Important Cell-cycle Genes Research Articles

Exploration of Involved Key Genes and Signaling Diversity in Brain Tumors.

Brain tumors are becoming a major cause of death. The classification of brain tumors has gone through restructuring with regard to some criteria such as the presence or absence of a specific genetic alteration in the 2016 central nervous system World Health Organization update. Two categories of genes with a leading role in tumorigenesis and cancer induction include tumor suppressor genes and oncogenes; tumor suppressor genes are inactivated through a variety of mechanisms that result in their loss of function. As for the oncogenes, overexpression and amplification are the most common mechanisms of alteration. Important cell cycle genes such as p53, ATM, cyclin D2, and Rb have shown altered expression patterns in different brain tumors such as meningioma and astrocytoma. Some genes in signaling pathways have a role in brain tumorigenesis. These pathways include hedgehog, EGFR, Notch, hippo, MAPK, PI3K/Akt, and WNT signaling. It has been shown that telomere length in some brain tumor samples is shortened compared to that in normal cells. As the shortening of telomere length triggers chromosome instability early in brain tumors, it could lead to initiation of cancer. On the other hand, telomerase activity was positive in some brain tumors. It is suggestive that telomere length and telomerase activity are important diagnostic markers in brain tumors. This review focuses on brain tumors with regard to the status of oncogenes, tumor suppressors, cell cycle genes, and genes in signaling pathways as well as the role of telomere length and telomerase in brain tumors.

P16 gene silencing along with p53 single-nucleotide polymorphism and risk of esophageal cancer in Northeast India.

The high incidence of esophageal cancer in Northeast India and the unique ethnic background and dietary habits provide a great opportunity to study the molecular genetics behind esophageal squamous cell carcinoma in this part of the region. We hypothesized that in addition to currently known environmental risk factors for esophageal cancer, genetic and epigenetic factors are also involved in esophageal carcinogenesis in Northeast India. Therefore, in this study, we explored the possible association between the two important G1 cell cycle regulatory genes p16 and p53 and environmental risk factors and risk of esophageal carcinogenesis. A total of 100 newly diagnosed esophageal cancer cases along with equal number of age-, sex-, and ethnicity-matched controls were included in this study. Methylation-specific polymerase chain reaction was used to determine the p16 promoter methylation status. Single-nucleotide polymorphism at codon 72 of p53 gene was assessed by the polymerase chain reaction-restriction fragment length polymorphism method. Aberrant methylation of p16 gene was seen in 81% of esophageal cancer cases. Hypermethylation of p16 gene was not found in healthy controls. p53 Pro/Pro genotype was found to be a risk genotype in Northeast India compared with Arg/Pro and Arg/Arg. p53 variant/polymorphism was significantly associated with esophageal cancer risk in the study population under all three genetic models, namely, dominant model (Arg/Pro + Pro/Pro vs Arg/Arg odds ratio = 2.25, confidence interval = 1.19-4.26; p = 0.012), recessive model (Arg/Arg + Arg/Pro vs Pro/Pro odds ratio = 2.35, confidence interval = 1.24-4.44; p = 0.008), and homozygous model (Pro/Pro vs Arg/Arg odds ratio = 3.33, confidence interval = 1.54-7.20; p = 0.002). However, p53 variant/polymorphism was not statistically associated with esophageal cancer risk under the heterozygous model (Pro/Pro vs Arg/Pro). In the case-only analysis based on p16 methylation, the p53 variant/polymorphism (Pro/Pro or Arg/Pro) showed significant association for esophageal cancer risk (odds ratio = 3.33, confidence interval = 1.54-7.20; p = 0.002). Gene-gene and gene-environment interaction using the case-only approach revealed a strong association between p16 methylation, p53 single-nucleotide polymorphism, and environmental factors and esophageal cancer risk. Cases with p16 methylation and p53 variant/polymorphism (Pro/Pro or Arg/Pro) along with both betel quid and tobacco chewing habit (odds ratio = 8.29, confidence interval = 1.14-60.23; p = 0.037) conferred eightfold increased risk toward esophageal cancer development. This study reveals a synergistic interaction between epigenetic, genetic, and environmental factors and risk of esophageal cancer in this high-incidence region of Northeast India. The inactivation of either p16 or p53 in a majority of esophageal cancer cases in this study suggests the possible crosstalk between the important cell cycle genes.

A Machine-Learning Analysis Suggests That FLX925, a FLT3/CDK4/6 Kinase Inhibitor, Is Potent Against FLT3-Wild Type Tumors Via Its CDK4/6 Activity

Fms-like tyrosine kinase 3 (FLT3) is universally expressed in Acute Myeloid Leukemia (AML) blast cells (Zheng R, et al. FLT3 ligand causes autocrine signaling in acute myeloid leukemia cells. Blood. 2004) and activating mutations of FLT3 are amongst the most common genetic lesions in AML (Levis M. FLT3 mutations in acute myeloid leukemia: what is the best approach in 2013? ASH Education Program Book. 2013). FLX925, a small molecule inhibitor of FLT3 would be expected to have antitumor efficacy against FLT3-driven AML tumors. However, FLX925 also inhibits two closely related cyclin-dependent kinases (CDKs), CDK4 and CDK6 (described together as CDK4/6). Since CDK4/6 are important cell cycle genes and CDK4/6 inhibitors have demonstrated anti-tumor activity, the anti-CDK4/6 activity of FLX925 may drive anti-tumor efficacy in additional and potentially overlapping patient populations.To generate hypotheses about which tumors would be sensitive to FLX925 treatment and to understand the relative contributions of FLX925's FLT3- and CDK4/6-inhibitory activities, a panel of XXX tumor-derived cell lines were screened for sensitivity to FLX925. We performed a Gradient Boosting Machine (GBM) analysis, a machine-learning approach, to generate a model that predicts sensitivity to FLX925 based on RNA-Seq expression data. This sensitivity model can predict which cell lines and tumors are likely to be sensitive to FLX925 and also which gene expression patterns contribute to that sensitivity.The GBM analysis was performed on 133 (75%) of the assayed cell lines with a random 45 (25%) of the cell line datasets reserved for model validation. Pearson's correlations of r=0.96 on the test cell lines and r=0.68 on the validation cell lines were observed, indicating good predictive performance with modest overfitting. The two most important predictive genes in the model were Retinoblastoma 1 (RB1) and by Cyclin-Dependent Kinase Inhibitor 2A (CDKN2A). RB1 and CDKN2A are important cell cycle genes immediately downstream and upstream, respectively, of CDK4/6, suggesting that sensitivity to FLX925 in these cell lines is driven by FLX925's CDK4/6 inhibitory activity. To strengthen this conclusion, the modeling was repeated but gene sets covering cell cycle genes or genes in the FLT3/STAT5 signaling pathway were separately excluded from the analysis. While excluding the FLT3/STAT5 pathway genes had no impact on the predictive power of the model, excluding the cell cycle gene set completely abrogated the ability of the GBM to predict sensitivity to FLX925. Thus, we conclude that in this panel of largely FLT3-wild type (FLT3-WT) cell lines, FLX925-sensitivity is driven solely by the compound's CDK4/6 activity.These results suggest that independent, but potentially overlapping, sets of tumors will be responsive to FLX925 due to both its FLT3- and its CDK4/6-inhibitory activities. To predict which tumor types would be most sensitive to FLX925 treatment, we applied our GBM model to the RNA-Seq expression data for 10,537 tumors from The Cancer Genome Atlas (TCGA) consortium. Even though this model is indifferent to FLT3/STAT5-pathway gene expression, it nevertheless identifies AML tumors as having the highest median predicted sensitivity to FLX925. This is true even when all haem/lymph malignancy-derived cell lines are excluded from the training set. Thus, both FLT3-WT and FLT3-activated tumors are expected to have sensitivity to FLX925 treatment, the former due to FLX925's CDK4/6 activity alone and the latter due to the independent FLT3 and CDK4/6 activities of the drug. The anti-tumor activity of FLX925 is currently being investigated in a Ph1/b dose-escalation study in subject with relapsed or refractory AML (NCT02335814). DisclosuresCutler:Amgen, Inc: Equity Ownership; FLX Bio: Employment, Equity Ownership. Fridman:FLX Bio: Employment, Equity Ownership.

Controlling False Discoveries in Multidimensional Directional Decisions, with Applications to Gene Expression Data on Ordered Categories

Microarray gene expression studies over ordered categories are routinely conducted to gain insights into biological functions of genes and the underlying biological processes. Some common experiments are time-course/dose-response experiments where a tissue or cell line is exposed to different doses and/or durations of time to a chemical. A goal of such studies is to identify gene expression patterns/profiles over the ordered categories. This problem can be formulated as a multiple testing problem where for each gene the null hypothesis of no difference between the successive mean gene expressions is tested and further directional decisions are made if it is rejected. Much of the existing multiple testing procedures are devised for controlling the usual false discovery rate (FDR) rather than the mixed directional FDR (mdFDR), the expected proportion of Type I and directional errors among all rejections. Benjamini and Yekutieli (2005, Journal of the American Statistical Association 100, 71-93) proved that an augmentation of the usual Benjamini-Hochberg (BH) procedure can control the mdFDR while testing simple null hypotheses against two-sided alternatives in terms of one-dimensional parameters. In this article, we consider the problem of controlling the mdFDR involving multidimensional parameters. To deal with this problem, we develop a procedure extending that of Benjamini and Yekutieli based on the Bonferroni test for each gene. A proof is given for its mdFDR control when the underlying test statistics are independent across the genes. The results of a simulation study evaluating its performance under independence as well as under dependence of the underlying test statistics across the genes relative to other relevant procedures are reported. Finally, the proposed methodology is applied to a time-course microarray data obtained by Lobenhofer et al. (2002, Molecular Endocrinology 16, 1215-1229). We identified several important cell-cycle genes, such as DNA replication/repair gene MCM4 and replication factor subunit C2, which were not identified by the previous analyses of the same data by Lobenhofer et al. (2002) and Peddada et al. (2003, Bioinformatics 19, 834-841). Although some of our findings overlap with previous findings, we identify several other genes that complement the results of Lobenhofer et al. (2002).

A Time to Divide: Does the Circadian Clock Control Cell Cycle?

A variety of molecular, genomic and epidemiological evidence has linked cell cycle regulation to circadian rhythms. In a recent issue of Molecular Cell, Koeffler and colleagues show that PER1 sensitizes human cancer cells to ionizing radiation-induced apoptosis. In addition, PER1 expression was found to be downregulated in human tumors, suggesting a tumor suppressor role for the PER1 protein. The significance of PERs, clocks, and cell cycle control is discussed.

The Molecular Biology of Cervical Cancer

Cervical cancer remains a major worldwide health problem, especially in developing countries. Over the last few decades many advancements have been made in determining the molecular genetics of the development of cancer. This paper attempts to summarize the major disturbances in cellular function known to date to play a role in the development of cervical cancer. The role of human papillomavirus (HPV) infection in the development of cervical cancer is a major player in the genetic abnormalities described thus far. The effects of HPV E6 and E7 on important cell cycle genes are discussed. As oncogenes and tumor suppressor genes have been described in the different types of cancer, their possible role in cervical cancer has been investigated. The possible role of angiogenesis and angiogenic factors is described. Because of the importance of HPV infection in the development of cervical cancer, the role of the body's immune function in this cancer is also under study, and the results of these findings are summarized. Although a complete paradigm of the development of cervical cancer from normal cervical epithelium is not yet known, continued study in this area will hopefully lead to a defined progression of molecular and immunologic abnormalities that cause the disease. The goal would be to use this information to help prevent and/or treat cervical cancer in the future.