Age-Related Remodeling Linked to Normal Aging

Mutations in some cancer driver genes can arise in seemingly normal esophageal tissue as early as in childhood, becoming increasingly common with age and in response to alcohol or cigarettes.

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. Esophageal squamous cell carcinoma is a type of esophageal carcinoma that can affect any part of the esophagus, but is usually located in the upper or middle third.


An international team of scientists led by those at Kyoto University (Kyoto, Japan) performed exome or whole-genome sequencing on 682 microscopic samples from 139 individuals with or without esophageal disease, including more than 90 individuals with esophageal squamous cell carcinoma (ESCC). The intensively sequenced micro-scale esophageal samples showed, in physiologically normal esophageal 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.

The team sequenced the exomes of 25 physiologically normal esophageal epithelia samples and two cancer-affected tissues, identifying somatic mutations in all but one of the seemingly normal samples. The team then sequenced the exomes of 157 physiologically normal punch biopsy samples from 21 individuals with ESCC or dysplasia and 40 healthy individuals, along with 20 tumor samples and a dozen samples marked by dysplasia. For 16 individuals, the group had access to samples from two to eight different regions of the esophagus. Compared with mutations in esophageal cancer, there is a marked overrepresentation of NOTCH1 and PPM1D mutations in physiologically normal esophageal 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 team looked at new whole-genome sequence data for 13 single cell-derived colonies representing physiologically normal tissue from seven individuals; meanwhile, it tracked down driver gene mutations in seven of the colonies. These mutations seemed to rise with age, as did mutations in driver genes such as NOTCH1 and PPM1D that were profiled across physiologically normal epithelial samples from individuals between the ages of less than 20 years old and more than 80 years old. The authors concluded that the remodeling of the esophageal epithelium by driver-mutated clones is an inevitable consequence of normal aging, which, depending on lifestyle risks, may affect cancer development. The study was published on January 2, 2019, in the journal Nature.

Related Links:
Kyoto University