The influence of the Cyclin D1 870 G>A polymorphism as an endometrial cancer risk factor.
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ABSTRACT:
SUBMITTER: Ashton KA
PROVIDER: S-EPMC2567988 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Alternative CCND1 splicing results in cyclin D1b, which has specialized, protumorigenic functions in prostate not shared by the cyclin D1a (full length) isoform. Here, the frequency, tumor relevance, and mechanisms controlling cyclin D1b were challenged.First, relative expression of both cyclin D1 isoforms was determined in prostate adenocarcinomas. Second, relevance of the androgen axis was determined. Third, minigenes were created to interrogate the role of the G/A870 polymorphism (within the splice site), and findings were validated in primary tissue. Fourth, the effect of G/A870 on cancer risk was assessed in two large case-control studies.Cyclin D1b is induced in tumors, and a significant subset expressed this isoform in the absence of detectable cyclin D1a. Accordingly, the isoforms showed noncorrelated expression patterns, and hormone status did not alter splicing. Whereas G/A870 was not independently predictive of cancer risk, A870 predisposed for transcript-b production in cells and in normal prostate. The influence of A870 on overall transcript-b levels was relieved in tumors, indicating that aberrations in tumorigenesis likely alter the influence of the polymorphism.These studies reveal that cyclin D1b is specifically elevated in prostate tumorigenesis. Cyclin D1b expression patterns are distinct from that observed with cyclin D1a. The A870 allele predisposes for transcript-b production in a context-specific manner. Although A870 does not independently predict cancer risk, tumor cells can bypass the influence of the polymorphism. These findings have major implications for the analyses of D-cyclin function in the prostate and provide the foundation for future studies directed at identifying potential modifiers of the G/A870 polymorphism.
| S-EPMC2849314 | biostudies-literature
Project description:BackgroundCyclin D1 (CCND1) G870A polymorphism may be associated with hepatocellular carcinoma (HCC) risk, but the results of previous studies were inconsistent. Available evidence was meta-analyzed to assess their potential association.MethodsDatabases PubMed, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature database, China National Knowledge Infrastructure, and Google Scholar were systematically searched. Meta-analyses were performed to investigate the association of G870A polymorphism with HCC risk by calculating odds ratios (ORs) and 95% confidence intervals (CIs) from the data of relevant case-control studies.ResultsResults of this meta-analysis of six case-control studies involving 1,030 cases and 1,683 controls indicate that G870A polymorphism was not associated with HCC risk in any of the five genetic models tested (recessive model: AA vs GG + AG: OR =1.38, 95% CI =0.95-2.00, P=0.09; dominant model: AG + AA vs GG: OR =1.38, 95% CI =0.87-2.20, P=0.17; homozygous model: AA vs GG: OR =1.60, 95% CI =0.87-2.94, P=0.13; heterozygous model: AG vs GG: OR =1.24, 95% CI =0.86-1.79, P=0.25; allelic model: A vs G: OR =1.30, 95% CI =0.95-1.80, P=0.10). Subgroup analyses according to ethnicity showing marginally significant association between this single nucleotide polymorphism and HCC risk indicate that G870A may be significantly associated with HCC risk in Caucasian populations (recessive model: AA vs GG + AG: OR =2.34, 95% CI =1.60-3.42, P<0.0001; dominant model: AG + AA vs GG: OR =2.44, 95% CI =1.19-4.97, P=0.01; homozygous model: AA vs GG: OR =3.42, 95% CI =1.80-6.50, P=0.0002; allelic model: A vs G: OR =2.06, 95% CI =1.31-3.24, P=0.002), but not in Asian populations.ConclusionAvailable evidence suggests that no significant association between G870A polymorphism and HCC risk was found in either total populations or Asian populations. However, significant association was found in Caucasian populations. These results should be verified and extended in further detailed and well-designed studies involving larger, multiethnic samples.
| S-EPMC4959597 | biostudies-literature
Project description:The G870A polymorphism in the exon 4/intron 4 boundary of CCND1 gene is thought to influence the generation of two mRNAs (cyclin D1a and cyclin D1b). The "A" allele codes for a truncated variant, cyclin D1b, which may have higher transforming activity. Herein, the tumor relevance of G870A polymorphism, the association between cyclin D1 variant expression and G870A genotype, and the oncogenic potential of cyclin D1 variants in HBV-related hepatocellular carcinoma (HCC) were examined. We found that there is no significant difference of G870A distribution among the HCC, chronic HBV (CHB) infection, cirrhotic CHB, and healthy control groups. Stratification analysis revealed that in younger patients (ages ≤ 50), cirrhotic CHB patients with AA genotype had an increased risk of developing HCC with odds ratio of 1.943 (95 % CI 1.022-3.694, p = 0.0411) as compared with AG/GG genotypes. The two variants were both transcripted from "A" and "G" alleles, and neither cyclin D1a nor D1b production was influenced by G870A genotype in HCC. The expression of both cyclins D1a and D1b decreased in HCC tissues (p = 0.003, p = 0.005), while increased in adjacent nontumor tissues as compared with normal liver tissues (p = 0.045, p = 0.034). Overexpression of cyclin D1a or D1b could promote the cell proliferation and cell-cycle progression in Huh-7 and LO2 cell lines. Collectively, our data suggest that G870A polymorphism has only very limited predictive value for HBV-related HCC. Both cyclins D1a and D1b could promote cell proliferation, which might contribute to the potential oncogenic role of cyclin D1 variants during the precancerous cirrhotic stage of hepatocarcinogenesis.
| S-EPMC4644212 | biostudies-literature
Project description:Introduction: Association between Cyclin D1 (CCND1) single nucleotide polymorphism (SNP) rs9344 and cancer risk is paradoxical. Thus, we performed a meta-analysis to explore the association between CCND1 variant and overall cancer risk in Indian population. Methods: Data from 12 published studies including 3739 subjects were collected using Pubmed and Embase. RevMan (Review Manager) 5.3 was used to perform the meta-analysis. OR with 95%CI were calculated to establish the association. Results: Overall, the cumulative findings demonstrated that CCND1 polymorphism (rs9344) was not significantly associated with cancer risk in all the genetic models studied (dominant model: GG vs GA+AA: OR (95%CI) = 0.81 (0.60-1.09), P=0.17; recessive model: GG+GA vs AA: OR (95%CI) = 1.23 (0.96-1.59), P=0.11; co-dominant model: GG vs AA: OR (95%CI) = 1.35 (0.93-1.97), P=0.12; co-dominant model: (GG vs GA: OR (95%CI) = 1.16 (0.85-1.59), P=0.34; allelic model: A vs G: OR (95%CI) = 1.20 (1.14-2.85), P=0.23; allelic model: G vs A: OR (95%CI) = 0.83 (0.62-1.12), P=0.23). Subgroup analysis according to cancer types presented significant association of CCND1 polymorphism and increased breast cancer risk in dominant model (GG vs GA+AA: OR = 2.75, 95%CI = 1.54-4.90, P=0.0006) and allelic model (G vs A: OR = 1.63, 95%CI = 1.22-2.19, P=0.001). An increased esophageal cancer risk in recessive model (GG+GA vs AA: OR = 1.51, 95%CI = 1.05-2.16, P=0.03) and co-dominant model (GG vs AA: OR = 2.51, 95%CI = 1.10-5.71, P=0.03) was detected. A higher risk for colorectal cancer was detected under both the co-dominant models (GG vs AA: OR = 2.46, 95%CI = 1.34-4.51, P=0.004 and GG vs GA: OR = 1.74, 95%CI = 1.14-2.67, P=0.01). However, in case of cervical cancer risk a non-significant association was reported under the recessive model (GG+GA vs AA: OR = 1.52, 95%CI = 0.60-3.90, P=0.38) with reference to CCND1 polymorphism (rs9344). The trial sequential analysis (TSA) showed that the cumulative Z-curve neither crossed the trial sequential monitoring boundary nor reached the required information size (RIS). Thus, present meta-analysis remained inconclusive due to insufficient evidence. Conclusion:CCND1 polymorphism rs9344 may not have a role in overall cancer susceptibility in Indian population. However, this polymorphism acts as a crucial risk factor for breast, esophageal, and colorectal cancer but not for cervical cancer. Future studies with larger sample size are required to draw a reliable conclusion.
| S-EPMC6265616 | biostudies-literature
Project description:Catechol-O-methyletransferase (COMT) enzyme is involved in the inactivation of catecholamine and catechol estrogens. Catechol estrogens have carcinogenic potential and DNA damaging ability. Several studies investigated COMT Val158Met polymorphism as risk factor for endometrial cancer but the results were inconclusive. Hence the objective of present study was to find out exact association between COMT gene Val158Met polymorphism and endometrial cancer by a meta-analysis. Pubmed, Google Scholar, Springer Link and Science Direct databases were searched for case-control articles which investigated COMT Val158Met polymorphism in endometrial cancer cases. All statistical analysis was performed using MetaAnalyst and Mix programs. The results of meta-analysis suggested that there were no association between COMT Val158Met polymorphism and endometrial cancer risk (allele contrast model-ORA vs. G = 0.97, 95% CI = 0.86-1.10, p = 0.67; co-dominant model-ORAG vs. GG = 0.91, 95% CI = 0.77-1.06, p = 0.23; homozygote model-ORAA vs. GG = 1.01, 95% CI = 0.84-1.19, p = 0.29; dominant model-ORAA+AG vs. GG = 0.93, 95% CI = 0.77-1.11, p = 0.43; recessive model-ORAA vs. AG+GG = 1.02, 95% CI = 0.89-1.20, p = 0.62). Publication bias was absent. Subgroup analysis based on source of controls was also performed. In conclusion, results of present meta-analysis showed no association between COMT Val158Met polymorphism and susceptibility to endometrial cancer.
| S-EPMC6995457 | biostudies-literature
Project description:Uterine leiomyoma (UL) is the most common benign tumor causing considerable morbidity during the reproductive years in women. Cyclin D1 (CCND1) is a cell cycle regulatory protein that is required for the G1 phase, and increased expression levels of this protein may affect tumorigenesis. The present study aimed to assess the possible effect of the CCND1 G870A polymorphism on UL susceptibility. A total of 154 women with UL and 197 healthy women who were age-, body mass index (BMI)- and ethnicity-matched were genotyped for the CCND1 G870A (rs9344) polymorphism using the polymerase chain reaction-restriction fragment length polymorphism method. The effects of G870A transition on the structure of mRNA and proteins of CCND1 was evaluated using bioinformatics tools. The frequency of the CCND1 870AA genotype was significantly higher in women with UL compared with the control subjects, and the risk of UL was 1.4-fold higher in women with the AA genotype when compared with the GG genotype before and after adjusting for age, BMI, and ethnicity [odds ratio (OR), 1.4; 95% confidence interval (CI), 1.1-2 (P=0.02)]. The frequency of CCND1 870GA genotype was not significantly different between the two groups. The frequency of the CCND1 870A allele was significantly higher in the women with UL when compared with the control subjects (57 vs. 48%; P=0.02). The in silico analysis revealed that the G870A transition may fundamentally alter the structure of the CCND1-mRNA. Thus, the CCND1 870AA genotype was associated with UL susceptibility in a sample of women from the southeast of Iran.
| S-EPMC5351390 | biostudies-literature
Project description:BackgroundCyclin D1 (CCND1) plays a key role in cell cycle regulation. It is a well-established human oncogene which is frequently amplified or overexpressed in cancers. The association between CCND1 G870A polymorphism and cancer risk has been widely assessed. However, a definitive conclusion between CCND1 G870A polymorphism and risk of nasopharyngeal carcinoma (NPC) remains elusive.MethodsWe firstly performed a hospital-based case-control study involving 165 NPC cases and 191 cancer-free controls in central-south China, and then conducted a meta-analysis with six case-control studies to evaluate the association between NPC risk and CCND1 G870A polymorphism.ResultsThe case-control study found a significant association between CCND1 G870A polymorphism and NPC risk in various comparison models (AA vs. GG: OR = 2.300, 95% CI 1.089-4.857, p = 0.029; AG vs. GG: OR = 2.832, 95% CI 1.367-5.867, p = 0.005; AA/AG vs. GG: OR = 2.597, 95% CI 1.288-5.237, p = 0.008; AA vs.Ag/ggOR = 0.984, 95% CI 0.638-1.518, p = 0.944). Further meta-analysis showed that there was no significant association between CCND1 G870A polymorphism and NPC risk in overall analysis. In the stratified analysis by race, however, significant associations were only found in Caucasians (for the allele model A vs. G: OR = 0.75, 95% CI 0.59-0.97, p = 0.03; for the co-dominant model AA vs. GG: OR = 0.52, 95% CI 0.32-0.86, p = 0.01; for the dominant model AA/AG vs. GG: OR = 0.49, 95% CI 0.32-0.74, p<0.01; for the recessive model AA vs.Ag/ggOR = 0.90, 95% CI 0.61-1.34, p = 0.60).ConclusionsA significant association between CCND1 G870A polymorphism and NPC risk was found in the central-southern Chinese population. The meta-analysis indicated that CCND1 G870A polymorphism may contribute to the development of NPC in Caucasians.
| S-EPMC4237450 | biostudies-literature
Project description:Aim: Cell cycle regulator cyclin D1 (CCND1) is a pivotal regulator for G1/S phase transition, playing a critical part in initiation of carcinogenesis. Triple negative breast cancer comprises a very heterogeneous group of cancer cells, but little is known about what is wrong in the genome of these patients. This study investigated contribution of CCND1 genotype to individual triple negative breast cancer susceptibility. Materials: In all, 2464 native Taiwan subjects consist of 1232 breast cancer cases and 1232 controls were enrolled in a hospital-based, case-control study. CCND1 A870G (rs9344) genotyping was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Risk-stratified analyses correlated genotype and age-related characteristics of breast cancer subgroups. Results: No significant difference was found between patient and control groups in distribution of genotypic and allelic frequencies in CCND1 genotype, yet CCND1 A870G (rs9344) GG genotype was far less prevalent in breast cancer patients younger than 55 years (OR=0.62, 95%CI=0.43-0.89, P=0.0362), with first menarche earlier than 12.2 years (OR=0.61, 95% CI=0.42-0.87, P=0.0241), with menopause earlier than 49.0 years (OR=0.57, 95%CI=0.39-0.82, P=0.0093), or showing triple-negative breast cancer (OR=0.28, 95%CI=0.13-0.62, P=0.0006). Such valuable findings suggest CCND1 A870G (rs9344) as a predictive marker for triple negative breast cancer in Taiwanese women; the authors sincerely hope these help us fight the toughest subtype in clinical management.
| S-EPMC4265020 | biostudies-literature
Project description:BackgroundA common 30 kb deletion affecting the APOBEC3A and APOBEC3B genes has been linked to increased APOBEC activity and APOBEC-related mutational signatures in human cancers. The role of this deletion as a cancer risk factor remains controversial.Materials and methodsWe genotyped the APOBEC3A/B deletion in a sample of 1,470 Norwegian endometrial cancer cases and compared to 1,918 healthy controls. For assessment across Caucasian populations, we mined genotypes of the SNP rs12628403, which is in strong linkage disequilibrium with the deletion, in a GWAS dataset of 4,274 cases and 18,125 healthy controls, through the ECAC consortium.ResultsWe found the APOBEC3A/B deletion variant to be significantly associated with reduced risk of endometrial cancer among Norwegian women (OR = 0.75; 95% CI = 0.62-0.91; p = 0.003; dominant model). Similar results were found in the subgroup of endometrioid endometrial cancer (OR = 0.64; 95% CI = 0.51-0.79; p = 3.6 × 10-5 ; dominant model). The observed risk reduction was particularly strong among individuals in the range of 50-60 years of age (OR = 0.51; 95% CI = 0.33-0.78; p = 0.002; dominant model). In the different populations included in the ECAC dataset, the ORs varied from 0.85 to 1.05. Although five out of six populations revealed ORs <1.0, the overall estimate was nonsignificant and, as such, did not formally validate the findings in the Norwegian cohort.ConclusionThe APOBEC3A/B deletion polymorphism is associated with a decreased risk of endometrial cancer in the Norwegian population.
| S-EPMC10067079 | biostudies-literature
Project description:Cyclin D1 (CCND1) is a core cell cycle regulator and is frequently overexpressed in human cancers, often via amplification, translocation or post-transcription regulation. Accumulating evidence suggests that mutations of the CCND1 gene that result in nuclear retention and constitutive activation of CDK4/6 kinases are oncogenic drivers in cancer. However, the spectrum of CCND1 mutations across human cancers has not been systematically investigated. Here, we retrospectively mined whole-exome sequencing data from 124 published studies representing up to 29,432 cases from diverse cancer types and sites of origin, including carcinoma, melanoma, sarcoma and lymphoma/leukemia, via online tools to determine the frequency and spectrum of CCND1 mutations in human cancers and their associated clinico-pathological characteristics. Overall, in contrast to gene amplification, which occurred at a frequency of 4.8% (1,419 of 28,769 cases), CCND1 mutations were of very low frequency (0.5%, 151 of 29,432 cases) across all cancers, but were predominantly enriched in uterine endometrioid-type adenocarcinoma (6.5%, 30 of 458 cases) in both primary tumors and in advanced, metastatic endometrial cancer samples. CCND1 mutations in endometrial endometrioid adenocarcinoma occurred most commonly in the c-terminus of cyclin D1, as putative driver mutations, in a region thought to result in oncogenic activation of cyclin D1 via inhibition of Thr-286 phosphorylation and nuclear export, thereby resulting in nuclear retention and protein overexpression. Our findings implicate oncogenic c-terminal mutations of CCND1 in the pathogenesis of a subset of human cancers and provide a key resource to guide future preclinical and clinical investigations.
| S-EPMC6029777 | biostudies-literature