Cyclin D1 Guanine/Adenine 870 Polymorphism With Altered Protein Expression Is Associated With Genomic Instability and Aggressive Clinical Biology of Esophageal Adenocarcinoma

Izzo, Julie; Wu, Tsung Teh; Wu, Xifeng; Ensor, Joe; Luthra, Rajyalakshmi; Pan, Jennifer Y.; Correa, Arlene M.; Swisher, Stephen G.; Chao, C.; Hittelman, Walter N.; Ajani, Jaffer A.

doi:10.1200/jco.2006.08.0283

Cited by 48 publications

(30 citation statements)

References 36 publications

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“…The polymorphism of 807 G/A increases the frequency of alternate splicing, leading to an altered protein that does not contain the sequences involved in protein turnover and may have a longer half-life (Betticher et al, 1995). However, different studies indicate that the polymorphism might not be involved in the predisposition to ESCC (Yu et al, 2003;Liu et al, 2010), whereas some other show contrasting results (Izzo et al, 2005(Izzo et al, , 2007. Other genetic variations of cell cycle related proteins, such as retinoblastoma and p21, which interact with CCND1, were found.…”

Section: Discussionmentioning

confidence: 98%

Genetic polymorphisms of CCND1 and PTEN in progression of esophageal squamous carcinoma

Jang¹,

Lu²,

Chen³

et al. 2013

Genet. Mol. Res.

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ABSTRACT. Cyclin D1 (CCND1) plays a significant role in G1-S transition of cell cycle, and phosphatase and a tensin homologue (PTEN) negatively regulate cell cycle through phosphatidylinositol 3-kinase (PI3K)/AKT signaling. CCND1 and PTEN genetic polymorphisms might induce susceptibility to the occurrence of esophageal squamous cell carcinoma (ESCC). Three hundred and four ESCC patients and 413 healthy controls from Anyang, China, were enrolled in this study. All genotyping at CCND1 (807 G/A) and PTEN (rs701848 T/C and rs2735343 C/G) were identified by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. Unconditional logistic regression model was used to analyze the correlation between the polymorphisms and the susceptibility to develop ESCC. Statistically significant differences were observed between cases and controls in

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Section: Discussionmentioning

confidence: 98%

Genetic polymorphisms of CCND1 and PTEN in progression of esophageal squamous carcinoma

Jang¹,

Lu²,

Chen³

et al. 2013

Genet. Mol. Res.

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“…However, the oncogenic alternatively spliced isoform of cyclin D1 lacks the phosphorylation site and remains nuclear (32), showing that at some stage, cancer cells can overcome the inhibition of DNA synthesis by cyclin D1. Remarkably, it was recently shown that in human esophageal adenocarcinoma, the appearance of this alternatively spliced cyclin D1 isoform was associated with increased genomic instability (52). Previously, it was shown that cyclin D1 overexpression induces centrosome and mitotic spindle abnormalities, as well as aneuploidy in murine hepatocytes in vivo and in human breast epithelial cells in vitro (53).…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Liver Carcinogenesis in the Mdr2-Knockout Mice

Katzenellenbogen¹,

Mizrahi²,

Pappo

et al. 2007

Molecular Cancer Research

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Mouse models of hepatocellular carcinoma (HCC) simulate specific subgroups of human HCC. We investigated hepatocarcinogenesis in Mdr2-knockout (Mdr2-KO) mice, a model of inflammationassociated HCC, using gene expression profiling and immunohistochemical analyses. Gene expression profiling showed that although Mdr2-KO mice differ from other published murine HCC models, they share several important deregulated pathways and many coordinately differentially expressed genes with human HCC data sets. Analysis of genome positions of differentially expressed genes in liver tumors revealed a prolonged region of down-regulated genes on murine chromosome 8 in three of the six analyzed tumor samples. This region is syntenic to human chromosomal regions that are frequently deleted in human HCC and harbor multiple tumor suppressor genes. Real-time reverse transcription-PCR analysis of 16 tumor samples confirmed down-regulation of several tumor suppressors in most tumors. We show that in the aged Mdr2-KO mice, cyclin D1 nuclear level is increased in dysplastic hepatocytes that do not form nodules; however, it is decreased in most dysplastic nodules and in liver tumors. We found that this decrease is mostly at the protein, rather than the mRNA, level.These findings raise the question on the role of cyclin D1 at early stages of hepatocarcinogenesis in the Mdr2-KO HCC model. Furthermore, we show that most liver tumors in Mdr2-KO mice were characterized by the absence of B-catenin activation.In conclusion, the Mdr2-KO mouse may serve as a model for B-catenin -negative subgroup of human HCCs characterized by low nuclear cyclin D1 levels in tumor cells and by down-regulation of multiple tumor suppressor genes.

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“…This novel correlation requires verification in other patient populations with EAC, particularly in other races, because our population was overwhelmingly Caucasian. EGF genotyping may thus eventually form one of a panel of molecular markers that includes p53 expression status (29) and cyclin D1 (30,31) that is clinically useful in predicting which GERD patients should have increased surveillance endoscopy. Although these molecular markers are not yet applicable in clinical practice, the EGF A61G polymorphism may be among the first markers that may identify EAC risk, with particular interest in women, nonobese individuals, and early-onset EAC, where few risk factors (either clinical or molecular) have been identified.…”

Section: Discussionmentioning

confidence: 99%

A Functional Epidermal Growth Factor (EGF) Polymorphism, EGF Serum Levels, and Esophageal Adenocarcinoma Risk and Outcome

Lanuti

Liu

Goodwin³

et al. 2008

Clinical Cancer Research

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Purpose:The epidermal growth factor (EGF) pathway is important in esophageal adenocarcinoma (EAC) tumorigenesis. We hypothesized that the EGF A61G homozygous variant genotype (GG) is (a) both a risk and poor prognostic factor for EAC and (b) associated with higher EGF serum levels in individuals with gastroesophageal reflux disease (GERD). Experimental Design: Using unconditional logistic regression, we compared EGF A61G in 312 EAC cases and 447 GERD-free controls, adjusting for age, gender, smoking history, and healthy adult body mass index. Using the method of Kaplan and Meier, log-rank tests, and Cox proportional hazard models, we correlated EGF A61G with overall and failure-free survival in the EAC cases. Serum EGF levels and EGF genotype (G/G versus others) were correlated in 144 GERD patients using Wilcoxon rank sum tests. Results:The EGFA61G G/G genotype conferred increased EAC risk, with an adjusted odds ratio of 1.81 (95% confidence interval, 1.2-2.7), and was even higher in the subgroup of EAC patients with concurrent Barrett's esophagus (adjusted odds ratio, 2.18; 95% confidence interval, 1.3-3.7). However, EGF A61G was not associated with a more aggressive phenotype or prognosis in EAC patients. Higher serum EGF levels were found in GERD patients carrying G/G compared with A/A or A/G (P = 0.03,Wilcoxon rank sum test). Conclusion: The EGF A61G G/G genotype is associated with a near 2-fold greater risk of EAC. The G/G allele was also associated with higher EGF levels in tumor-free patients with GERD. EGF genotyping can potentially identify high-risk patients with GERD and Barrett's metaplasia who might benefit from increased surveillance.

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Cyclin D1 Guanine/Adenine 870 Polymorphism With Altered Protein Expression Is Associated With Genomic Instability and Aggressive Clinical Biology of Esophageal Adenocarcinoma

Cited by 48 publications

References 36 publications

Genetic polymorphisms of CCND1 and PTEN in progression of esophageal squamous carcinoma

Genetic polymorphisms of CCND1 and PTEN in progression of esophageal squamous carcinoma

Molecular Mechanisms of Liver Carcinogenesis in the Mdr2-Knockout Mice

A Functional Epidermal Growth Factor (EGF) Polymorphism, EGF Serum Levels, and Esophageal Adenocarcinoma Risk and Outcome

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