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      Polymorphisms in the AKT1 and AKT2 genes and oesophageal squamous cell carcinoma risk in an Eastern Chinese population

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          Abstract

          Ethnic Han Chinese are at high risk of developing oesophageal squamous cell carcinoma ( ESCC). Aberrant activation of the AKT signalling pathway is involved in many cancers, including ESCC. Some single nucleotide polymorphisms ( SNPs) in genes involved in this pathway may contribute to ESCC susceptibility. We selected five potentially functional SNPs in AKT1 (rs2494750, rs2494752 and rs10138277) and AKT2 (rs7254617 and rs2304186) genes and investigated their associations with ESCC risk in 1117 ESCC cases and 1096 controls in an Eastern Chinese population. None of individual SNPs exhibited an association with ESCC risk. However, the combined analysis of three AKT1 SNPs suggested that individuals carrying one of AKT1 variant genotypes had a decreased ESCC risk [adjusted odds ratio ( OR) = 0.60, 95% CI = 0.42–0.87]. Further stratified analysis found that AKT1 rs2294750 SNP was associated with significantly decreased ESCC risk among women (adjusted OR = 0.63, 95% CI = 0.43–0.94) and non‐drinkers ( OR = 0.79, 95% CI = 0.64–0.99). Similar protective effects on women (adjusted OR = 0.56, 95% CI = 0.37–0.83) and non‐drinker (adjusted OR = 0.75, 95% CI = 0.60–0.94) were also observed for the combined genotypes of AKT1 SNPs. Consistently, logistic regression analysis indicated significant gene–gene interactions among three AKT1 SNPs ( P < 0.015). A three‐ AKT1 SNP haplotype (C‐A‐C) showed a significant association with a decreased ESCC risk (adjusted OR = 0.70, 95% CI = 0.52–0.94). Multifactor dimensionality reduction analysis confirmed a high‐order gene–environment interaction in ESCC risk. Overall, we found that three AKT1 SNPs might confer protection against ESCC risk; nevertheless, these effects may be dependent on other risk factors. Our results provided evidence of important gene–environment interplay in ESCC carcinogenesis.

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          Most cited references39

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          Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR Inhibitors: Rationale and Importance to Inhibiting These Pathways in Human Health

          The Ras/Raf/MEK/ERK and PI3K/PTEN/Akt/mTOR cascades are often activated by genetic alterations in upstream signaling molecules such as receptor tyrosine kinases (RTK). Integral components of these pathways, Ras, B-Raf, PI3K, and PTEN are also activated/inactivated by mutations. These pathways have profound effects on proliferative, apoptotic and differentiation pathways. Dysregulation of these pathways can contribute to chemotherapeutic drug resistance, proliferation of cancer initiating cells (CICs) and premature aging. This review will evaluate more recently described potential uses of MEK, PI3K, Akt and mTOR inhibitors in the proliferation of malignant cells, suppression of CICs, cellular senescence and prevention of aging. Ras/Raf/MEK/ERK and Ras/PI3K/PTEN/Akt/mTOR pathways play key roles in the regulation of normal and malignant cell growth. Inhibitors targeting these pathways have many potential uses from suppression of cancer, proliferative diseases as well as aging.
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            Multifactor dimensionality reduction software for detecting gene-gene and gene-environment interactions.

            Polymorphisms in human genes are being described in remarkable numbers. Determining which polymorphisms and which environmental factors are associated with common, complex diseases has become a daunting task. This is partly because the effect of any single genetic variation will likely be dependent on other genetic variations (gene-gene interaction or epistasis) and environmental factors (gene-environment interaction). Detecting and characterizing interactions among multiple factors is both a statistical and a computational challenge. To address this problem, we have developed a multifactor dimensionality reduction (MDR) method for collapsing high-dimensional genetic data into a single dimension thus permitting interactions to be detected in relatively small sample sizes. In this paper, we describe the MDR approach and an MDR software package. We developed a program that integrates MDR with a cross-validation strategy for estimating the classification and prediction error of multifactor models. The software can be used to analyze interactions among 2-15 genetic and/or environmental factors. The dataset may contain up to 500 total variables and a maximum of 4000 study subjects. Information on obtaining the executable code, example data, example analysis, and documentation is available upon request. All supplementary information can be found at http://phg.mc.vanderbilt.edu/Software/MDR.
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              A meta-analysis of alcohol drinking and cancer risk

              To evaluate the strength of the evidence provided by the epidemiological literature on the association between alcohol consumption and the risk of 18 neoplasms, we performed a search of the epidemiological literature from 1966 to 2000 using several bibliographic databases. Meta-regression models were fitted considering linear and non-linear effects of alcohol intake. The effects of characteristics of the studies, of selected covariates (tobacco) and of the gender of individuals included in the studies, were also investigated as putative sources of heterogeneity of the estimates. A total of 235 studies including over 117 000 cases were considered. Strong trends in risk were observed for cancers of the oral cavity and pharynx, oesophagus and larynx. Less strong direct relations were observed for cancers of the stomach, colon and rectum, liver, breast and ovary. For all these diseases, significant increased risks were found also for ethanol intake of 25 g per day. No significant nor consistent relation was observed for cancers of the pancreas, lung, prostate or bladder. Allowance for tobacco appreciably modified the relations with laryngeal, lung and bladder cancers, but not those with oral, oesophageal or colorectal cancers. This meta-analysis showed no evidence of a threshold effect for most alcohol-related neoplasms. The inference is limited by absence of distinction between lifelong abstainers and former drinkers in several studies, and the possible selective inclusion of relevant sites only in cohort studies. © 2001 Cancer Research Campaign http://www.bjcancer.com
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                Author and article information

                Journal
                J Cell Mol Med
                J. Cell. Mol. Med
                10.1111/(ISSN)1582-4934
                JCMM
                Journal of Cellular and Molecular Medicine
                John Wiley and Sons Inc. (Hoboken )
                1582-1838
                1582-4934
                01 February 2016
                April 2016
                : 20
                : 4 ( doiID: 10.1111/jcmm.2016.20.issue-4 )
                : 666-677
                Affiliations
                [ 1 ] Cancer InstituteFudan University Shanghai Cancer Center ShanghaiChina
                [ 2 ] Department of Oncology Shanghai Medical CollegeFudan University ShanghaiChina
                [ 3 ] Molecular Epidemiology Laboratory and Department of Laboratory MedicineHarbin Medical University Cancer Hospital Harbin HeilongjiangChina
                [ 4 ] Department of Pediatric Surgery Guangzhou Women and Children's Medical CenterGuangzhou Medical University GuangzhouChina
                [ 5 ] Department of OncologyXinhua Hospital Affiliated to Shanghai Jiaotong University, School of Medicine ShanghaiChina
                [ 6 ] Ministry of Education Key Laboratory of Contemporary Anthropology State Key Laboratory of Genetic Engineering School of Life SciencesFudan University ShanghaiChina
                [ 7 ]Fudan‐Taizhou Institute of Health Sciences Taizhou JiangsuChina
                [ 8 ] Department of Thoracic Surgery Fudan University Shanghai Cancer CenterFudan University ShanghaiChina
                [ 9 ] Duke Cancer InstituteDuke University Medical Center Durham NCUSA
                Author notes
                [*] [* ] Correspondence to: Jia‐Qing XIANG and Qingyi WEI.

                E‐mails: j.q.xiang@ 123456hotmail.com and weiqingyi@ 123456yahoo.com / qingyi.wei@ 123456duke.edu

                [†]

                Jinhong Zhu and Mengyun Wang contributed equally to this study and should be considered as co‐first authors.

                Article
                JCMM12750
                10.1111/jcmm.12750
                5126231
                26828791
                3895af25-dc53-41b1-8970-b3ed6cf9a8ad
                © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

                This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 July 2015
                : 02 November 2015
                Page count
                Pages: 12
                Funding
                Funded by: China Recruitment Program of Global Experts at Fudan University
                Funded by: National Natural Science Foundation of China
                Award ID: 81302101
                Funded by: Ministry of Health
                Award ID: 201002007
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                jcmm12750
                April 2016
                Converter:WILEY_ML3GV2_TO_NLMPMC version:4.9.8 mode:remove_FC converted:28.11.2016

                Molecular medicine
                akt1,akt2,oesophageal squamous cell carcinoma,risk,polymorphism
                Molecular medicine
                akt1, akt2, oesophageal squamous cell carcinoma, risk, polymorphism

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