Somatic mutations passively accumulate in healthy cells throughout life. Technical challenges associated with identifying mutations occurring only in a small number of cells have limited our understanding of somatic evolution in normal tissues. Yet, these studies have implications for early cancer development. Now, researchers at the Wellcome Sanger Institute have used genome sequencing to characterize the mutational landscape of normal oesophageal tissue during ageing.

Credit: Lara Crow/Springer Nature Limited

To detect somatic coding mutations, Martincorena, Fowler et al. utilized ultra-deep targeted sequencing of 844 small samples from a cumulative area of ~17 cm2 of normal oesophageal epithelium taken from nine organ transplant donors aged between 20 to 75 years. This revealed that the numbers of detectable mutations as well as the size of the mutant clones increase with age, wherein the several hundred mutations present in a healthy oesophageal cell from a person in their twenties can rise to more than 2,000 mutations per cell in an older individual. Furthermore, analysis of mutational signatures revealed that most of the mutations were generated by intrinsic mutational processes related to ageing and transcription.

Interestingly, the authors identified widespread positive selection in the normal oesophagus of clones with mutations in cancer-associated genes. Of the 14 positively selected genes found, 11 were known canonical drivers of oesophageal squamous cell carcinoma (OSCC).

One such driver, NOTCH1, was mutated at a high frequency (12–80%) in aged normal oesophageal tissue compared with OSCCs (10%), hinting that the presence of NOTCH1 mutations might protect against cancer. In contrast, TP53 mutations present in over 90% of OSCCs were found in only a small fraction of normal oesophageal cells. Overall, however, the mutational burden in normal oesophageal epithelium was approximately ten times lower than in OSCCs. Other differences between mutant clones in ageing normal tissue and OSCCs were an absence of APOBEC mutagenesis and a low level of copy number changes, implying that these events may have been acquired later in the evolution of oesophageal cancers.

reconsider the role of some cancer-driver genes, given their high mutation frequency in normal cells

This work highlights the importance of studying healthy tissues to provide insight into the transition from normal to cancer but also suggests we might need to reconsider the role of some cancer-driver genes, given their high mutation frequency in normal cells.