Cyclin D1 gene polymorphism as a risk factor for oral premalignant lesions

BACKGROUND: Deregulation of cell cycle plays an important role in tumorigenesis. Cyclin D1 gene (CCND1) is a key regulator of the G(1) phase of the cell cycle. METHODS: In this case-control study of 115 oral premalignant lesion (OPL) patients and 230 controls, we genotyped the CCND1 single nucleotide polymorphism (SNP) at the exon 4 splice site (G870A) and determined the association of this SNP with the risk of developing OPLs. RESULTS: We found significant associations between the heterozygous variant allele (GA), the homozygous variant allele (AA) and OPL risk, with adjusted odds ratios (ORs) of 1.91 [95% confidence interval (CI), 1.05-3.48] and 2.38 (95% CI, 1.16-4.87), respectively. The OR for individuals with at least one variant allele was 2.04 (95% CI, 1.15-3.60). When further stratified analyses were performed, the increased risk was more evident in younger individuals (OR = 2.82; 95% CI, 1.32-6.02), in men (OR = 2.97; 95%CI, 1.31-6.71) and in never smokers (OR = 2.92; 95% CI, 1.09-7.82). Finally, we found joint effects between the variant alleles and the smoking status. Using never smokers with the wild-type (GG) genotypes as the reference group, the ORs for never smokers with the variant genotypes (G/A + A/A), smokers with the G/G genotype and smokers with the G/A + A/A genotypes were 2.92 (1.09-7.82), 3.95 (1.36-11.5) and 7.01 (2.68-18.4), respectively. CONCLUSION: Our results suggest that the CCND1 G870A SNP may contribute to genetic susceptibility to OPLs and involve in oral cancer development.     

Cyclin D1 polymorphism and risk for squamous cell carcinoma of the head and neck: a case-control study

A G-->A polymorphism (G870A) in exon 4 of the cyclin D1 (CCND1) gene creates an alternative splice site in its mRNA, encoding a protein with an altered C-terminal domain. It has been suggested that DNA damage in cells with the A allele bypasses the G(1)/S checkpoint of the cell cycle more easily than damage in cells without the A allele. Because CCND1 plays a critical role in cell cycle control and reduced DNA repair capacity is associated with an increased risk for squamous cell carcinoma of the head and neck (SCCHN), we hypothesize that this CCND1 polymorphism modulates individual susceptibility to SCCHN. To test this hypothesis we evaluated the frequency of the polymorphism in a hospital-based case-control study of 233 newly diagnosed SCCHN patients and 248 non-cancer controls. The cases and controls were frequency matched by age (+/-5 years), sex and tobacco use. All subjects were non-Hispanic whites. We found that the A allele frequency was slightly higher in the cases (0.485) than in the controls (0.425), but the difference was borderline statistically significant (P = 0.064). The frequencies of the CCND1 AA, GA and GG genotypes were 23.6, 49.8 and 26.6%, respectively, in cases and 16.5, 52.5 and 31.5%, respectively, in controls. Multivariate logistic regression analysis adjusting for age (in years), sex, smoking and alcohol use was performed to calculate odds ratios (OR) and 95% confidence intervals (CI). Compared with the wild-type CCND1 GG, the CCND1 A G genotype was associated with a non-significantly increased risk (adjusted OR 1.15, 95% CI 0.75-1.76), but the CCND1 AA genotype was associated with a significantly increased risk (adjusted OR 1.77, 95% CI 1.04-3.02) for SCCHN. Results from a trend test using a logistic regression model were statistically significant (P = 0.044). Among the cases the mean age of onset was 59.0, 56.8 and 55.5 years for the GG, GA and AA genotypes, respectively. In the stratification analysis the CCND1 AA variant genotype was associated with a >3-fold increased risk in individuals who were 相似文献   

Dietary risk factors for squamous cell carcinoma of the upper aerodigestive tract in central and eastern Europe

Objective  The incidence of squamous cell carcinoma of upper aerodigestive tract (UADT: oral cavity, pharynx, larynx, and esophagus) has been increasing in central and eastern European countries. We investigated the relationship between diet and UADT cancers in these high risk areas. Methods  We used data from hospital-based case–control study of 948 UADT cancer cases and 1,228 controls conducted in Romania, Hungary, Poland, Russia, Slovakia, and Czech Republic. Standardized questionnaire were used to collect information on 23 different food items, along with alcohol and tobacco consumptions. Logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for the UADT cancers after adjusting for center, age, sex, tobacco & alcohol intake, and other food groups. Results  Consumption of dairy product was negatively associated with selected UADT cancers: larynx (OR: 0.38, CI: 0.23–0.62) and esophagus (OR: 0.55, CI: 0.33–0.93). While consumption of yellow/orange vegetables were inversely associated with oral/pharyngeal and laryngeal cancer (OR: 0.53, CI: 0.35–0.81 and OR: 0.62, CI: 0.38–1.00, respectively), preserved vegetable was positively associated with oral/pharyngeal and laryngeal cancer risk (p _trend < 0.01 for both). Conclusion  Specific dietary components may play a role in the development of UADT cancers in the high-risk region of central and eastern Europe.     

Cyclin D1 G870A polymorphism and squamous cell carcinoma of the uterine cervix in Korean women

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.     

Cyclin D1 overexpression associates with radiosensitivity in oral squamous cell carcinoma.

Overexpression of cyclin D1, a G1 cell cycle regulator, is often found in many different tumor types, including oral squamous cell carcinomas (SCC). Recent laboratory experiments have demonstrated that cyclin D1 levels can influence radiosensitivity in various cell lines. This study evaluated the relationship between cyclin D1 expression levels and radiosensitivity in nine oral SCC cell lines (HSC2, HSC3, HSC4, SCC15, SCC25, SCC66, SCC111, Ca9-22, and NAN2) and 41 clinical patients with oral SCC who underwent preoperative radiation therapy. Radiosensitivity of the nine oral SCC cell lines differed greatly in their response to radiation, assessed by a standard colony formation assay. Likewise, the expression of cyclin D1 varied, and the magnitude of the cyclin D1 expression correlated with increased tumor radiosensitivity. The similar significant association between the response to preoperative radiation therapy and cyclin D1 overexpression was observed in the oral SCC patients who were treated with preoperative radiation therapy. These results suggest that cyclin D1 expression levels correlate to radiosensitivity and could be used to predict the effectiveness of radiation therapy on oral SCC.     

cyclin D 1 表达对cN2 口腔鳞癌患者TPF 诱导化疗的预测性研究*

目的：探讨cyclinD1 在局部晚期口腔鳞癌患者中预后价值以及能否作为多西他赛联合顺铂、5- 氟尿嘧啶（TPF）诱导化疗的预测生物标志物。方法：2008年3 月至2010年12月上海交通大学医学院附属第九人民医院局部晚期口腔鳞状细胞癌患者256 例行TPF 诱导化疗的前瞻性随机临床试验为研究对象。随机分为试验组（术前TPF 诱导化疗+ 手术+ 术后放疗）和对照组（手术+ 术后放疗）。 采用免疫组织化学法检测患者活检标本中cyclinD1 蛋白的表达情况,分析cyclinD1 表达与行TPF 诱导化疗患者预后的关系。结果：256 例患者中232 例符合cyclinD1 检测条件,其中cyclinD1 低表达者比高表达者有较高的总生存率（P =0.001）、无病生存率（P = 0.003）、无局部复发生存率（P = 0.004）和无远处转移生存率（P = 0.001）。 试验组和对照组之间的患者预后无差异,cyclinD1 表达水平与患者行TPF 诱导化疗后的疗效无显著相关性,但cN2 患者中cyclinD1 高表达者可从TPF 诱导化疗在总生存率（P = 0.024）和无远处转移生存率（P = 0.024）中获益。结论：cyclinD1 可作为局部晚期口腔鳞癌患者的预后生物标志物,cyclinD1 高表达的cN2 口腔鳞癌患者可从TPF 诱导化疗中获益。     

Cyclin D1 overexpression in esophageal dysplasia: a possible biomarker for carcinogenesis of esophageal squamous cell carcinoma

There is controversy as to whether esophageal squamous dysplasia is a pre-cancerous lesion or a non-cancerous lesion. In this study, we conducted an immunohistochemical investigation of cyclin D1, retinoblastoma (Rb), p16INK4 and p27KIP1 expression in 36 squamous dysplasias and 34 early squamous cell carcinomas of the esophagus. The frequency of cyclin D1 overexpression was similar in dysplasias and early cancers (30% vs. 35%). Loss of p16INK4 and p27KIP1 expression was less frequent in dysplasias than in early cancers (p=0.005 and 0.001, respectively). Loss of Rb protein expression was not detected in dysplasia and rarely observed in early cancer (7%). The proliferation cell nuclear antigen index increased from moderate dysplasia to mucosal invasive carcinoma and was correlated significantly with the expression of cyclin D1, p16INK4 and p27KIP1 (p=0.0001, 0.003, and 0.007, respectively). Thus, this study found that cyclin D1 overexpression starts early in dysplasia and could be a useful marker for its malignant potentiality while reduction of p16INK4 and p27KIP1 occurs during the transformation from dysplasia to cancer. These findings suggest that esophageal dysplasia should be treated as a precancerous lesion.     

Cyclin D1 overexpression as a prognostic factor in patients with esophageal carcinoma.

BACKGROUND AND OBJECTIVES: Cyclin D1 is known to play important roles in the G1/S check-point of the cell cycle. We investigated the correlation between cyclin D1 overexpression and clinical characteristics to clarify its prognostic significance in patients with esophageal cancer. METHODS: From 1991 to 1998, cyclin D1 was investigated in esophageal cancers from 86 patients who underwent esophagectomy. Overexpression of cyclin D1 was demonstrated using an immunohistochemical method. RESULTS: Overexpression of cyclin D1 was found in 23 (26.7%) of 86 cases. Overexpression of cyclin D1 correlated with lymph node metastasis (P = 0.0083) and lymphatic vessel invasion (P = 0.018). Cyclin D1 overexpression may indicate resistance to chemotherapy. The patients with cyclin D1 overexpression had a significantly lower survival rate than those without overexpression (P = 0.013). The multivariate analysis revealed cyclin D1 overexpression to be an important prognostic factor in patients with esophageal cancer. CONCLUSIONS: Immunohistochemical examination of cyclin D1 expression may provide important prognostic information in univariate and multivariate analysis and may be necessary for determining therapeutic strategies for esophageal cancer.     

喉鳞癌组织Cyclin G1基因表达及其临床意义的研究

目的：探讨Cyclin G1基因在喉鳞状细胞癌组织中的表达及其临床意义。方法：取40例喉鳞癌组织、10例癌旁正常喉黏膜组织及10例声带息肉组织，应用RT-PCR方法检测Cyclin G1基因mRNA的表达，并分析表达结果与患者临床病理特征之间的关系。结果：喉癌组织中的Cyclin G1 mRNA表达明显高于癌旁正常黏膜组织及声带息肉组织中的表达，P〈0．05。中、低分化与高分化喉癌比较，后者Cyclin G1表达较低，差异有统计学意义，P〈0．05。有淋巴结转移组比无淋巴结转移组喉癌组织Cyclin G1表达显著增高，P〈0．05。Cyclin G1的表达与癌组织分化及颈淋巴结转移有关。结论：Cyclin G1在喉癌组织中有异常高表达，并与喉癌发生发展有一定联系，其高表达可能是喉癌预后不良的因素之一。     

Revisit of field cancerization in squamous cell carcinoma of upper aerodigestive tract: better risk assessment with epigenetic markers

We quantified field cancerization of squamous cell carcinoma in the upper aerodigestive tract with epigenetic markers and evaluated their performance for risk assessment. Methylation levels were analyzed by quantitative methylation-specific PCR of biopsied specimens from a training set of 255 patients and a validation set of 224 patients. We also measured traditional risk factors based on demographics, lifestyle, serology, genetic polymorphisms, and endoscopy. The methylation levels of four markers increased stepwise, with the lowest levels in normal esophageal mucosae from healthy subjects without carcinogen exposure, then normal mucosae from healthy subjects with carcinogen exposure, then normal mucosae from cancer patients, and the highest levels were in cancerous mucosae (P < 0.05). Cumulative exposure to alcohol increased methylation of homeobox A9 in normal mucosae (P < 0.01). Drinkers had higher methylation of ubiquitin carboxyl-terminal esterase L1 and metallothionein 1M (P < 0.05), and users of betel quid had higher methylation of homeobox A9 (P = 0.01). Smokers had increased methylation of all four markers (P < 0.05). Traditional risk factors allowed us to discriminate between patients with and without cancers with 74% sensitivity (95% CI: 67%-81%), 74% specificity (66%-82%), and 80% area under the curve (67%-91%); epigenetic markers in normal esophageal mucosa had values of 74% (69%-79%), 75% (67%-83%), and 83% (79%-87%); and both together had values of 82% (76%-88%), 81% (74%-88%), and 91% (88%-94%). Epigenetic markers done well in the validation set with 80% area under the curve (73%-85%). We concluded that epigenetics could improve the accuracies of risk assessment.     

Cyclin D1 amplification correlates with early recurrence of squamous cell carcinoma of the tongue

Amplification of CCND1 was studied in 23 tongue carcinoma patients by fluorescence in situ hybridization (FISH) using a paraffin embedded specimen. All the patients received complete resection of the primary site with or without neck dissection. CCND1 amplification was positive in 13 (56.5%) out of 23 cases. Correlations between CCND1 amplification and histological grading, T category, N category, and Stages were not significant. The 5-year disease-free survival rate, which was 23.1% for CCND1 amplification positive patients and 80.0% for negative patients, was significantly better for the CCND1 amplification negative patients (P=0.0070). Nine patients were examined by dual-color FISH with the probe for centromere of chromosome 11 and 11q13. In five patients, who had positive amplification for CCND1, cell numbers with a larger number of signals for 11q13 than the centromere of chromosome 11 were significantly higher than those of CCND1 amplification negative patients (P=0.013). This indicates that amplification of 11q13 occurs more frequently than aberration of chromosome 11 in CCND1 amplification positive patients. From these results, the amplification of CCND1 is a key factor in predicting the aggressiveness of tongue cancer. Furthermore, FISH proved to be a useful method for such evaluation.     

Association between the G870A polymorphism of Cyclin D1 gene and glioma risk

Previous studies have shown the association of the Cyclin D1 (CCND1) G870A polymorphism with glioma risk, but the findings are inconsistent and inconclusive. To shed some light on the findings across individual studies and acquire a quantitative assessment of this association, we conducted a meta-analysis of all published case–control studies thus far. Four independent studies with a total of 690 cases and 1,014 controls were identified after a systematic search of the PubMed, Embase, Web of Science, and Wanfang databases. The strength of the association between the CCND1 G870A polymorphism and glioma risk was estimated by the pooled odds ratios (ORs) with 95 % confidence intervals (95 %CIs). Subgroup analysis by ethnicity was also performed. Overall, a statistically significant association was found between the CCND1 G870A polymorphism and glioma risk in three genetic models (OR_{A vs. G}?=?1.178, 95 %CI 1.025–1.354, P _OR?=?0.021; OR_{AA vs. GG}?=?1.328, 95 %CI 1.007–1.750, P _OR?=?0.045; OR_{AA?+?AG vs. GG}?=?1.253, 95 %CI 1.006–1.516, P _OR?=?0.044). In subgroup analysis, the pooled ORs suggested that the CCND1 G870A polymorphism was associated with an increased risk of glioma in Caucasians under the heterozygote and dominant genetic models (OR_{AG vs. GG}?=?1.329, 95 %CI 1.001–1.766, P _OR?=?0.049; OR_{AA?+?AG vs. GG}?=?1.332, 95 %CI 1.019–1.740, P _OR?=?0.036). The meta-analysis suggests that the CCND1 G870A polymorphism is a risk factor for the development of glioma.     

Cyclin D1 overexpression related to retinoblastoma protein expression as a prognostic marker in human oesophageal squamous cell carcinoma.

The relationship between aberrant expression of cyclin D1 and retinoblastoma (RB) protein and clinicopathological factors was investigated in 80 patients with oesophageal SCC using immunohistochemical analyses. Heterogeneous staining of cancer cell nuclei with antibody to cyclin D1 was found in 31.3% of patients (25 out of 80 patients). Nuclear staining of cancer cells with anti-RB antibody was homogeneous in 10.0% (8 out of 80 patients) and heterogeneous in 58.8% (47 out of 80 patients). Among cases with homogeneous staining for RB protein, 75% (six out of eight patients) exhibited simultaneous positivity for cyclin D1 (P < 0.05). No significant relationship was found between cyclin D1 or RB protein expression and various clinicopathological parameters. The prognosis of patients with cyclin D1-positive tumours was significantly poorer than that of the other patients (P < 0.01). In addition, when patients with cyclin D1-positive and -negative tumours were stratified according to presence or absence of lymph node metastasis and RB status, the cumulative survival rates in the cyclin D1-positive groups were significantly lower for patients without lymph node metastasis (P < 0.01) and for patients whose tumours were positive for RB (P< 0.0001). These findings suggest the possibility that cyclin D1 positivity is a useful prognostic marker related to lymph node metastasis and RB protein expression in human oesophageal SCC, in addition to clinicopathological factors.     

Risk of metachronous squamous cell carcinoma in the upper aerodigestive tract of Japanese alcoholic men with esophageal squamous cell carcinoma: a long-term endoscopic follow-up study

East Asian case–control studies have shown a strong relationship between alcohol consumption combined with inactive heterozygous aldehyde dehydrogenase-2 ( ALDH2 * 1/ * 2 ) and the development of squamous cell carcinoma (SCC), especially multiple SCC, of the upper aerodigestive tract (UADT). This study aimed to identify determinants of the development of metachronous SCC in the UADT in alcoholics with esophageal SCC. Follow-up endoscopic examinations were carried out 4–160 months (median, 41 months) after initial diagnosis in 110 Japanese alcoholic men with esophageal SCC diagnosed by screening using endoscopy combined with oropharyngolaryngeal inspection and esophageal iodine staining. ALDH2 * 1/ * 2 was significantly associated with the presence of multiple primary intraesophageal SCC at the time of initial diagnosis. Metachronous primary SCC of the esophagus was diagnosed in 29 of the 81 patients whose initial esophageal SCC was treated by endoscopic mucosal resection alone, and metachronous primary SCC of the oropharyngolarynx was diagnosed in 23 of the 99 patients without synchronous primary SCC of the oropharyngolarynx at the time of initial diagnosis. The risks of metachronous esophageal SCC and oropharyngolaryngeal SCC were significantly higher in ALDH2 * 1/ * 2 heterozygotes than in ALDH2 * 1/ * 1 homozygotes (age-adjusted and alcohol-adjusted hazard ratio = 3.38 [95% confidence interval: 1.45–7.85] and 4.27 [1.42–12.89], respectively), and in patients with multiple intraesophageal SCC at the time of initial diagnosis than in patients with a solitary intraesophageal SCC (3.09 [1.41–6.78] and 3.25 [1.41–7.47], respectively). ALDH2 * 1/ * 2 and multiple synchronous intraesophageal SCC were found to be predictors of metachronous SCC in the UADT in this population. ( Cancer Sci 2008; 99: 1164–1171)     

Reflux esophagitis as a possible risk factor in the development of pharyngolaryngeal squamous cell carcinoma

AIMS AND BACKGROUND: To determine the role of reflux esophagitis in the development of pharyngolaryngeal squamous cell carcinoma in non-smoking and non-drinking patients. METHODS: The study population consisted of 92 consecutive non-smoking and non-drinking patients with histologically confirmed squamous cell carcinoma of the pharynx and the larynx. As a control, a group of 125 lifetime non-smoking and non-drinking cancer-free subjects was selected. RESULTS: Patients with pharyngolaryngeal cancer had a higher prevalence of reflux esophagitis than the control subjects (P <0.0001). CONCLUSIONS: Our results confirm that reflux esophagitis in itself is associated with an increased risk of upper aerodigestive tract cancer.     

Cyclin D1 overexpression correlates with poor prognosis in patients with tongue squamous cell carcinoma

Tongue squamous cell carcinoma makes up a large percentage of head and neck cancers, and the incidence among young patients is increasing. The aim of this study was to reveal the correlation between cyclin D1 (CCND1) expression and clinical and histologic features. We performed an immunohistochemical study on the level of CCND1 expression in tumor specimens obtained from 94 patients with tongue squamous cell carcinoma. The relationship between the expression and the following features such as age, sex, smoking and alcohol intake history, T, N, histologic grade, and multiple primary cancer was analyzed. Eighteen patients (19%) showed CCND1 overexpression (tumor cell nuclei positivity >/=50%). The 5-year survival rate of high CCND1 expressors was 39%, which was significantly poor (p=0.04). N classification correlated with CCND1 expression. CCND1 overexpression is associated with poor survival associated with progression of lymph node spread in patients with tongue squamous cell carcinomas. CCND1 expression may be a useful biologic marker for prognosis.     

Carbohydrate antigens as a risk factor for hematogenous recurrence of esophageal squamous cell carcinoma patients

The patients with hematogenous recurrence have a poor prognosis in esophageal squamous cell carcinoma (SCC). Recent developments have suggested the important role of sialyl Lewis A and X in the step of hematogenous metastasis. To evaluate the role of two carbohydrate antigens on hematogenous recurrence in esophageal SCC, we examined clinicopathological features and the expression of sialyl Lewis A and X in 125 patients retrospectively. Thirty-three out of 125 patients had hematogenous recurrence after curative esophagectomy. sLeA and sLex expression correlated with hematogenous recurrence (p=0.026, p=0.043 respectively), and sLeA expression was correlated with pM (lymph). Cox proportional hazards model and logistic regression analysis revealed that pN and pM lymph were significant prognostic factors and predictive factors of hematogenous recurrence in esophageal SCC. Although, neither sLeA nor sLeX were significant factors affecting survival in esophageal SCC, logistic regression analysis demonstrated that increased tumoral expression of sLeA and sLeX were risk factors of hematogenous recurrence in esophageal SCC. In conclusion, patients with lymph node metastasis, in particular those with distant lymph node metastasis, the expression of sLeA and sLeX may suggest a higher incidence of hematogenous recurrence in esophageal SCC. New strategies for specific inhibition of cancer cell attachment to vascular endothelial cells should be considered for the patients with the increased tumoral expression of either sLeA or sLeX.