{
  "abstract": "Background The identification and characterisation of somatic cancer driver mutations in the non-coding genome remains challenging.Objective To broadly characterise non-coding driver mutations for pancreatic ductal adenocarcinoma (PDAC).Design Using mutation calls from whole-genome sequence data in PDACs and genome-scale maps of accessible gene regulatory regions in normal-derived and tumour-derived pancreatic samples, we analysed enrichment of non-coding mutations in gene regulatory regions relevant to normal-derived and tumour-derived pancreatic contexts. Functional follow-up of potential driver mutations was performed using chromatin interaction analyses, massively parallel reporter assays (MPRA) and targeted analysis of selected non-coding somatic mutations (NCSMs).Results We first created genome-scale maps of accessible chromatin regions (ACRs) and histone modification marks (HMMs) in pancreatic cell lines and purified pancreatic acinar and duct cells. Integration with whole-genome mutation calls from 506 PDACs revealed 314 ACRs/HMMs significantly enriched with 3614 NCSMs. Chromatin interaction analysis identified 416 potential target genes and MPRA revealed 178 NCSMs impacting reporter activity (19.45% of those tested). Targeted luciferase validation confirmed negative effects on gene regulatory activity for NCSMs near ZFP36L2 and CDKN2A. For the former, CRISPR interference identified ZFP36L2 as a target gene (16.0–24.0% reduced expression, p=0.023–0.0047), and growth inhibition after overexpression of ZFP36L2 (4.1–14.1-fold reduction, p=6.0×10–4 − 3.2×10–3) implicates a possible tumour suppressor function.Conclusion Our integrative approach provides a catalogue of potential non-coding driver mutations and nominates ZFP36L2 as a novel PDAC driver gene with a likely tumour suppressor function.",
  "authors": [
    {
      "affiliations": [
        "Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Jun Zhong"
    },
    {
      "affiliations": [
        "Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA",
        "The Patrick G Johnston Centre for Cancer Research, Queen’s University Belfast, Belfast, Northern Ireland, UK"
      ],
      "name": "Aidan O’Brien"
    },
    {
      "affiliations": [
        "Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Minal B Patel"
    },
    {
      "affiliations": [
        "Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Daina Eiser"
    },
    {
      "affiliations": [
        "Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Michael Mobaraki"
    },
    {
      "affiliations": [
        "Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Irene Collins"
    },
    {
      "affiliations": [
        "Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Li Wang"
    },
    {
      "affiliations": [
        "Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Konnie Guo"
    },
    {
      "affiliations": [
        "Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland, USA"
      ],
      "name": "ThucNhi TruongVo"
    },
    {
      "affiliations": [
        "Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Ashley Jermusyk"
    },
    {
      "affiliations": [
        "Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, Maryland, USA"
      ],
      "name": "Sudipto Das"
    },
    {
      "affiliations": [
        "Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, Maryland, USA"
      ],
      "name": "Maura O’Neill"
    },
    {
      "affiliations": [
        "Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Courtney D Dill"
    },
    {
      "affiliations": [
        "Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Andrew D Wells"
    },
    {
      "affiliations": [
        "Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Michelle E Leonard"
    },
    {
      "affiliations": [
        "Center for Spatial and Functional Genomics, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA"
      ],
      "name": "James A Pippin"
    },
    {
      "affiliations": [
        "Center for Applied Genomics, The Children’s Hospital of Philadelphia Research Institute, Philadelphia, Pennsylvania, USA",
        "Department of Genetics, Department of Pediatrics, and Institute for Diabetes, Obesity and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA"
      ],
      "name": "Struan F A Grant"
    },
    {
      "affiliations": [
        "Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Tongwu Zhang"
    },
    {
      "affiliations": [
        "Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Frederick, Maryland, USA"
      ],
      "name": "Thorkell Andresson"
    },
    {
      "affiliations": [
        "Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Katelyn E Connelly"
    },
    {
      "affiliations": [
        "Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Jianxin Shi"
    },
    {
      "affiliations": [
        "Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, Center for Cancer Research, NIH, Bethesda, Maryland, USA"
      ],
      "name": "H Efsun Arda"
    },
    {
      "affiliations": [
        "Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Jason W Hoskins"
    },
    {
      "affiliations": [
        "Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA"
      ],
      "name": "Laufey T Amundadottir"
    }
  ],
  "title": "Large-scale multiomic analysis identifies non-coding somatic driver mutations and nominates ZFP36L2 as a driver gene for pancreatic ductal adenocarcinoma",
  "uid": "5780b12e-baa5-5922-91c5-6f9e33b6b2b7"
}