Nucleotide excision repair pathway genes and oral premalignant lesions.

PURPOSE: Oral premalignant lesions (OPL) are associated with tobacco exposure and an increase in risk of oral cancer. Nucleotide excision repair (NER) is one of the major DNA repair pathways involved in the removal of tobacco carcinogen adducts. Polymorphisms in NER genes may cause variations in DNA repair capacity and increase susceptibility to both premalignant lesions and cancer. EXPERIMENTAL DESIGN: In this case-control study of 144 OPL patients and 288 controls, we genotyped 11 polymorphisms in 8 major NER genes, including XPA [A23G at 5' untranslated region (UTR)], XPD (Asp312Asn, Lys751Gln), XPC (Ala499Val, Lys939Gln), XPG (His1104Asp), XPF (Pro662Ser), ERCC6 (Met1097Val, Arg1230Pro) Rad23B (Ala249Val), and CCNH (Val270Ala). RESULTS: We found significant or borderline-significant associations between OPL risk and the polymorphisms XPA (A23G), XPD (Lys751Gln), XPC (Ala499Val), Rad23B (Ala249Val), and XPD (Asp312Asn), with adjusted odds ratios (ORs) of 1.97 [95% confidence interval (95% CI), 1.27-3.06], 1.60 (95% CI, 1.02-2.51), 0.63 (95% CI, 0.40-1.00), 0.67 (95% CI, 0.41-1.07), and 1.42 (95% CI, 0.90-2.23), respectively. When further stratified analyses were done, the decreased risk conferred by the XPC (Ala499Val) variant allele was more evident in older individuals (OR, 0.50; 95% CI, 0.24-1.03), in women (OR, 0.46; 95% CI, 0.21-1.01), in ever smokers (OR, 0.59; 95% CI, 0.33-1.05), and in never drinkers (OR, 0.42; 95% CI, 0.18-1.00). Finally, we found joint effects between these NER gene variants and smoking status. For example, when never smokers with the XPA 23A genotypes were used as the reference group, the ORs for never smokers with the XPA 23G genotype, smokers with the 23A genotype, and smokers with 23G genotypes were 2.19 (1.07-4.46), 2.64 (1.42-4.89), and 5.04 (2.62-9.69), respectively. Gene-gene and gene-smoking interaction for OPLs risk were also confirmed by multifactor dimensionality reduction (MDR) analysis in our study. MDR analysis revealed that a model containing ever smoking, XPA (A23G), XPC (Ala499Val), and XPD (Asp312Asn) was the best model to predict OPL risk with maximum average cross-validation consistency and minimum prediction error (P < 0.001). CONCLUSION: Our results suggest that polymorphisms in NER genes may contribute to genetic susceptibility to OPLs and may therefore contribute to the development of oral cancer.     

The association of cyclin D1 G870A and E-cadherin C-160A polymorphisms with the risk of colorectal cancer in a case control study and meta-analysis

Cyclin D1 (CCND1) and E-cadherin (CDH1) have been shown to be important genes of the beta-catenin/LEF pathway that is involved in colorectal carcinogenesis. However, epidemiological studies on relationship between genetic variants of these two genes and colorectal cancer (CRC) have shown inconsistent results. In a population-based case-control study (498 cases and 600 controls), we assessed the association of CCND1 G870A and CDH1 C-160A polymorphisms with CRC risk. Multivariable logistic regression analysis was used to estimate the association between genotypes, environmental exposures and CRC risk, adjusting for potential confounders. Compared to common homozygotes, the OR for heterozygous and homozygote variant genotype was 1.08 (95% CI, 0.80-1.46) in CCND1 and 0.97 (95% CI, 0.75-1.25) in CDH1. Neither tumor stage nor location showed an association with genetic susceptibility. However, a significant interaction between hormone replacement therapy (HRT) and CCND1 genotypes in CRC risk was found among postmenopausal women (p(interaction) = 0.02). The risk reduction associated with HRT was substantial (OR, 0.09; 95% CI, 0.02-0.35) in women who were GG homozygous. A meta-analyses including 11 published studies on CCND1 G870A in addition to our study showed a slightly increased risk of CRC for carriers of the A allele (OR, 1.19; 95% CI, 1.06-1.34); however, there was some indication of publication bias. We conclude that the CCND1 G870A and CDH1 C-160A polymorphisms are not associated with the risk of CRC in the German population. However, the CCND1 G870A polymorphism may modify the protective effect of postmenopausal hormone use on the development of CRC.     

Cyclooxygenase‐2 gene polymorphisms reduce the risk of oral premalignant lesions

BACKGROUND:

Oral premalignant lesions (OPLs) have the potential to transform into malignant oral cancers. Overexpression of the cyclooxygenase‐2 gene (COX‐2) is observed frequently in OPLs and oral cancers, suggesting that this gene may play an important role in the progression of oral cancer. Single‐nucleotide polymorphisms of COX‐2 have been associated with the risk of multiple cancers; however, to date, their effects on OPL susceptibility have not been evaluated sufficiently.

METHODS:

The authors conducted a case‐control study that included 147 patients with OPL and a group of 147 healthy, matched controls. The effects of 3 potentially functional COX‐2 polymorphisms on the risk of OPL were evaluated: the ?765 G→C polymorphism (rs20417), the exon 10 +837 T→C polymorphism (rs5275), and the exon 10 ?90 C→T polymorphism (rs689470).

RESULTS:

The variant‐containing genotypes of COX‐2 exon 10 +837T→C variant were associated with a significantly reduced risk of OPL (odds ratio [OR], 0.48; 95% confidence interval [95% CI], 0.28‐0.80). This protective effect also was significant in men, younger individuals, ever smokers, and ever drinkers. Consistently, a common halotype WMW (in the following order: ?765G→C, exon 10 +837T→C, and exon 10 ?90C→T; w, widetype; M, variable allele) and a common diplotype (WWW/WMW) that contained the variant allele of exon 10 +837T→C, both were associated with a reduced risk of OPL (WMW: OR, 0.55; 95% CI, 0.33‐0.93; WWW/WMW: OR, 0.44; 95% CI, 0.22‐0.89). In addition, using never smokers with the variant‐containing genotypes as the reference group, interaction effects were observed between specific COX‐2 variants and tobacco smoking in the modulation of OPL risk.

CONCLUSIONS:

Overall, the current results provided the first epidemiologic evidence indicating that potentially functional polymorphisms of the COX‐2 gene may have an impact on individual susceptibility to OPLs. Cancer 2009. © 2009 American Cancer Society.     

Genetic variants in cell cycle control pathway confer susceptibility to lung cancer.

PURPOSE: To test the hypothesis that common sequence variants of cell cycle control genes may affect lung cancer predisposition. EXPERIMENTAL DESIGN: We explored lung cancer risk associations of 11 polymorphisms in seven cell cycle genes in a large case-control study including 1,518 Caucasian lung cancer patients and 1,518 controls. RESULTS: When individuals with variant-containing genotypes were compared with homozygous wild-type carriers, a significantly increased lung cancer risk was identified for polymorphisms in p53 intron 6 [rs1625895; odds ratio (OR), 1.29; 95% confidence interval (95% CI), 1.08-1.55] and in p27 5' untranslated region (UTR; rs34330; OR, 1.27; 95% CI, 1.01-1.60). Compared with homozygous wild-types, the homozygous variant genotypes of STK15 F31I and CCND1 G870A were associated with a significantly altered lung cancer risk with ORs of 0.58 (95% CI, 0.37-0.90) and 1.26 (95% CI, 1.03-1.53), respectively. To assess the cumulative effects of all the investigated polymorphisms on lung carcinogenesis, we conducted a combined analysis and found that compared with low-risk individuals with few adverse alleles, individuals with more adverse alleles had an increased risk in a significant dose-dependent manner (P(trend) = 0.041). This pattern was more evident in ever smokers (P(trend) = 0.037), heavy smokers (P(trend) = 0.020), and older subjects (P(trend) = 0.011). Higher-order gene-gene interactions were evaluated using the classification and regression tree analysis, which indicated that STK15 F31I and p53 intron 6 polymorphisms might be associated with lung carcinogenesis in never/light-smokers and heavy smokers, respectively. CONCLUSIONS: Our results suggest that cell cycle gene polymorphisms and smoking may function collectively to modulate the risk of lung cancer.     

Cyclin D1 G870A polymorphism and breast cancer risk: a meta-analysis involving 23,998 subjects

Cyclin D1 (CCND1) plays an essential role in tumor development and progression through regulating the cell transition from G1 to the proliferative S phase. The CCND1 G870A polymorphism has been associated with an increased susceptibility to squamous cell carcinoma of the head and neck, bladder, prostate, and gastric cardiac cancers. There are a number of studies that explored the relationship between CCND1 G870A polymorphism and breast cancer risk, with inconsistent conclusions. In order to better define the predictive value of CCND1 G870A polymorphism in breast cancer, we searched PubMed and EBSCO for relevant publications. A total of 13 studies were indentified, which included 11,235 cases and 12,763 controls. We calculated the summary odds ratios and the corresponding 95% confidence interval. Our meta-analysis showed that carriers of AA genotype have a significantly higher risk in developing breast cancer compared with that of GG genotype (OR = 1.08, 95% CI = 1.01-1.17, p > = 0.03) in overall population. Furthermore, in subgroup analysis, CCND1 G870A polymorphism was associated with a marginally increased risk of breast cancer for Chinese compared to Caucasian populations with an OR = 1.14, 95% CI = 1.00-1.20, p-trend = 0.06 for AA + GA versus GG, if the controls were hospital-based population with an OR = 1.21, 95% CI = 0.99-1.47, p = 0.06 for AA versus GG and if the distributions of genotypes in control groups were consistent with the Hardy-Weinberg equilibrium (HWE) with an OR = 1.08, 95% CI = 1.00-1.15, p = 0.04 for AA versus GA + GG. Our meta-analysis represents the largest study to date indicating that the G870A polymorphism in CCND1 confers an increased risk for breast cancer. Further studies are warranted to explore the preventive measures to detect and manage the breast cancers attributable to the G870A polymorphism.     

Cyclin D1 G870A polymorphism and lung cancer risk: a meta-analysis

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?C1.24; OR_{AA versus GG}?=?1.20, 95?% CI 1.07?C1.35; OR_{AA versus AG + GG}?=?1.23, 95?% CI 1.02?C1.50). 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?C1.15; OR_{AA versus GG}?=?1.17, 95?% CI 1.04?C1.32). 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.     

Association between glutathione S-transferase p1 polymorphisms and lung cancer risk in Caucasians: a case-control study

Glutathione transferases (GSTs), a multiple gene family of phase II enzymes, catalyze detoxifying endogenous reactions with glutathione and protect cellular macromolecules from damage caused by cytotoxic and carcinogenic agents. Glutathione S-transferase p1 (GSTP1), the most abundant GST isoform in the lung, metabolizes numerous carcinogenic compounds including benzo[a]pyrene, a tobacco carcinogen. Previous studies suggest that genetic polymorphisms of GSTP1 exon 5 (Ile105Val) and exon 6 (Ala114Val) have functional effects on the GST gene product resulting in reduced enzyme activity. Individuals with reduced GST enzymatic activity may be at a greater risk for cancer due to decreased detoxification of carcinogenic and mutagenic compounds. Utilizing a hospital-based case-control study, we investigated the association between GSTP1 polymorphisms at exons 5 and 6 with lung cancer risk. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay was used to successfully genotype the GSTP1 exons 5 and 6 polymorphism in 582 Caucasian lung cancer cases and 600 frequency matched Caucasian controls. There was no association between the exon 5 variant genotypes (A/G+G/G) and overall lung cancer risk (OR=1.09; 95% CI 0.82-1.45) nor when stratified by age, gender, and smoking status. However, the exon 6 variant genotypes (C/T+T/T) were associated with a statistically significant elevated lung cancer risk (OR=1.40; 95% CI 1.06-1.92). Additionally, there was an increase in lung cancer risk for the exon 6 variant genotypes in younger individuals (<62 years) (OR=1.63; 95% C.I. 1.07-2.49) but no effect in older individuals (OR=1.14; 95% CI 0.72-1.81). A statistically significant increased risk of lung cancer was also observed for the exon 6 variant genotypes among men (OR=2.17; 95% CI 1.41-3.33), but not among women (OR=0.80; 95% CI 0.51-1.28). Among ever smokers, the exon 6 variant genotypes were associated with an elevated lung cancer risk (OR=1.58; 95% CI 1.14-2.19), which was not evident for never smokers (OR=0.53; 95% CI 0.21-1.33). These data demonstrate that the GSTP1 exon 6 polymorphism, but not the exon 5 polymorphism, is associated with lung cancer risk that is especially evident in men, younger individuals, and ever smokers.     

The CCND1 G870A Gene Polymorphism and Brain Tumor Risk: a Meta-analysis

Background: In recent years, numerous studies have been performed to investigate the CCND1 G870Agene polymorphism impact on brain tumors susceptibility. Unfortunately, the results of previous studies wereinconsistent. 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 papersup to November, 2013. Odds ratios (ORs) and their 95% confidence intervals (95%CIs) were applied to assessassociations. Results: A total of 6 publications including 9 case-control studies met the inclusion criteria. Thepooled 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 vsGG (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 tumorrisk, especially for gliomas. However, more primary large scale and well-designed studies are still required toevaluate the interaction of CCND1 G870A polymorphism with brain tumor risk.     

The CCND1 G870A Gene Polymorphism and Leukemia or Non-Hodgkin Lymphoma Risk: a Meta-analysis

In recent years, mounting evidence has indicated that the CCND1 G870A gene polymorphism, which impacts the mitotic cell cycle, may influence leukemia or non-Hodgkin lymphoma risk. Unfortunately, the previous results were inconsistent. Therefore, a meta-analysis was performed to obtain a more precise estimation of any association. We conducted a search in PubMed, Embase and CNKI covering all published papers up to March, 2014. A total of 9 publications including 10 case-control studies met the inclusion criteria. Odds ratios (ORs) and their 95% confidence intervals (95%CIs) were applied to assess association. The pooled ORs showed significant association in non-Hodgkin lymphoma (comparison A vs G: OR= 1.114, 95%CI=1.053-1.179, p=0.000; homozygote comparison AA vs GG: OR=1.245, 95%CI=1.110-1.396, p=0.000; heterozygote comparison AG vs GG: OR=1.095, 95%CI=1.000-1.199, p=0.05; dominant model AA/GA vs GG: OR=1.137, 95%CI=1.043-1.239, p=0.003; and recessive model AA vs GA/GG: OR=1.177, 95%CI=1.066-1.301, p=0.001). However, there was no association between the CCND1 G870A polymorphism and leukemia risk. In conclusion, the CCND1 G870A polymorphism may increase risk of non-Hodgkin lymphoma, but not leukemia. However, more primary large scale and well-designed studies are still required to evaluate the interaction of CCND1 G870A polymorphism with leukemia and non-Hodgkin lymphoma risk.     

Cyclin D1 gene polymorphism and susceptibility to lung cancer in a Chinese population

The objective was to study the relationship between cyclin D1 gene (CCND1) polymorphism and lung cancer in the Chinese population. Blood samples of 182 cases and 185 controls were collected from a hospital based case-control study. PCR-SSCP was used to examine the G/A polymorphism in exon 4 of CCND1. The results showed that the frequencies of the CCND1 AA, GA and GG genotypes were 31.3, 46.7 and 22.0% respectively in cases, and 21.1, 53.0 and 25.9 respectively in controls. Adjusted by age (in years), sex and smoking status, multivariate logistic regression analysis showed that the AA genotype was associated with a significantly increased risk (OR = 1.87, 95% CI 1.01-3.45) for lung cancer. In the stratification analysis, the CCND1 AA variant genotype was associated with increased risk in individuals who were 相似文献   

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.     

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.     

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.     

Role of BCL2 (ala43thr), CCND1 (G870A) and FAS (A-670G) polymorphisms in modulating the risk of developing esophageal cancer

BACKGROUND: Perturbations in the cell cycle and apoptotic genes have been implicated in human malignancies. A study of BCL2 ala43thr, CCND1 G870A and FAS A-670G gene polymorphisms was undertaken to explore their role in influencing the susceptibility for development of esophageal cancer. METHODS: A total of 151 patients and age and gender matched 201 controls were investigated for BCL2 ala43thr, CCND1 G870A and FAS A-670G polymorphisms by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP). RESULTS: The ala43ala genotype of BCL2 anti-apoptotic gene was significantly associated with risk of developing esophageal cancer (OR 2.1, 95%CI=1.0-4.4, P=0.03), more so in males (OR 2.6, 95%CI=P=0.03). In CCND1 G870A polymorphism, the AA genotype was marginally associated with higher risk of esophageal cancer (OR 1.5, 95%CI=0.98-2.4, P=0.05). No significant differences in genotype frequencies of FAS A-670G polymorphism were seen between esophageal cancer patients and controls (P=0.32). Interaction of BCL2 ala43ala, CCND1 870AA and FAS -670AA genotypes did not increase the risk multiplicatively. Association with clinical characteristics showed BCL2 ala43ala genotype to be at increased risk for developing tumors in the middle third location (OR 2.3, 95%CI=1.0-5.3, P=0.03), while patients with CCND1 870AA genotypes were at higher risk for the development of cancer in the upper third location (OR 3.8, 95%CI=1.6-9, P=0.002). BCL2 ala43ala genotype did not modulate the cancer risk in tobacco users. However, patients with CCND1 870AA and FAS -670AA genotypes were associated with a significantly lower number of smoking and chewing pack-years, suggesting a dose-dependent interaction in the risk for esophageal cancer (P=0.005). CONCLUSION: There appears to be an influence of BCL2 ala43ala and CCND1 870AA genotypes on esophageal cancer phenotype, particularly with regard to tumor location, which supports the theory of prevalence of site-specific genetic alterations. FAS A-670G was not associated with the risk of developing esophageal cancer. Gene-environment interaction analysis showed cancer susceptibility in CCND1 870AA and FAS -670AA genotype to be influenced by quantity of tobacco.     

Genetic variations in cell-cycle pathway and the risk of oral premalignant lesions

BACKGROUND: Cell-cycle checkpoint controls regulate cell-cycle progression and proliferation. Alterations in cell-cycle control mechanisms are linked to tumorigenesis. METHODS: This case-control study included 147 cases and 147 controls. The authors used a pathway-based approach to assess the association between 10 potential functional single-nucleotide polymorphisms from 7 cell-cycle control genes and the risk of oral premalignant lesions (OPLs). They also used classification and regression tree analysis to examine high-order gene-gene and gene-smoking interactions. RESULTS: Compared with the homozygous wild-type GG genotype of CCND1 P241P, individuals with the AG genotype exhibited an increased risk of OPL (odds ratio, 1.58; 95% confidence interval, 0.89-2.83), and carriers of the AA genotype had a significantly increased risk of OPL (odds ratio, 2.75; 95% confidence interval, 1.33-5.71), with risk increasing significantly with the increasing number of variant alleles (P= .006). The risk of OPL increased significantly as the number of unfavorable genotypes in the pathway increased (P= .002). The final decision tree in the classification and regression tree analysis contained 5 terminal nodes. Compared with the never smokers (the lowest risk group), the odds ratios for terminal nodes 2 through 5 ranged from 1.21 to 5.40. CONCLUSIONS: The results illustrated the advantage of using a pathway-based approach for analyzing gene-gene and gene-smoking interactions. Specifically, the authors showed that genetic polymorphisms in cell-cycle control pathway genes may contribute to the risk of OPL.     

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   

Cyclin D1 Pro241Pro (CCND1-G870A) polymorphism is associated with increased cancer risk in human populations: a meta-analysis

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 相似文献   

Polymorphism of the cyclin D1 gene, CCND1, and risk for incident sporadic colorectal adenomas

Cyclin D1, encoded by the CCND1 gene and activated by the adenomatous polyposis coli-beta-catenin-T-cell factor/lymphoid enhancing factor pathway, induces G(1) to S-phase cell cycle transition, promoting cell proliferation. A recently described codon 242, exon 4, G to A single nucleotide polymorphism (A870G) produces a longer half-life cyclin D1. To investigate whether CCND1 genotype influences risk for colorectal adenoma, we genotyped CCND1 by PCR/RFLP on 161 incident sporadic adenoma cases and 213 controls ages 30-74 years in a North Carolina colonoscopy-based case-control study. At least one polymorphic A allele was found in 68% of cases and 60% of controls. Having an A allele was associated with increased risk for adenoma: the age- and sex-adjusted odds ratio (OR) was 1.5 [95% confidence interval (CI) 1.0-2.4], a finding that was stronger for those whose adenomas were multiple (OR 2.9, 95% CI 1.4-6.0), larger (>or=1 cm; OR 2.4, 95% CI 1.2-4.8), had moderate to severe dysplasia (OR 2.1, 95% CI 1.1-3.8), or were in the right side of the colon (OR 3.6, 95% CI 1.3-10.0). Joint risk factor multivariate analyses revealed stronger positive associations among those who were older (>57 years; OR 2.8, 95% CI 1.4-5.5), male (OR 2.8, 95% CI 1.3-5.7), currently smoked (OR 2.7, 95% CI 1.3-5.7), or currently drank alcohol (OR 2.2, 95% CI 1.2-4.2) if they had an A allele and stronger inverse associations among those who used nonsteroidal anti-inflammatory drugs (OR 0.4, 95% CI 0.2-0.9) or had higher calcium intakes (OR 0.4, 95% CI 0.2-0.9) if they had no A allele. These data support the hypothesis that the CCND1 A870G polymorphism may increase risk for colorectal neoplasms.