04 April 2022

By studying mutations in normal cells and pre-cancer lesions, we can detect clonal expansions in pre-malignant tissues. We have observed clonal expansions across essentially all normal tissue types by performing careful analysis of RNA sequences from normal bulk tissues in the Genotype–Tissue Expression (GTEx) project to uncover somatic mutations using our RNA-MuTect tool (Yizhak, et al., Science 2019). Interestingly, our findings show that lung, sun-exposed skin, and esophagus –– tissues routinely exposed to the environment –– acquired the most clones and increased with the age of the individual. These findings demonstrating the extent of somatic mosaicism in humans have implications for interpreting screening results from cancerous and precancerous lesions, wherein detecting a known cancer mutation may not necessarily indicate the presence of cancer.

Moreover, in other efforts, we are leveraging the association between mutation density and the epigenetic state of a cell to reveal the landscape of tissue- and cell-of-origins of all major cancer types, enabling better understanding the transition from pre-malignant clones to cancer (Kübler, Karlič, et al., bioRxiv 2019).