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      WTAP Gene Variants Confer Hepatoblastoma Susceptibility: A Seven-Center Case-Control Study

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          Abstract

          Hepatoblastoma is a rare disease, and its etiology remains to be revealed. Wilms tumor suppressor-1-associated protein (WTAP) plays a critical role in tumorigenesis. However, whether single nucleotide polymorphisms (SNPs) of the WTAP gene predispose to hepatoblastoma risk awaits to be investigated. With the use of the TaqMan assay, we evaluated the genotype frequencies of three WTAP SNPs (rs7766006 G > T, rs9457712 G > A, and rs1853259 A > G) in Chinese children with 313 hepatoblastoma patients and 1,446 controls. Among these three SNPs, only the rs7766006 T allele exhibited a significant association with hepatoblastoma risk (GT versus GG: adjusted odds ratio [OR] = 0.70, 95% confidence interval [CI] = 0.53–0.92, p = 0.009; GT/TT versus GG: adjusted OR = 0.73, 95% CI = 0.57–0.95, p = 0.017). Combined analysis indicated that subjects with two risk genotypes showed significantly higher hepatoblastoma risk, compared to individuals without a risk genotype (adjusted OR = 1.38, 95% CI = 1.02–1.88, p = 0.037). The stratified analysis revealed that the rs1853259 GG genotype, the rs7766006 GT/TT genotype, and two risk genotypes modified hepatoblastoma risk in certain subgroups. The significant results were validated by haplotype analyses and false-positive report probability analyses. Furthermore, the expression quantitative trait locus analysis indicated that rs7766006 T was associated with decreased expression of WTAP mRNA. Collectively, our results suggest that WTAP SNPs may be genetic modifiers for the development of hepatoblastoma.

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          Abstract

          The role of WTAP gene SNPs in hepatoblastoma remains to be elucidated. He and colleagues showed that the WTAP gene rs7766006 T allele exhibited a significant association with hepatoblastoma risk, possibly by decreasing expression of WTAP mRNA. Their work suggests that WTAP gene SNPs may be genetic modifiers for hepatoblastoma susceptibility.

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          Most cited references 42

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          Genetic variations of mTORC1 genes and risk of gastric cancer in an Eastern Chinese population.

          Mammalian target of rapamycin complex 1 (mTORC1) plays an important role in maintaining proper cellular functions, and genetic variations in this complex may affect cancer risk. In this study, we examined the associations between eight potential functional single nucleotide polymorphisms in the mTORC1 genes (rs2536T>C and rs1883965G>A for mTOR, rs3160T>C, and rs26865A>G for mLST8, rs3751934C>A, rs1062935T>C, rs3751932T>C, and rs12602885G>A for Raptor, not included in published gastric cancer genome-wide association studies) and gastric cancer risk in 1125 gastric cancer cases and 1196 cancer-free controls. We performed conditional logistic regression and multifactor dimensionality reduction (MDR) analyses to assess their associations with gastric cancer risk. We also used false-positive report probabilities (FPRP) for assessing significant findings. We found that only the rs1883965A variant genotypes were associated with an increased risk of gastric cancer (AG vs. GG: adjusted odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.00-1.59; AA vs. GG: adjusted OR = 1.85, 95% CI = 0.67-5.16 and dominant model: adjusted OR = 1.28, 95% CI = 1.03-1.61). Patients with ≥1 risk genotypes of mTOR had significant increased risk (adjusted OR = 1.25, 95% CI = 1.04-1.49), compared with those having zero risk genotypes. In the stratified analysis, the risk effect of the rs1883965 AG/AA genotypes was evident in subgroups of ever-smokers, non-gastric cardia adenocarcinoma and clinical stage I + II, which were noteworthy findings as evaluated by FPRP. The MDR analysis identified smoking status and rs1883965 as the strongest two-factors for gastric cancer risk. These data support the hypothesis that functional polymorphisms of mTOR may contribute to gastric cancer risk. Clearly, our results require validation in larger studies with different ethnic populations. © 2013 Wiley Periodicals, Inc.
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            Association of Common Genetic Variants in Pre-microRNAs and Neuroblastoma Susceptibility: A Two-Center Study in Chinese Children.

            Neuroblastoma is a commonly occurring extracranial pediatric solid tumor without defined etiology. Polymorphisms in pre-miRNAs have been demonstrated to associate with the risk of several cancers. So far, no such polymorphism has been investigated in neuroblastoma. With this in mind, we performed a two-center case-control study to assess the association of genetic variants in pre-miRNAs and neuroblastoma susceptibility in Chinese children, including 393 cases and 812 controls. We found that miR-34b/c rs4938723 T > C polymorphism was significantly associated with decreased neuroblastoma risk (TC versus TT: adjusted odds ratio [OR] = 0.51, 95% confidence interval [CI] = 0.39-0.67; TC/CC versus TT: adjusted OR = 0.62, 95% CI = 0.48-0.79). We also observed the significant association between the miR-218 rs11134527 A > G polymorphism and decreased neuroblastoma risk (AG versus AA: adjusted OR = 0.73, 95% CI = 0.56-0.96). Stratified analysis further demonstrated that the protective effect of the rs4938723 T > C polymorphism remained prominent in the subgroups, regardless of age, gender, and clinical stages. In term of sites of origin, this polymorphism significantly reduced the risk of tumors originating from the adrenal gland. We further validated the significant results using false-positive report probability analyses. Overall, the miR-34b/c rs4938723 T > C and miR-218 rs11134527 A > G polymorphisms displayed a protective role from neuroblastoma. These findings need further validation.
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              The epidemiology of hepatoblastoma.

              Few causes of hepatoblastoma have been conclusively identified, mainly due to the extreme rarity of the disease. Inherited conditions including Familial Adenomatous Polyposis and Beckwith-Wiedemann Syndrome dramatically raise risk of hepatoblastoma but account for few cases overall. A small number of case-control studies investigating risk factors for sporadic hepatoblastoma have been conducted to date. Although most of these studies feature fewer than 200 cases, several clues have emerged. Most notably there is a roughly 20-fold increased risk of hepatoblastoma among children with very low birth weight (<1,500 g) and a doubling of risk among those with moderately low birth weight (1,500-2,500 g). A modicum of evidence points to a possible role of parental tobacco use prior to or during pregnancy in the causation of hepatoblastoma as well. Copyright © 2012 Wiley Periodicals, Inc.
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                Author and article information

                Contributors
                Journal
                Mol Ther Oncolytics
                Mol Ther Oncolytics
                Molecular Therapy Oncolytics
                American Society of Gene & Cell Therapy
                2372-7705
                09 June 2020
                25 September 2020
                09 June 2020
                : 18
                : 118-125
                Affiliations
                [1 ]Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, Guangzhou, Guangdong 510623, China
                [2 ]Department of Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China
                [3 ]Department of Pediatric Surgery, Capital Institute of Pediatrics, Beijing 100020, China
                [4 ]Department of Clinical Laboratory, Biobank, Harbin Medical University Cancer Hospital, Harbin, Heilongjiang 150040, China
                [5 ]Department of Pediatric Surgery, Shengjing Hospital of China Medical University, Shenyang, Liaoning 110004, China
                [6 ]Department of Pediatric Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
                [7 ]Department of Pediatric Surgery, Hunan Children’s Hospital, Changsha, Hunan 410004, China
                [8 ]Kunming Key Laboratory of Children Infection and Immunity, Yunnan Key Laboratory of Children’s Major Disease Research, Yunnan Institute of Pediatrics Research, Yunnan Medical Center for Pediatric Diseases, Kunming Children’s Hospital, Kunming, Yunnan 650228, China
                [9 ]Department of Pathology, Children Hospital and Women Health Center of Shanxi, Taiyuan, Shannxi 030013, China
                [10 ]Clinical Laboratory Medicine Center of PLA, Xijing Hospital, Air Force Medical University, Xi’an, Shaanxi 710032, China
                Author notes
                []Corresponding author: Jing He, Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, Guangdong 510623, China. hejing198374@ 123456gmail.com
                [∗∗ ]Corresponding author: Huimin Xia, Department of Pediatric Surgery, Guangzhou Institute of Pediatrics, Guangdong Provincial Key Laboratory of Research in Structural Birth Defect Disease, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou, Guangdong 510623, China. xia-huimin@ 123456foxmail.com
                [11]

                These authors contributed equally to this work.

                Article
                S2372-7705(20)30086-3
                10.1016/j.omto.2020.06.007
                7338985
                © 2020 The Author(s)

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                Categories
                Article

                susceptibility, hepatoblastoma, m6a, wtap, polymorphism

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