{
  "abstract": "Introduction Diffuse cutaneous systemic sclerosis (dcSSc) is a lethal rheumatic disease that is characterized by progressive skin and visceral fibrosis. Autologous hematopoietic stem cell transplant (AHSCT) is a disease modifying therapy that is known to improve the quality of life, and life span in patients with the most severe form of dcSSc. We and others have recently shown that genomic instability is an important feature of dcSSc, although the impact of AHSCT on mutational changes is unknown. In this cross-sectional study, we compared the effects of AHSCT on the mutational landscape in dcSSc and downstream pro-fibrotic signals in fibroblasts.Material and Methods We recruited 25 sequential dcSSc patients, and 9 patients treated with AHSCT. Then, we performed whole exome sequencing (WES) on microdissected dermis from each patient and determined the mutational frequencies by comparing DNA sequences from the microdissected dermis with autologous DNA from buccal samples using two pipelines (MuTect2 and Strelka). We also generated dermal fibroblasts (DFs) from dcSSc patients, patients treated with AHSCT and age/sex matched controls to determine the effects of the mutational landscape on markers associated with senescence, and myofibroblast differentiation, which are known to be associated with disease progression and fibrosis in dcSSc.Results We identified numerous recurrent mutations in dcSSc, with the most frequent ones in the known cancer antigen (MUC16, (or CA125)) ( figure 1). Notably, recurrent MUC16 mutations were associated with poor outcomes in dcSSc and were persistently present in AHSCT non-responders. In contrast, dcSSc patients responding to AHSCT no longer had detectable MUC16, and the overall frequency of recurrent mutations substantially decreased (figure 1). Finally, DF from dcSSc patients had higher levels of markers associated with senescence and myofibroblast activation – suggesting that genomic mutations may promote pro-fibrotic signals.Conclusions We propose that recurrent mutations in dcSSc, particularly in MUC16, may amplify the inflammatory reaction in dcSSc, and potentially promote myofibroblast differentiation and senescence-like signals to accelerate disease progression. We also postulate that AHSCT may improve fibrosis in dcSSc by altering the mutational landscape. Future studies assessing these notions may be instrumental in further delineating the impact of genomic mutations on fibrosis and the importance of genomic mutations for predicting responses to AHSCT in dcSSc.Funding CIHR, National Scleroderma Foundation and the Arthritis Society.Abstract OC.45 Figure 1A. MUC16 is the most frequently mutated gene in the dermis of dcSSc patients. B. AHSCT reduces recurrent mutations. C. Map showing types/locations of the recurrent mutations present in MUC16",
  "authors": [
    {
      "affiliations": [
        "Department of Medicine, University of Alberta, Edmonton, Canada"
      ],
      "name": "Mohammed Osman"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Alberta, Edmonton, Canada"
      ],
      "name": "Dylan Hennessey"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Alberta, Edmonton, Canada"
      ],
      "name": "Lamia Khan"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Alberta, Edmonton, Canada"
      ],
      "name": "Junqin Wang"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Alberta, Edmonton, Canada"
      ],
      "name": "Sandra O’Keefe"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Alberta, Edmonton, Canada"
      ],
      "name": "Desiree Redmond"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Alberta, Edmonton, Canada"
      ],
      "name": "Charmaine van Eeden"
    },
    {
      "affiliations": [
        "Faculty of Sciences, University of Alberta, Edmonton, Canada"
      ],
      "name": "Lisa Willis"
    },
    {
      "affiliations": [
        "University of Rochester, Rochester, USA"
      ],
      "name": "Benjamin Korman"
    },
    {
      "affiliations": [
        "University of Western Ontario, London, Canada"
      ],
      "name": "Janet Pope"
    },
    {
      "affiliations": [
        "University of Calgary, Calgary, Canada"
      ],
      "name": "Caylib Durand"
    },
    {
      "affiliations": [
        "University of Calgary, Calgary, Canada"
      ],
      "name": "Jan Storek"
    },
    {
      "affiliations": [
        "Department of Medicine, University of Alberta, Edmonton, Canada"
      ],
      "name": "Robert Gniadecki"
    }
  ],
  "title": "OC.45 MUC16 mutations are associated with genomic instability and poor outcomes in diffuse cutaneous systemic sclerosis",
  "uid": "1c23d7d5-7406-545f-abea-9d2329bf2e0c"
}