Molecular chemoprevention by selenium: a genomic approach

Basic research and clinical chemoprevention trials support the protective role of selenium in cancer prevention but the mechanisms based on the molecular level remain to be fully defined. This mini-review focuses only on the elucidation of the molecular mechanisms of cancer prevention by selenium using the genomics approach; target organs discussed here are breast, prostate, colon and lung. The results described here support the utility of microarray technology in delineating the molecular mechanisms of cancer prevention by selenium. These results are based on studies employing human and rodent cell lines and tissues from animal models ranging from normal to frank cancer. The dose and the form of selenium are determining factors in cancer chemoprevention. The results of the microarray analysis reviewed here indicate that selenium, independent of its form and the target organ examined, alters several genes in a manner that can account for cancer prevention. Selenium can up regulate genes related to phase II detoxification enzymes, certain selenium-binding proteins and select apoptotic genes, while down regulating those related to phase I activating enzymes and cell proliferation. Independent of tissue type, selenium arrests cells in G1 phase of cell cycle, inhibits CYCLIN A, CYCLIN D1, CDC25A, CDK4, PCNA and E2F gene expressions while induces the expressions of P19, P21, P53, GST, SOD, NQO1, GADD153 and certain CASPASES. In addition to those described above, genes such as OPN, which is mainly involved in metastasis and recently reported to be down regulated by selenium, should be considered as potential molecular marker in clinical chemoprevention trials. Collectively, literature data indicate that some of these genes that were altered by selenium are also involved in the development of human cancers described in this review. It appears that androgen receptor status may influence the effect of selenium on gene expression profile in prostate cancer; whether estrogen receptor may influence the effect of selenium on gene expression in breast cancer requires further studies. Knowledge from gene array data in combination with proteomics approaches, using homogenous population of cell types with the aid of laser capture microdissection, may provide an individualized dimension of information on cancer risk and potential targets for its prevention. The molecular (genetic) biomarkers presented in this review will provide the foundation for future studies of the chemopreventive properties of structurally varied selenium compounds.     

The use of common genetic polymorphisms to enhance the epidemiologic study of environmental carcinogens

Overwhelming evidence indicates that environmental exposures, broadly defined, are responsible for most cancer. There is reason to believe, however, that relatively common polymorphisms in a wide spectrum of genes may modify the effect of these exposures. We discuss the rationale for using common polymorphisms to enhance our understanding of how environmental exposures cause cancer and comment on epidemiologic strategies to assess these effects, including study design, genetic and statistical analysis, and sample size requirements. Special attention is given to sources of potential bias in population studies of gene--environment interactions, including exposure and genotype misclassification and population stratification (i.e., confounding by ethnicity). Nevertheless, by merging epidemiologic and molecular approaches in the twenty-first century, there will be enormous opportunities for unraveling the environmental determinants of cancer. In particular, studies of genetically susceptible subgroups may enable the detection of low levels of risk due to certain common exposures that have eluded traditional epidemiologic methods. Further, by identifying susceptibility genes and their pathways of action, it may be possible to identify previously unsuspected carcinogens. Finally, by gaining a more comprehensive understanding of environmental and genetic risk factors, there should emerge new clinical and public health strategies aimed at preventing and controlling cancer.     

Xiphophorus interspecies hybrids as genetic models of induced neoplasia

Fishes of the genus Xiphophorus (platyfishes and swordtails) are small, internally fertilizing, livebearing, and derived from freshwater habitats in Mexico, Guatemala, Belize, and Honduras. Scientists have used these fishes in cancer research studies for more than 70 yr. The genus is presently composed of 22 species that are quite divergent in their external morphology. Most cancer studies using Xiphophorus use hybrids, which can be easily produced by artificial insemination. Phenotypic traits, such as macromelanophore pigment patterns, are often drastically altered as a result of lack of gene regulation within hybrid fishes. These fish can develop large exophytic melanomas as a result of upregulated expression of these pigment patterns. Because backcross hybrid fish are susceptible to the development of melanoma and other neoplasms, they can be subjected to potentially deleterious chemical and physical agents. It is thus possible to use gene mapping and cloning methodologies to identify and characterize oncogenes and tumor suppressors implicated in spontaneous or induced neoplasia. This article reviews the history of cancer research using Xiphophorus and recent developments regarding DNA repair capabilities, mapping, and cloning of candidate genes involved in neoplastic phenotypes. The particular genetic complexity of melanoma in these fishes is analyzed and reviewed.     

Trichloroethylene: Using New Information To Improve the Cancer Characterization

The views expressed in this paper are those of the authors and do not necessarily reflect the views or policies of the U.S. Environmental Protection Agency. Assessments of TCE's potential to cause cancer in humans have had to address issues concerning the strength of the human evidence and the relevance of the animal tumors to humans. The epidemiological database now includes analyses of multiple studies and molecular information. A recent analysis strongly suggests that TCE may induce cancer in humans at multiple sites, including kidney, liver, and lympho-hematopoietic cancer. Molecular analyses have found mutations of the von Hippel-Lindau tumor suppressor gene in renal tumors of TCE-exposed individuals. The animal bioassays have been followed up with mechanistic studies that provide insight into TCE's possible modes of action at each tumor site. This information suggests that TCE may act through mechanisms that can be relevant to human cancers. The mechanistic information can also be used to identify risk factors that may make some people more susceptible to TCE's adverse effects, allowing a fuller characterization of TCE's cancer potential in different groups of people.     

Genetic basis of trypanotolerance in cattle and mice

Under most circumstances, certain breeds of domestic ruminants show a remarkable resistance to the effects of African trypanosomiasis: they can tolerate the presence of parasites while apparently controlling levels of parasitaemia and, crucially, not showing the severe anaemia and production loss that are characteristic of infection in susceptible hosts. As discussed here by Stephen Kemp and Alan Teale, the genetic control of this phenomenon might finally be yielding to gene mapping studies. Genetic regions determining susceptibility to trypanosomiasis in mice have been identified and parallel studies are well advanced in cattle. There is growing evidence that only modest numbers of genes are involved in determining the difference between a susceptible and a resistant animal. These observations raise a new series of important questions concerning the possible exploitation of major trypanotolerance genes and the way that they might function in different genetic and physical environments.     

Multi-locus association study of schizophrenia susceptibility genes with a posterior probability method

Schizophrenia is a serious neuropsychiatric illness affecting about 1% of the world’s population. Family, twin and adoption studies have demonstrated that 65%―85% of the susceptibility to schizophrenia can be attributed to genes. On the basis of genetic model-ing of epidemiological data and recent results of a number of whole-genome screens for susceptibility genes, schizophrenia has been considered a complex disorder. A number of genes with small to moderate effects are involved in combinat…     

Individual and cumulative effects of GWAS susceptibility loci in lung cancer: associations after sub-phenotyping for COPD

Epidemiological studies show that approximately 20–30% of chronic smokers develop chronic obstructive pulmonary disease (COPD) while 10–15% develop lung cancer. COPD pre-exists lung cancer in 50–90% of cases and has a heritability of 40–77%, much greater than for lung cancer with heritability of 15–25%. These data suggest that smokers susceptible to COPD may also be susceptible to lung cancer. This study examines the association of several overlapping chromosomal loci, recently implicated by GWA studies in COPD, lung function and lung cancer, in (n = 1400) subjects sub-phenotyped for the presence of COPD and matched for smoking exposure. Using this approach we show; the 15q25 locus confers susceptibility to lung cancer and COPD, the 4q31 and 4q22 loci both confer a reduced risk to both COPD and lung cancer, the 6p21 locus confers susceptibility to lung cancer in smokers with pre-existing COPD, the 5p15 and 1q23 loci both confer susceptibility to lung cancer in those with no pre-existing COPD. We also show the 5q33 locus, previously associated with reduced FEV₁, appears to confer susceptibility to both COPD and lung cancer. The 6p21 locus previously linked to reduced FEV₁ is associated with COPD only. Larger studies will be needed to distinguish whether these COPD-related effects may reflect, in part, associations specific to different lung cancer histology. We demonstrate that when the “risk genotypes” derived from the univariate analysis are incorporated into an algorithm with clinical variables, independently associated with lung cancer in multivariate analysis, modest discrimination is possible on receiver operator curve analysis (AUC = 0.70). We suggest that genetic susceptibility to lung cancer includes genes conferring susceptibility to COPD and that sub-phenotyping with spirometry is critical to identifying genes underlying the development of lung cancer.     

基因的单核苷酸多态性与乳腺癌关系的研究进展

乳腺癌是女性发病率最高的恶性肿瘤,具有家族聚集性,其发生发展是一个复杂的过程,涉及多种不同基因的相互作用和相互调控。随着基因技术和分子生物技术的飞速发展,许多基因被揭示在乳腺癌的发生发展中起关键作用,如BRCA、FGFR、ATM、ZNF365、Pokemon基因等。基于流行病学研究,这些易感基因可被分为高外显率易感基因和低外显率易感基因,其多态性对乳腺癌具有重要的影响。对乳腺癌易感基因的研究有助于阐明乳腺癌的发生机制、发展过程,对其早期诊断、预后判断和良恶性鉴别也有着重要的意义,可为乳腺癌的临床生物基因靶向治疗提供新的靶点和理论基础。本文主要对这些基因的单核苷酸多态性与乳腺癌关系的研究进展进行了综述。     

Ionizing radiation-induced DNA injury and damage detection in patients with breast cancer

Breast cancer is the most common malignancy in women. Radiotherapy is frequently used in patients with breast cancer, but some patients may be more susceptible to ionizing radiation, and increased exposure to radiation sources may be associated to radiation adverse events. This susceptibility may be related to deficiencies in DNA repair mechanisms that are activated after cell-radiation, which causes DNA damage, particularly DNA double strand breaks. Some of these genetic susceptibilities in DNA-repair mechanisms are implicated in the etiology of hereditary breast/ovarian cancer (pathologic mutations in the BRCA 1 and 2 genes), but other less penetrant variants in genes involved in sporadic breast cancer have been described. These same genetic susceptibilities may be involved in negative radiotherapeutic outcomes. For these reasons, it is necessary to implement methods for detecting patients who are susceptible to radiotherapy-related adverse events. This review discusses mechanisms of DNA damage and repair, genes related to these functions, and the diagnosis methods designed and under research for detection of breast cancer patients with increased radiosensitivity.     

Molecular targets of HPV oncoproteins: Potential biomarkers for cervical carcinogenesis

Cervical cancer is the second most common cancer among women worldwide and is responsible for 275,000 deaths each year. Persistent infection with high-risk human papillomavirus (HR-HPV) is an essential factor for the development of cervical cancer. Although the process is not fully understood, molecular mechanisms caused by HPV infection are necessary for its development and reveal a large number of potential biomarkers for diagnosis and prognosis. These molecules are host genes and/or proteins, and cellular microRNAs involved in cell cycle regulation that result from disturbed expression of HR-HPV E5, E6 and E7 oncoproteins. One of the current challenges in medicine is to discover potent biomarkers that can correctly diagnose cervical premalignant lesions and standardize clinical management. Currently, studies are showing that some of these molecules are potential biomarkers of cervical carcinogenesis, and it is possible to carry out a more accurate diagnosis and provide more appropriate follow-up treatment for women with cervical dysplasia. In this paper, we review recent research studies on cell cycle molecules deregulated by HPV infections, as well as their potential use for cervical cancer screening.     

Childhood acute lymphocytic leukemia and perspectives on risk assessment of early-life stage exposures

Recognition that children are a potentially susceptible subpopulation has led to the development of child-specific sensitivity factors. Establishing reliable sensitivity factors in support of risk assessment of early-life stage exposures can be aided by evaluating studies that enhance our understanding both of the biological basis of disease processes and the potential role of environmental exposures in disease etiology. For these reasons, we evaluated childhood acute lymphocytic leukemia (ALL) studies from the point of view of mechanism and etiology. ALL is the most common form of childhood cancer proposed to result from a prenatal primary event and a postnatal second event. This multi-stage model is supported by the observation that chromosomal translocations/fusion genes (e.g., TEL-AML1) involved in producing ALL are detected at birth (prenatal event), and a postnatal event (e.g., TEL deletion) is required for disease manifestation. It appears that a proportion of ALL cases are the result of environmental exposures, in which case preconceptional, prenatal, and postnatal stages are likely to be critical exposure windows. To this end, we recognized postnatal infection-related risk factors as potential candidates associated with the ALL second event. Additionally, we discuss use of ALL-associated fusion genes and genetic polymorphisms, together or separately, as indicators of ALL susceptibility and increased risk. The possibility of using fusion genes alone as biomarkers of response is also discussed because they can serve as predictors of key events in the development of a mode of action (a sequence of key events, starting with interaction of an agent with a cell, ultimately resulting in cancer formation) for particular environmental exposures. Furthermore, we discuss use of an initiated animal model for ALL, namely transgenic mice with TEL-AML1 expression, for exploring mechanisms by which different classes of environmental exposures could be involved in inducing the postnatal step in ALL formation.     

A Network Based Method for Analysis of lncRNA-Disease Associations and Prediction of lncRNAs Implicated in Diseases

Increasing evidence has indicated that long non-coding RNAs (lncRNAs) are implicated in and associated with many complex human diseases. Despite of the accumulation of lncRNA-disease associations, only a few studies had studied the roles of these associations in pathogenesis. In this paper, we investigated lncRNA-disease associations from a network view to understand the contribution of these lncRNAs to complex diseases. Specifically, we studied both the properties of the diseases in which the lncRNAs were implicated, and that of the lncRNAs associated with complex diseases. Regarding the fact that protein coding genes and lncRNAs are involved in human diseases, we constructed a coding-non-coding gene-disease bipartite network based on known associations between diseases and disease-causing genes. We then applied a propagation algorithm to uncover the hidden lncRNA-disease associations in this network. The algorithm was evaluated by leave-one-out cross validation on 103 diseases in which at least two genes were known to be involved, and achieved an AUC of 0.7881. Our algorithm successfully predicted 768 potential lncRNA-disease associations between 66 lncRNAs and 193 diseases. Furthermore, our results for Alzheimer''s disease, pancreatic cancer, and gastric cancer were verified by other independent studies.     

Multi-locus association study of schizophrenia susceptibility genes with a posterior probability method

Schizophrenia is a serious neuropsychiatric illness affecting about 1% of the world’s population. It is considered a complex inheritance disorder. A number of genes are involved in combination in the etiology of the disorder. Evidence implicates the altered dopaminergic transmission in schizophrenia. In the present study, in order to identify susceptibility genes for schizophrenia in dopaminergic metabolism, we analyzed 59 single nucleotide polymorphisms (SNPs) in 24 genes of the dopaminergic pathway among 82 unrelated patients with schizophrenia and 108 matched normal controls. Considering that traditional single-locus association studies ignore the multigenic nature of complex diseases and do not take into account possible interactions between susceptibility genes, we proposed a multi-locus analysis method, using the posterior probability of morbidity as a measure of absolute disease risk for a multi-locus genotype combination, and developed an algorithm based on perturbation and average to detect the susceptibility multi-locus genotype combinations, as well as to repress noise and avoid false positive results at our best. A three-locus SNP genotype combination involved in the interactions ofCOMT andALDH3B1 genes was detected to be significantly susceptible to schizophrenia.     

Potential Therapeutic Targets for Oral Cancer: ADM,TP53, EGFR,LYN, CTLA4, SKIL,CTGF, CD70

In India, oral cancer has consistently ranked among top three causes of cancer-related deaths, and it has emerged as a top cause for the cancer-related deaths among men. Lack of effective therapeutic options is one of the main challenges in clinical management of oral cancer patients. We interrogated large pool of samples from oral cancer gene expression studies to identify potential therapeutic targets that are involved in multiple cancer hallmark events. Therapeutic strategies directed towards such targets can be expected to effectively control cancer cells. Datasets from different gene expression studies were integrated by removing batch-effects and was used for downstream analyses, including differential expression analysis. Dependency network analysis was done to identify genes that undergo marked topological changes in oral cancer samples when compared with control samples. Causal reasoning analysis was carried out to identify significant hypotheses, which can explain gene expression profiles observed in oral cancer samples. Text-mining based approach was used to detect cancer hallmarks associated with genes significantly expressed in oral cancer. In all, 2365 genes were detected to be differentially expressed genes, which includes some of the highly differentially expressed genes like matrix metalloproteinases (MMP-1/3/10/13), chemokine (C-X-C motif) ligands (IL8, CXCL-10/-11), PTHLH, SERPINE1, NELL2, S100A7A, MAL, CRNN, TGM3, CLCA4, keratins (KRT-3/4/13/76/78), SERPINB11 and serine peptidase inhibitors (SPINK-5/7). XIST, TCEAL2, NRAS and FGFR2 are some of the important genes detected by dependency and causal network analysis. Literature mining analysis annotated 1014 genes, out of which 841 genes were statistically significantly annotated. The integration of output of various analyses, resulted in the list of potential therapeutic targets for oral cancer, which included targets such as ADM, TP53, EGFR, LYN, CTLA4, SKIL, CTGF and CD70.     

Genetic epidemiology of multistage carcinogenesis

It is commonly believed that cancer is a multistage, polygenic disease. Even though conceptually appealing, the evidence supporting the multistage theory remains limited. Most known tumor suppresser genes are associated with monogenic dominant cancers following a two-hit pathway. We review results from a recent twin study on 90000 individuals that give support to the multistage theory. Statistically significant heritability estimates were shown for cancers of the colorectum (35%), breast (27%), and prostate (42%). These estimates are much higher than those obtained from family studies in which parents and offspring, or sibs are compared. The difference can be accounted for by the involvement of many genes. A polygenic cancer would show small effects in family studies but large effects in twin studies. We present calculations on the decrease in familial risks when the number of genes involved increases or when the penetrance decreases. We test the apparent number of stages involved in the main cancers from the Swedish Family-Cancer Database. The logarithms of the slopes suggest large differences in the apparent numbers of mutations involved in different cancers. The number of mutations required appears to be less in familial breast cancer compared to sporadic breast cancer. Study designs for gene identification should be revised to accommodate polygenic cancers.     

Death-associated proteins: from gene identification to the analysis of their apoptotic and tumour suppressive functions

Aberrations of apoptosis are implicated in many diseases, including cancer, autoimmune disease, cardiovascular disease and neurodegeneration. The cell's apoptotic machinery is, therefore, an important potential target for the development of new therapies. Our laboratory has used a strategy called technical knockout (TKO) to identify novel genes involved in apoptosis. TKO is based on random inactivation of gene expression with antisense cDNA libraries, followed by selection of those cells that survive in the continuous presence of an apoptotic stimulus. Using this approach, we have isolated five novel genes, including a serine/threonine kinase, a nucleotide-binding protein and a homologue of the p220 translation initiation factor. Expression of one of these genes (DAP kinase) is lost in some cancers, and this loss appears to increase the metastatic potential of some tumours.     

Gene expression profiles of the Southern house mosquito Culex quinquefasciatus during exposure to permethrin

Insecticide resistance is a major obstacle to the management of disease‐vectoring mosquitoes worldwide. The genetic changes and detoxification genes involved in insecticide resistance have been extensively studied in populations of insecticide‐resistant mosquitoes, however few studies have focused on the resistance genes upregulated upon insecticide exposure and the possible regulation pathways involved in insecticide resistance. To characterize the changes in gene expression during insecticide exposure, and to investigate the possible connection of known regulation pathways with insecticide resistance, we conducted RNA‐Seq analysis of a highly permethrin‐resistant strain of Culex quinquefasciatus following permethrin exposure. Gene expression profiles revealed a total of 224 upregulated and 146 downregulated genes when compared to a blank acetone carrier treated control, respectively, suggesting that there were multiple, but specific genes involved in permethrin resistance. Functional enrichment analysis showed that the upregulated genes contained multiple detoxification genes including a glutathione S‐transferase and multiple cytochrome P450 genes, as well as several immune‐related genes, while the downregulated genes consisted primarily of proteases and carbohydrate metabolism and transport. Further analysis showed that permethrin exposure resulted in a decrease in the expression of serum storage proteins and likely represented a delay in the development of the fourth instar possibly due to a decrease in feeding. This effect was more pronounced in an insecticide‐resistant strain than in an insecticide‐susceptible strain and may represent a behavioral mechanism of insecticide resistance in Culex mosquitoes.