Age-related remodelling of oesophageal epithelia by mutated cancer drivers.
Nature
; 565(7739): 312-317, 2019 01.
Article
em En
| MEDLINE
| ID: mdl-30602793
ABSTRACT
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Lesões Pré-Cancerosas
/
Envelhecimento
/
Neoplasias Esofágicas
/
Epitélio
/
Mutação
Tipo de estudo:
Etiology_studies
/
Risk_factors_studies
Limite:
Aged80
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article