Convergent somatic mutations in metabolism genes in chronic liver disease.

Autor: Ng SWK; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Rouhani FJ; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK.; Department of Surgery, Addenbrooke's Hospital, Cambridge, UK., Brunner SF; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Brzozowska N; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Aitken SJ; CRUK Cambridge Institute, Cambridge, UK.; Department of Pathology, Addenbrooke's Hospital, Cambridge, UK.; MRC Toxicology Unit, University of Cambridge, Cambridge, UK., Yang M; MRC Cancer Unit, University of Cambridge, Cambridge, UK., Abascal F; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Moore L; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Nikitopoulou E; MRC Cancer Unit, University of Cambridge, Cambridge, UK., Chappell L; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Leongamornlert D; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Ivovic A; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Robinson P; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Butler T; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Sanders MA; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK.; Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands., Williams N; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Coorens THH; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Teague J; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Raine K; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Butler AP; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Hooks Y; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Wilson B; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Birtchnell N; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Naylor H; Department of Surgery, Addenbrooke's Hospital, Cambridge, UK., Davies SE; Department of Pathology, Addenbrooke's Hospital, Cambridge, UK., Stratton MR; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Martincorena I; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Rahbari R; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK., Frezza C; MRC Cancer Unit, University of Cambridge, Cambridge, UK., Hoare M; CRUK Cambridge Institute, Cambridge, UK. Matthew.Hoare@cruk.cam.ac.uk.; Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK. Matthew.Hoare@cruk.cam.ac.uk., Campbell PJ; Cancer Genome Project, Wellcome Sanger Institute, Hinxton, UK. pc8@sanger.ac.uk.; Stem Cell Institute, University of Cambridge, Cambridge, UK. pc8@sanger.ac.uk.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Oct; Vol. 598 (7881), pp. 473-478. Date of Electronic Publication: 2021 Oct 13.
DOI: 10.1038/s41586-021-03974-6
Abstrakt: The progression of chronic liver disease to hepatocellular carcinoma is caused by the acquisition of somatic mutations that affect 20-30 cancer genes 1-8 . Burdens of somatic mutations are higher and clonal expansions larger in chronic liver disease 9-13 than in normal liver 13-16 , which enables positive selection to shape the genomic landscape 9-13 . Here we analysed somatic mutations from 1,590 genomes across 34 liver samples, including healthy controls, alcohol-related liver disease and non-alcoholic fatty liver disease. Seven of the 29 patients with liver disease had mutations in FOXO1, the major transcription factor in insulin signalling. These mutations affected a single hotspot within the gene, impairing the insulin-mediated nuclear export of FOXO1. Notably, six of the seven patients with FOXO1 S22W hotspot mutations showed convergent evolution, with variants acquired independently by up to nine distinct hepatocyte clones per patient. CIDEB, which regulates lipid droplet metabolism in hepatocytes 17-19 , and GPAM, which produces storage triacylglycerol from free fatty acids 20,21 , also had a significant excess of mutations. We again observed frequent convergent evolution: up to fourteen independent clones per patient with CIDEB mutations and up to seven clones per patient with GPAM mutations. Mutations in metabolism genes were distributed across multiple anatomical segments of the liver, increased clone size and were seen in both alcohol-related liver disease and non-alcoholic fatty liver disease, but rarely in hepatocellular carcinoma. Master regulators of metabolic pathways are a frequent target of convergent somatic mutation in alcohol-related and non-alcoholic fatty liver disease.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: