{
  "abstract": "Background and Aims The contribution of somatic mutations to end-stage metabolic-dysfunction associated steatotic liver disease (MASLD) has recently been discovered. Enlarging hepatocyte clones, sequestered by fibrosis, independently acquire recurrent somatic mutations in genes encoding regulators of lipid metabolism. The heterogeneity of MASLD has been reflected through inter-patient variability in the somatic mutation landscape from a modest number of donors with cirrhosis to date. The temporal accrual of such mutations and their role in MASLD disease progression, remain unknown.Method DNA from archival fresh-frozen needle biopsies of 20 patients with MASLD fibrosis stages F0-F3 underwent single DNA molecule sequencing with whole-exome NanoSeq (total duplex coverage = 3,164dx). The cohort had a median age of 52 years (IQR 47–59), median BMI 33kg/m2 (IQR 31–36) and 65% of patients had confirmed type 2 diabetes (n=13). Over a median follow-up period of 12 years post-biopsy, 10 donors experienced MASLD progression and 10 had stable liver disease. Genes under positive selection pressure were identified using dNdScv, a statistical model comparing ratios of non-synonymous somatic mutations to evolutionarily neutral synonymous mutations. Genes were considered to have significant excess of non-synonymous mutations after correction for multiple hypothesis testing with a q-value of <0.1.Results The pattern and density of somatic mutations varied extensively between individuals, even in this early disease stage. There was minimal correlation of mutation burden to age, fibrosis stage or clinical outcome. 10 genes were found to have a significant excess of non-synonymous somatic mutations. These included lineage-defining, highly hepatocyte-specific genes such as Albumin (ALB) and transferrin (TF), with a pattern of short insertion and deletion (‘indel’) excess, hypothesised to relate to high gene expression. Recurrent variants in genes recognised as drivers in end-stage MASLD were found to be under positive selection, including ACVR2A and TNRC6B, as well as in genes encoding regulators of lipid metabolism including CIDEB.Conclusion We provide evidence of positive selection of somatic variants across the MASLD disease spectrum. Recurrent somatic mutagenesis of genes implicated in lipid metabolism suggest hepatocytes develop adaptive pathways in attempt to escape their lipotoxic environment prior to development of advanced liver disease. Deep-targeted sequencing across a wider cohort spanning the disease spectrum will now be conducted. Ultimately, through understanding the interplay between environmental, clinical phenotypic variables and the somatic and germline mutational landscapes influencing MASLD progression, we will gain insights into novel biological mechanisms and potentially identify targeted approaches to therapeutics in this field.References Ng SW, Rouhani FJ, Brunner SF, Brzozowska N, Aitken SJ, Yang M, Abascal F, Moore L, Nikitopoulou E, Chappell L, Leongamornlert D. Convergent somatic mutations in metabolism genes in chronic liver disease. Nature 2021 Oct 21;598(7881):473–8.Abascal F, Harvey LM, Mitchell E, Lawson AR, Lensing SV, Ellis P, Russell AJ, Alcantara RE, Baez-Ortega A, Wang Y, Kwa EJ. Somatic mutation landscapes at single-molecule resolution. Nature. 2021 May 20;593(7859):405–10.Martincorena I, Raine KM, Gerstung M, Dawson KJ, Haase K, Van Loo P, Davies H, Stratton MR, Campbell PJ. Universal patterns of selection in cancer and somatic tissues. Cell 2017 Nov 16;171(5):1029–41.",
  "authors": [
    {
      "affiliations": [
        "Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton, UK",
        "Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK",
        "Early Cancer Institute, Department of Oncology, Cambridge, UK"
      ],
      "name": "Georgeina L Jarman"
    },
    {
      "affiliations": [
        "Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton, UK"
      ],
      "name": "Andrew RJ Lawson"
    },
    {
      "affiliations": [
        "Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton, UK"
      ],
      "name": "Natalia Brzozowska"
    },
    {
      "affiliations": [
        "Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton, UK"
      ],
      "name": "Pantelis Nicola"
    },
    {
      "affiliations": [
        "Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton, UK"
      ],
      "name": "Federico Abascal"
    },
    {
      "affiliations": [
        "Department of Histopathology, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK"
      ],
      "name": "Anna Paterson"
    },
    {
      "affiliations": [
        "Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK",
        "Cambridge NIHR Biomedical Research Centre, Cambridge, UK"
      ],
      "name": "Michael Allison"
    },
    {
      "affiliations": [
        "Cambridge Liver Unit, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK",
        "Early Cancer Institute, Department of Oncology, Cambridge, UK"
      ],
      "name": "Matthew Hoare"
    },
    {
      "affiliations": [
        "Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton, UK"
      ],
      "name": "Iñigo Martincorena"
    },
    {
      "affiliations": [
        "Cancer, Ageing and Somatic Mutation Programme, Wellcome Sanger Institute, Hinxton, UK"
      ],
      "name": "Peter Campbell"
    }
  ],
  "title": "P53 Acquired mutations in early stage metabolic-dysfunction associated steatotic liver disease (MASLD)",
  "uid": "fd653913-2ea8-5f85-923f-64aac833e6f6"
}