Somatic mutant clones colonize the human esophagus with age

Area of Science:

• Genetics
• Cancer Biology
• Aging Research

Background:

• Understanding somatic mutation accumulation in normal tissues is crucial for aging and cancer research.
• Previous studies have not fully elucidated the extent and drivers of clonal expansion in healthy adult tissues.

Purpose of the Study:

• To map and characterize mutant clones in normal human esophageal epithelium.
• To investigate the relationship between age, somatic mutations, and clonal expansion.
• To identify specific genes under positive selection in normal esophageal epithelium.

Main Methods:

• Genome sequencing of normal esophageal epithelium from nine donors across a wide age range (20-75 years).
• Analysis of somatic mutation accumulation and clonal expansion patterns.
• Identification of genes with mutations under positive selection.

Main Results:

• Somatic mutations accumulate with age, primarily due to intrinsic mutational processes.
• Significant positive selection was observed for clones with mutations in 14 cancer genes.
• In older donors, clones with cancer-associated mutations (NOTCH1, TP53) occupied substantial portions of the epithelium.
• NOTCH1 mutation prevalence in normal esophagus exceeded that in esophageal cancers.

Conclusions:

• Normal esophageal epithelium harbors expanding clones with cancer-associated mutations, influenced by age and intrinsic mutational processes.
• The high prevalence of NOTCH1 mutations in normal tissue suggests complex roles in cancer development and aging.
• These findings necessitate a re-evaluation of early mutational events in cancer pathogenesis and aging.