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      Is MDM2 SNP309 Variation a Risk Factor for Head and Neck Carcinoma? : An Updated Meta-Analysis Based on 11,552 Individuals

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      , MD, , MD, , MS, , MS, , MD
      Medicine
      Wolters Kluwer Health

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          Abstract

          Murine double minute-2 (MDM2) is a negative regulator of P53, and its T309G polymorphism has been suggested as a risk factor for a variety of cancers. Increasing evidence has shown the association of MDM2 T309G polymorphism with head and neck carcinoma (HNC) risk. However, the results are inconsistent. Thus, we performed a meta-analysis to elucidate the association.

          The meta-analysis retrieved studies published up to August 2015, and essential information was extracted for analysis. Separate analyses on ethnicity, source of controls, sample size, detection method, and cancer types were also conducted. Odds ratios (ORs) and their 95% confidence intervals (CIs) were used to estimate the association.

          Pooled data from 16 case–control studies including 4625 cases and 6927 controls failed to indicate a significant association. However, in the subgroup analysis of sample sizes, an increased risk was observed in the largest sample size group (>1000) under a recessive model (OR = 1.52; 95% CI = 1.08–2.13). Increased risks were also found in the nasopharyngeal cancer in the subgroup analysis of cancer types (GG vs TT: OR = 2.07; 95% CI = 1.38–3.12; dominant model: OR = 1.48; 95% CI = 1.13–1.93; recessive model: OR = 1.76; 95% CI = 1.17–2.65).

          The results suggest that homozygote GG alleles of MDM2 SNP309 may be a low-penetrant risk factor for HNC, and G allele may confer nasopharyngeal cancer susceptibility.

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          Most cited references51

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          A single nucleotide polymorphism in the MDM2 promoter attenuates the p53 tumor suppressor pathway and accelerates tumor formation in humans.

          The tumor suppressor p53 gene is mutated in minimally half of all cancers. It is therefore reasonable to assume that naturally occurring polymorphic genetic variants in the p53 stress response pathway might determine an individual's susceptibility to cancer. A central node in the p53 pathway is the MDM2 protein, a direct negative regulator of p53. In this report, a single nucleotide polymorphism (SNP309) is found in the MDM2 promoter and is shown to increase the affinity of the transcriptional activator Sp1, resulting in higher levels of MDM2 RNA and protein and the subsequent attenuation of the p53 pathway. In humans, SNP309 is shown to associate with accelerated tumor formation in both hereditary and sporadic cancers. A model is proposed whereby SNP309 serves as a rate-limiting event in carcinogenesis.
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            Regulation of the p53 response and its relationship to cancer.

            p53 has been studied intensively as a major tumour suppressor that detects oncogenic events in cancer cells and eliminates them through senescence (a permanent non-proliferative state) or apoptosis. Consistent with this role, p53 activity is compromised in a high proportion of all cancer types, either through mutation of the TP53 gene (encoding p53) or changes in the status of p53 modulators. p53 has additional roles, which may overlap with its tumour-suppressive capacity, in processes including the DNA damage response, metabolism, aging, stem cell differentiation and fertility. Moreover, many mutant p53 proteins, termed 'gain-of-function' (GOF), acquire new activities that help drive cancer aggression. p53 is regulated mainly through protein turnover and operates within a negative-feedback loop with its transcriptional target, MDM2 (murine double minute 2), an E3 ubiquitin ligase which mediates the ubiquitylation and proteasomal degradation of p53. Induction of p53 is achieved largely through uncoupling the p53-MDM2 interaction, leading to elevated p53 levels. Various stress stimuli acting on p53 (such as hyperproliferation and DNA damage) use different, but overlapping, mechanisms to achieve this. Additionally, p53 activity is regulated through critical context-specific or fine-tuning events, mediated primarily through post-translational mechanisms, particularly multi-site phosphorylation and acetylation. In the present review, I broadly examine these events, highlighting their regulatory contributions, their ability to integrate signals from cellular events towards providing most appropriate response to stress conditions and their importance for tumour suppression. These are fascinating aspects of molecular oncology that hold the key to understanding the molecular pathology of cancer and the routes by which it may be tackled therapeutically.
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              Risk factors for head and neck cancer in young adults: a pooled analysis in the INHANCE consortium.

              Increasing incidence of head and neck cancer (HNC) in young adults has been reported. We aimed to compare the role of major risk factors and family history of cancer in HNC in young adults and older patients.
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                Author and article information

                Journal
                Medicine (Baltimore)
                Medicine (Baltimore)
                MEDI
                Medicine
                Wolters Kluwer Health
                0025-7974
                1536-5964
                March 2016
                07 March 2016
                : 95
                : 9
                : e2948
                Affiliations
                From the Department of Otolaryngology, Southwest Hospital, Third Military Medical University, Chongqing (XZ, QL, ZX, XZ); and Affiliated Hospital of Guiyang Medical University, Guiyang, China (XZ, HY).
                Author notes
                Correspondence: Xianlu Zhuo, Department of Otolaryngology, Southwest Hospital, Third Military Medical University, Chongqing, China (e-mail: zhuoxianlu@ 123456gmc.edu.cn).
                Xueyuan Zhang, Department of Otolaryngology, Southwest Hospital, Third Military Medical University, Chongqing, China (e-mail: sydzxy@ 123456aliyun.com).
                Article
                02948
                10.1097/MD.0000000000002948
                4782892
                26945408
                c77a0b89-2228-4d2b-bc14-1d4e219048f3
                Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

                This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0, where it is permissible to download, share and reproduce the work in any medium, provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

                History
                : 24 September 2015
                : 15 January 2016
                : 8 February 2016
                Categories
                4400
                Research Article
                Systematic Review and Meta-Analysis
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