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         headline:Integrated multi-dimensional analysis highlights DHCR7 mutations involving in cholesterol biosynthesis and contributing therapy of gastric cancer
         description:Genetic background plays an important role in the occurrence and development of gastric cancer (GC). With the application of genome-wide association study (GWAS), an increasing number of tumor susceptibility genes in gastric cancer have been discovered. While little of them can be further applicated in clinical diagnosis and treatment due to the lack of in-depth analysis. A GWAS of peripheral blood leukocytes from GC patients was performed to identify and obtain genetic background data. In combination with a clinical investigation, key SNP mutations and mutated genes were screened. Via in vitro and in vivo experiments, the function of the mutated gene was verified in GC. Via a combination of molecular function studies and amino acid network analysis, co-mutations were discovered and further identified as potential therapeutic targets. At the genetic level, the G allele of rs104886038 in DHCR7 was a protective factor identified by the GWAS. Clinical investigation showed that patients with the rs104886038 A/G genotype, age ≥ 60, smoking ≥ 10 cigarettes/day, heavy drinking and H. pylori infection were independent risk factors for GC, with odds ratios of 12.33 (95% CI, 2.10 ~ 72.54), 20.42 (95% CI, 2.46 ~ 169.83), and 11.39 (95% CI, 1.82 ~ 71.21), respectively. Then molecular function studies indicated that DHCR7 regulated cell proliferation, migration, and invasion as well as apoptosis resistance via cellular cholesterol biosynthesis pathway. Further amino acid network analysis based on the predicted structure of DHCR7 and experimental verification indicated that rs104886035 and rs104886038 co-mutation reduced the stability of DHCR7 and induced its degradation. DHCR7 mutation suppressed the malignant behaviour of GC cells and induced apoptosis via inhibition on cell cholesterol biosynthesis. In this work, we provided a comprehensive multi-dimensional analysis strategy which can be applied to in-depth exploration of GWAS data. DHCR7 and its mutation sites identified by this strategy are potential theratic targets of GC via inhibition of cholesterol biosynthesis.
         datePublished:2023-01-30T00:00:00Z
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            GWAS
            DHCR7
            Mutations
            Cholesterol biosynthesis
            Cancer Research
            Immunology
            Apoptosis
            Oncology
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      headline:Integrated multi-dimensional analysis highlights DHCR7 mutations involving in cholesterol biosynthesis and contributing therapy of gastric cancer
      description:Genetic background plays an important role in the occurrence and development of gastric cancer (GC). With the application of genome-wide association study (GWAS), an increasing number of tumor susceptibility genes in gastric cancer have been discovered. While little of them can be further applicated in clinical diagnosis and treatment due to the lack of in-depth analysis. A GWAS of peripheral blood leukocytes from GC patients was performed to identify and obtain genetic background data. In combination with a clinical investigation, key SNP mutations and mutated genes were screened. Via in vitro and in vivo experiments, the function of the mutated gene was verified in GC. Via a combination of molecular function studies and amino acid network analysis, co-mutations were discovered and further identified as potential therapeutic targets. At the genetic level, the G allele of rs104886038 in DHCR7 was a protective factor identified by the GWAS. Clinical investigation showed that patients with the rs104886038 A/G genotype, age ≥ 60, smoking ≥ 10 cigarettes/day, heavy drinking and H. pylori infection were independent risk factors for GC, with odds ratios of 12.33 (95% CI, 2.10 ~ 72.54), 20.42 (95% CI, 2.46 ~ 169.83), and 11.39 (95% CI, 1.82 ~ 71.21), respectively. Then molecular function studies indicated that DHCR7 regulated cell proliferation, migration, and invasion as well as apoptosis resistance via cellular cholesterol biosynthesis pathway. Further amino acid network analysis based on the predicted structure of DHCR7 and experimental verification indicated that rs104886035 and rs104886038 co-mutation reduced the stability of DHCR7 and induced its degradation. DHCR7 mutation suppressed the malignant behaviour of GC cells and induced apoptosis via inhibition on cell cholesterol biosynthesis. In this work, we provided a comprehensive multi-dimensional analysis strategy which can be applied to in-depth exploration of GWAS data. DHCR7 and its mutation sites identified by this strategy are potential theratic targets of GC via inhibition of cholesterol biosynthesis.
      datePublished:2023-01-30T00:00:00Z
      dateModified:2023-01-30T00:00:00Z
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      pageEnd:17
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      keywords:
         Gastric cancer
         GWAS
         DHCR7
         Mutations
         Cholesterol biosynthesis
         Cancer Research
         Immunology
         Apoptosis
         Oncology
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         name:Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
         type:PostalAddress
      name:The First Affiliated Hospital of Soochow University
      address:
         name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
         type:PostalAddress
      name:The First Affiliated Hospital of Soochow University
      address:
         name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
         type:PostalAddress
      name:Soochow University
      address:
         name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
         type:PostalAddress
      name:The First Affiliated Hospital of Soochow University
      address:
         name:Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
         type:PostalAddress
      name:The First Affiliated Hospital of Soochow University
      address:
         name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
         type:PostalAddress
      name:The First Affiliated Hospital of Soochow University
      address:
         name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
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      address:
         name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
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      name:The First Affiliated Hospital of Soochow University
      address:
         name:Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
         type:PostalAddress
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Person:
      name:Yuqi Chen
      affiliation:
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      name:Wenying Yan
      affiliation:
            name:Medical College of Soochow University
            address:
               name:Department of Bioinformatics, Center for Systems Biology, School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China
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            type:Organization
      name:Kexi Yang
      affiliation:
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      name:Yiting Qian
      affiliation:
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      name:Yanjun Chen
      affiliation:
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      name:Ruoqin Wang
      affiliation:
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      name:Jinghan Zhu
      affiliation:
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      name:Yuxin He
      affiliation:
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      name:Hongya Wu
      affiliation:
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
            name:Soochow University
            address:
               name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      name:Guangbo Zhang
      affiliation:
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
            name:Soochow University
            address:
               name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      name:Tongguo Shi
      affiliation:
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
            name:Soochow University
            address:
               name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      email:[email protected]
      name:Weichang Chen
      affiliation:
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
            name:Soochow University
            address:
               name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
            name:The First Affiliated Hospital of Soochow University
            address:
               name:Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
               type:PostalAddress
            type:Organization
      email:[email protected]
PostalAddress:
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Bioinformatics, Center for Systems Biology, School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
      name:Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
      name:Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
      name:Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China
      name:Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China
      name:Jiangsu Key Laboratory of Gastrointestinal Tumor Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China

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