Age-related remodelling of oesophageal epithelia by mutated cancer drivers.

Adolescent Adult Aged Aged, 80 and over Aging / genetics Alcohol Drinking / genetics Biopsy Cell Count Cell Transformation, Neoplastic / genetics Child Child, Preschool Clone Cells / metabolism DNA Copy Number Variations Epithelium / metabolism Esophageal Neoplasms / genetics Evolution, Molecular Female Gene-Environment Interaction Genome, Human / genetics Humans Infant Life Style Male Middle Aged Mutation Mutation Accumulation Precancerous Conditions / genetics Protein Phosphatase 2C / genetics Receptor, Notch1 / genetics Risk Factors Sequence Analysis, DNA Single-Cell Analysis Smoking / genetics Young Adult

Journal

Nature

ISSN: 1476-4687

Titre abrégé: Nature

Pays: England

ID NLM: 0410462

Informations de publication

Date de publication:
01 2019

Historique:

received: 26 06 2018

accepted: 22 11 2018

pubmed: 4 1 2019

medline: 2 7 2019

entrez: 4 1 2019

Statut: ppublish

Résumé

Clonal expansion in aged normal tissues has been implicated in the development of cancer. However, the chronology and risk dependence of the expansion are poorly understood. Here we intensively sequence 682 micro-scale oesophageal samples and show, in physiologically normal oesophageal epithelia, the progressive age-related expansion of clones that carry mutations in driver genes (predominantly NOTCH1), which is substantially accelerated by alcohol consumption and by smoking. Driver-mutated clones emerge multifocally from early childhood and increase their number and size with ageing, and ultimately replace almost the entire oesophageal epithelium in the extremely elderly. Compared with mutations in oesophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal oesophageal epithelia; these mutations can be acquired before late adolescence (as early as early infancy) and significantly increase in number with heavy smoking and drinking. The remodelling of the oesophageal epithelium by driver-mutated clones is an inevitable consequence of normal ageing, which-depending on lifestyle risks-may affect cancer development.

Identifiants

DOI: 10.1038/s41586-018-0811-x PMID: 30602793

pubmed: 30602793

doi: 10.1038/s41586-018-0811-x

pii: 10.1038/s41586-018-0811-x

doi:

Substances chimiques

NOTCH1 protein, human 0

Receptor, Notch1 0

PPM1D protein, human EC 3.1.3.16

Protein Phosphatase 2C EC 3.1.3.16

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

Pagination

312-317

Commentaires et corrections

Type : CommentIn

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