.004-1.481, p-value=0.016) whiledifferences in frequency were not significant within each group (p-value=0.070). The genotype distributions ofp16 (rs11515 and rs3088440) and NQO1 (rs1800566) did not show any significantly higher frequency in cancersamples (p-value=0.106, 0.675 and 0.132, respectively) or within each group (p-value=0.347, 0.939 and 0.111,respectively). The results indicated that the polymorphism in TP53 (rs1042522) might be associated with riskof cervical cancer development in HPV16 infected women. Further studies of possible mechanisms of influenceon cervical cancer development would be useful to manage HPV infected patients.     

Cyclin D1 gene polymorphism as a risk factor for squamous cell carcinoma of the upper aerodigestive system in non-alcoholics

Squamous cell carcinoma of the upper aerodigestive tract (UADT) is associated with environmental factors, especially tobacco and alcohol consumption. Genetic factors, including cyclin D1 (CCND1) polymorphism have been suggested to play an important role in tumorigenesis and progression of UADT cancer. To investigate the relationship between CCND1 polymorphism on susceptibility for UADT cancers, 147 cancer and 135 non-cancer subjects were included in this study. CCND1 genotype at codon 242(G870A) in exon 4 was undertaken using denaturing high performance liquid chromatography (DHPLC) and DNA sequencing. Significant odds ratio (OR) of the AA+GA genotypes [OR=7.5 (95% CI: 1.4-39.7)] was observed in non-drinkers but for non-smokers a non-significant [OR=5.4 (95% CI: 0.9-31.4)] was found in the adjusted model. These results suggest that allele A may be a risk factor for UADT cancer, especially in non-alcoholics. However, further epidemiological studies are needed to establish the exact role of CCND1 polymorphism and the development of UADT cancers.     

Relevance of cyclin D1b expression and CCND1 polymorphism in the pathogenesis of multiple myeloma and mantle cell lymphoma

Background  

The CCND1 gene generates two mRNAs (cyclin D1a and D1b) through an alternative splicing at the site of a common A/G polymorphism. Cyclin D1a and b proteins differ in their C-terminus, a region involved in protein degradation and sub-cellular localization. Recent data have suggested that cyclin D1b could be a nuclear oncogene. The presence of cyclin D1b mRNA and protein has been studied in two hemopathies in which cyclin D1 could be present: multiple myeloma (MM) and mantle cell lymphoma (MCL). The A/G polymorphism of CCND1 has also been verified in a series of patients.