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A multilayered post-GWAS assessment on genetic susceptibility to pancreatic cancer.

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اقرأ على الانترنت اقرأ أكثر حفظ في قائمتي
  • معلومة اضافية
    • Corporate Authors:
      PanGenEU Investigators; SBC/EPICURO Investigators
    • المصدر:
      Publisher: BioMed Central Country of Publication: England NLM ID: 101475844 Publication Model: Electronic Cited Medium: Internet ISSN: 1756-994X (Electronic) Linking ISSN: 1756994X NLM ISO Abbreviation: Genome Med Subsets: MEDLINE
    • بيانات النشر:
      Original Publication: [London] : BioMed Central
    • الموضوع:
      Genetic Predisposition to Disease* ; Genome-Wide Association Study*; Pancreatic Neoplasms/*genetics; Biomarkers, Tumor/genetics ; Cell Line, Tumor ; Computer Simulation ; Gene Regulatory Networks ; Genome, Human ; Humans ; Linkage Disequilibrium/genetics ; Reproducibility of Results ; Signal Transduction/genetics
    • نبذة مختصرة :
      Background: Pancreatic cancer (PC) is a complex disease in which both non-genetic and genetic factors interplay. To date, 40 GWAS hits have been associated with PC risk in individuals of European descent, explaining 4.1% of the phenotypic variance.
      Methods: We complemented a new conventional PC GWAS (1D) with genome spatial autocorrelation analysis (2D) permitting to prioritize low frequency variants not detected by GWAS. These were further expanded via Hi-C map (3D) interactions to gain additional insight into the inherited basis of PC. In silico functional analysis of public genomic information allowed prioritization of potentially relevant candidate variants.
      Results: We identified several new variants located in genes for which there is experimental evidence of their implication in the biology and function of pancreatic acinar cells. Among them is a novel independent variant in NR5A2 (rs3790840) with a meta-analysis p value = 5.91E-06 in 1D approach and a Local Moran's Index (LMI) = 7.76 in 2D approach. We also identified a multi-hit region in CASC8-a lncRNA associated with pancreatic carcinogenesis-with a lowest p value = 6.91E-05. Importantly, two new PC loci were identified both by 2D and 3D approaches: SIAH3 (LMI = 18.24), CTRB2/BCAR1 (LMI = 6.03), in addition to a chromatin interacting region in XBP1-a major regulator of the ER stress and unfolded protein responses in acinar cells-identified by 3D; all of them with a strong in silico functional support.
      Conclusions: This multi-step strategy, combined with an in-depth in silico functional analysis, offers a comprehensive approach to advance the study of PC genetic susceptibility and could be applied to other diseases.
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    • Grant Information:
      HHSN261200800001E United States CA NCI NIH HHS; P50 CA062924 United States CA NCI NIH HHS; UG1 CA189974 United States CA NCI NIH HHS; P30 CA086862 United States CA NCI NIH HHS; P30 CA008748 United States CA NCI NIH HHS; R01 CA154823 United States CA NCI NIH HHS; U01 CA247283 United States CA NCI NIH HHS; U10 CA037429 United States CA NCI NIH HHS; U01 CA182883 United States CA NCI NIH HHS; 001 International WHO_ World Health Organization; UM1 CA182910 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: 3D genomic structure; Genetic susceptibility; Genome-wide association analysis; Local indices of genome spatial autocorrelation; Pancreatic cancer risk
    • الرقم المعرف:
      0 (Biomarkers, Tumor)
    • الموضوع:
      Date Created: 20210201 Date Completed: 20220119 Latest Revision: 20240330
    • الموضوع:
      20240330
    • الرقم المعرف:
      PMC7849104
    • الرقم المعرف:
      10.1186/s13073-020-00816-4
    • الرقم المعرف:
      33517887