Notch1 mutations drive clonal expansion in normal esophageal epithelium but impair tumor growth.

Autor: Abby E; Wellcome Sanger Institute, Hinxton, UK., Dentro SC; Wellcome Sanger Institute, Hinxton, UK.; European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge, UK.; Artificial Intelligence in Oncology (B450), Deutsches Krebsforschungszentrum, Heidelberg, Germany., Hall MWJ; Wellcome Sanger Institute, Hinxton, UK.; Department of Oncology, University of Cambridge, Cambridge, UK., Fowler JC; Wellcome Sanger Institute, Hinxton, UK., Ong SH; Wellcome Sanger Institute, Hinxton, UK., Sood R; Wellcome Sanger Institute, Hinxton, UK., Herms A; Wellcome Sanger Institute, Hinxton, UK.; Department of Biomedical Sciences, Faculty of Medicine, University of Barcelona, Barcelona, Spain., Piedrafita G; Department of Biochemistry and Molecular Biology, Complutense University, Madrid, Spain.; Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain., Abnizova I; Wellcome Sanger Institute, Hinxton, UK., Siebel CW; Department of Discovery Oncology, Genentech, South San Francisco, CA, USA., Gerstung M; European Molecular Biology Laboratory, European Bioinformatics Institute, Cambridge, UK.; Artificial Intelligence in Oncology (B450), Deutsches Krebsforschungszentrum, Heidelberg, Germany., Hall BA; Department of Medical Physics and Biomedical Engineering, University College London, London, UK., Jones PH; Wellcome Sanger Institute, Hinxton, UK. pj3@sanger.ac.uk.; Department of Oncology, University of Cambridge, Cambridge, UK. pj3@sanger.ac.uk.
Jazyk: angličtina
Zdroj: Nature genetics [Nat Genet] 2023 Feb; Vol. 55 (2), pp. 232-245. Date of Electronic Publication: 2023 Jan 19.
DOI: 10.1038/s41588-022-01280-z
Abstrakt: NOTCH1 mutant clones occupy the majority of normal human esophagus by middle age but are comparatively rare in esophageal cancers, suggesting NOTCH1 mutations drive clonal expansion but impede carcinogenesis. Here we test this hypothesis. Sequencing NOTCH1 mutant clones in aging human esophagus reveals frequent biallelic mutations that block NOTCH1 signaling. In mouse esophagus, heterozygous Notch1 mutation confers a competitive advantage over wild-type cells, an effect enhanced by loss of the second allele. Widespread Notch1 loss alters transcription but has minimal effects on the epithelial structure and cell dynamics. In a carcinogenesis model, Notch1 mutations were less prevalent in tumors than normal epithelium. Deletion of Notch1 reduced tumor growth, an effect recapitulated by anti-NOTCH1 antibody treatment. Notch1 null tumors showed reduced proliferation. We conclude that Notch1 mutations in normal epithelium are beneficial as wild-type Notch1 favors tumor expansion. NOTCH1 blockade may have therapeutic potential in preventing esophageal squamous cancer.
(© 2023. The Author(s).)
Databáze: MEDLINE
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