| Objective and Significance:Head and neck cancer (HNC) is one of the most common human tumor types. It is the sixth malignant among the incidence of malignant tumors in the world. The HNC includes three parts:cancers of ear/nose/throat, neck cancers, oral and maxillofacial cancers. Neck cancers mainly includes:thyroid carcinoma and cervical metastatic carcinoma with unknown primary. Cancers of ear/nose/throat mainly include nasal, paranasal sinus tumors, nasopharyngeal carcinoma and laryngeal cancer. Oral and maxillofacial cancers are mainly of buccal mucosa cancer, lip cancer, tongue cancer, carcinoma of floor of mouth and gingival carcinoma. During the study of Head and neck cancers, inactivation of tumor suppressor is universal. To explore the pathogenesis of oncogenes and tumor suppressor genes in head and neck cancers has become one of the hot spots in the basic research of cancer.Nasopharyngeal carcinoma (NPC) is one of the most common malignant tumors in China. The distribution of NPC in China is with obvious regional difference. NPC mainly distributed in southern China (Guangdong, Guangxi, Hunan and Jiangxi). In the worldwide, countries in Southeast Asia (Malaysia, Singapore, Indonesia and Thailand) is a high incidence area. Research shows that:Chinese ancestral living abroad also belongs to high risk population for NPC. With the completion of human genome draft drawn in2000June, the project of cancer genome anatomy have been launched. Aim to solve the problem of molecular genetics of human diseases including cancer. After several years’research, researchers found that chromosome variations of nasopharyngeal carcinoma tumor cell are mainly located in1,3,11,12and17chromosomes. Multiple chromosomal loss of heterozygosity area (1p、9p、9q、11q、13q、14q and16q) was revealed in nasopharyngeal carcinoma cells. The present results suggest that there are variations of multiple tumor suppressor genes and oncogenes in the development process of nasopharyngeal carcinoma. In addition to considering the factors of molecular genetics, the result of epidemiological study hints that there is EB virus antibody in serum of nasopharyngeal carcinoma patients. The antibody is increased during the progress of nasopharyngeal carcinoma. The EB virus has obvious effect to induce development of tumor. Nasopharyngeal carcinoma is related to environmental carcinogenic factors:eating salted fish (fish contains more nitrosamines, nitrosamine compounds which have been seriously shown to be carcinogenic), contacting aromatic hydrocarbon, residence environment with high trace element nickel etc.Single nucleotide polymorphism (SNPs) is defined as a single nucleotide insertion, deletion, transition and transversion caused polymorphism in genomic DNA sequence (A, G, C, T). Single base in the genome of a particular individual nucleotide positions occur mutation.The mutation includes conversion, single base transversion, insertion or deletion. Strictly speaking, only when the allele frequency is more than or equal to1%, the mutation can be called the SNPs. According to estimates, the human genome in each of the1000nucleotide has a SNP. There are more than3000thousand bases of human SNPs. SNP spreads all over the whole human genome. According to different SNP site in the gene, SNPs can be divided into three categories:gene coding region of SNPs (cSNPs), Perigenic SNPs (pSNPs) and Intergenic SNPs (iSNPs). Most of the SNPs in the genome noncoding region, and part of the SNPs in coding sequence did not affect the expression of amino acid sequence after translation. The SNPs had no significant effect on the individual phenotype. But some SNPs are located in the gene promoter, leading to gene transcription activity increased or decreased, resulting in increased or decrease of proteins expression, affect its biological function. Some SNPs in the protein coding region may affect the amino acid sequence of translation of the functional genes, which affect protein function, leading to sensitivity to specific environment. Another gene polymorphism classification includes two categories:Site polymorphism and length polymorphism.1. Site polymorphism:There are differences between alleles at specific sites on DNA sequence. That means base scattered in the genome with difference, including point mutation (transition and transversion), replacement, deletion and insertion of a single base.2. Length polymorphism:variable number of repeats (VNTRS), it is because of the different repeated times in the same order. It determines the minisatellite polymorphism. Minisatellite is composed of15-65BP basic units. Repeats times are highly variable in the crowd. Another length polymorphism is due to a lack of gene fragment or insert, such as microsatellite DNA (microsatellite), which is composed of repetitive sequences, basically only the1-8bp sequence, such as (TA) n and (CGG) n, usually repeat10-60times. Length polymorphism is genetic in Mendel mode. They are widely used in the analysis and diagnosis of genetic disease, analysis in gene mapping, DNA fingerprinting. Biological effects of polymorphisms are as following:the changes in the genetic code: a missense mutation, a nonsense mutation, synonymous mutation, frameshift mutation;2. Effect of mRNA splicing:if a point mutation in intron, it can produce two kinds of effects:one is the disappearance of the original two splice sites, another is to produce new splice-site. No matter what kind of form, all of them can lead to errors in mRNA splicing, abnormal mRNA, resulting in abnormal expression. A number of deletions, deletion may cause the lack of splice site.3. Absence of protein peptide chain:in the:nonsense mutation and lack of DNA fragments can result in the deletion of the gene encoding the polypeptide chain, the original function of the protein is lost. Frameshift mutation can not only result to amino acid translation of the peptide sequence changes, but also lead to large deletions in the peptides.4Promoter mutation and untranslated region:it can enhance or reduce the level or activity of gene transcription. The present research between diseases and polymorphism mainly focused on the study of stress protein polymorphism, oncogene, tumor suppressor gene polymorphism, metabolic enzyme gene polymorphism and repair gene polymorphism. Stress protein gene polymorphism:from prokaryotic bacteria to eukaryotic human, when exposed to high temperature or other stress factors, it can synthesize a group of protein known as heat shock proteins (HSPs). HSPs polymorphism is related to diseases or the body suffers from stress susceptibility or tolerance.2oncogene, tumor suppressor gene polymorphism:ras gene family has three kinds of genes associated with human tumor, namely H-ras, K-ras, N-ras. In human tumors, one of3ras genes produces a point mutation will cause the changes in the gene mutation, mutations of these sites activate ras gene, resulting in excessive generation of P21protein, continuous send signal into cells, causing cell malignant transformation.3. Polymorphism metabolic enzyme genes:the present study is focus on cytochrome P450, mainly involved CYP1to CYP3family and CYP4family members of gene products in human metabolism. Exogenous chemical substance through the respiratory tract, gastrointestinal tract, skin and other ways to enter the body, in most cases, first through the cytochrome P450enzyme catalyzed reaction after activation by phase Ⅰ, transfer procarcinogens into carcinogens, and biological molecular adduct, cause genetic damage, and carcinogenesis.4. Polymorphism of repair gene:the role of exotic harmful factors can induce intracellular DNA change, such as the base mismatch, insertion, deletion. DNA repair enzyme in the human body through different mechanisms to help the body repair these errors and protect human health. If the repair gene mutations that repair enzyme functional defect may result in occurrence of certain diseases. Therefore, the detection of different gene polymorphisms and study the pathogenesis of a variety of tumors and diseases and disease susceptibility has become the hotspot in the research of life science.The tumor suppressor gene p53is located on the short arm of human chromosome17(17p.13.1), approximately20KBS in length, encoding protein with molecular mass of53kDa, namely gene regulatory protein p53. Wild-type p53protein can be used as cell cycle regulatory protein, inhibit excessive proliferation of cell, with the function of anti-tumor cell proliferation, monitoring injury and induced apoptosis. Once the p53gene mutation, p53protein inactivation, cell division lost control, cell carcinogenesis. Human murine double minute2gene is located on chromosome12q13-14. Under normal circumstances, expression of MDM2mRNA is found in many human organs. It is the highest in skeletal muscle. Extensive expression of MDM2in mammals means that it has a role in fundamental cellular physiological processes. Analysis of the MDM2oncogene product showed that it has a certain role in the control of cell growth. Therefore, MDM2is considered to be the primary carcinoma gene in recent years. It plays a negative role in the p53in many ways. Research shows that:MDM2proteins can directly bind to p53to inhibit its activity, and lead to the degradation of p53through the ubiquitin. Abnormal amplification of MDM2or protein expression level increased the functional inactivation of p53in a variety of tumors. In the population, a single nucleotide polymorphism in MDM2gene promoter region (SNP309T/G mutation), as a kind of functional polymorphisms, can strengthen the binding capacity of SP1transcription factor, so that the MDM2transcription enhancer, leads to increased expression of MDM2, thereby inhibiting p53in regulating and to prevent the process of tumor cell proliferation. It has been confirmed that MDM2SNP309G allele is associated with a variety of human malignancies, such as lung cancer, breast cancer and colon cancer.Human murine double minute4gene is located on chromosome1q32. MDM4and MDM2are structurely similarity, containing490and491amino acid sequences respectively, contain three conserved domains:the N terminal domain connection binds to p53N end; a zinc finger domain; RING domain in C terminal. MDM2N end and the p53N end bind through hydrophobic interaction, the conformational change of MDM2and p53N combination, acidic domain can be stabilized in MDM2and p53DNA binding domain. The RING domain of C terminal for MDM2and MDM4form a homologous or heterologous. MDM2is a p53E3ligase, RING domain of MDM2mediated ubiquitination of p53so as to reduce the stability of p53, while MDM4had no deubiquitinating enzyme activity. It does not mediate degradation of p53. MDM4mainly by combining with active transcription of p53inhibit the transcription activity of p53on its downstream gene. MDM2and MDM4have inhibitory effect on p53by different mechanisms. At present, many clinical and basic researches show that:MDM2SNP309G may be an independent marker of nasopharyngeal carcinoma. Evidence-based medicine analysis can quantitatively analysis and combine different research, but so far, for the risk between MDM2SNP309polymorphism and NPC, there is no definite conclusion. Because researchers used different measurement methods, different populations in different studies, the results are inconsistent. So we make a general analysis of the related literature, in order to obtain a stable and credible result between the MDM2SNP309polymorphism and nasopharyngeal carcinoma risk.In the past ten years, studies on MDM2gene function are inceasing thorough, but the MDM4in tumorigenesis is an oncogene or tumor suppressor gene function remains controversially. Some researchers believe that the similar structure and function of MDM4and MDM2, MDM4is also an important factor inhibiting p53, may be a potential cancer gene. MDM4gene knockout mice results confirm:simple knockout of MDM4gene leads to embryonic lethality in mice, but at the same time knockout wild-type p53and MDM4gene, mice can normal development, presumably because of the knockdown of MDM4relieved the inhibition effect of MDM4, the release activity leads to embryonic lethality in mice. The MDM4has a role in the control of p53, but this regulation may have a dual nature:MDM4can be combined with p53in the cytoplasm, inhibits p53transcriptional activity, and inhibit tumor cell apoptosis. The MDM4in mitochondria combined with Bcl-2, promotes phosphorylation of p53on the mitochondrial membrane, can promote the release of cytochrome C, and promote the apoptosis pathway of mitochondrial endogenous. The role of MDM4in cancer cells may have different apoptotic pathway. Research shows that rsl563828, single nucleotide polymorphism in intron10of MDM4gene region (C>T) of the base conversion may be associated with multiple cancers.Based on relationship between the MDM2and head and neck cancer susceptibility especially for nasopharyngeal carcinoma, considering MDM4and MDM2in the function and structure with a lot of correlation, there is no relationship between MDM4rs1563828and nasopharyngeal carcinoma, this study on the MDM4polymorphism of rs1563828gene type distribution and its relationship with the nasopharyngeal carcinoma. Provide theoretical and practical support for the pathogenesis of nasopharyngeal carcinoma and clinical drug development in the future.Methods:1. Search the study about the relationship between patients with head and neck cancer and healthy populations of MDM2SNP309polymorphism in literature. Use keywords:"head and neck" or "oral" or "larynx" or "pharynx" or "nasopharyngeal" and "cancer" or "carcinoma" and "MDM2SNP309T/G". This study used database for Pubmed. Published before April2011relevant documents in the database, retrieval does not make special limited. According to predefined inclusion and exclusion criteria, screening into the analysis meeting the requirements of the documents. Data in the literature independently extracted by two authors, in all the details are agreed. We extracted the following information:the first author, publication time, the country, the source of the sample, study design and sample size. Correction of OR and95%CI are extracted for the meta analysis. Using the corrected OR value evaluate the relationship between MDM2SNP309polymorphism and head and neck cancer, especially nasopharyngeal carcinoma. According to the heterogeneity of variances, the meta analysis using the fixed effect model and random effect model. If the total OR is with some heterogeneity, the following methods were used to explore the sources of heterogeneity:1. analysis of subgroups;2. sensitive analysis of cause bias excluded; if the heterogeneity still exists, the random effect model is used. Heterogeneity between studies using I1to represent the various research results with rationality. There is heterogeneity in merge results if P<O.10. With Egger’s test to evaluate the results of publication bias; There was publication bias if P... |
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