Advances in sequencing have revealed a highly variegated landscape of mutational signatures and somatic driver mutations in a range of normal tissues. Normal tissues accumulate mutations at varying rates ranging from 11 per cell per year in the liver, to 1879 per cell per year in the bladder. In addition, some normal tissues are also comprised of a large proportion of cells which possess driver mutations while appearing phenotypically normal, as in the oesophagus where a majority of cells harbour driver mutations. Individual tissue proliferation and mutation rate, unique mutagenic stimuli, and local tissue architecture contribute to this highly variegated landscape which confounds the functional characterization of driver mutations found in normal tissue. In particular, our understanding of the relationship between normal tissue somatic mutations and tumour initiation or future cancer risk remains poor. Here, we describe the mutational signatures and somatic driver mutations in solid and hollow viscus organs, highlighting unique characteristics in a tissue-specific manner, while simultaneously seeking to describe commonalities which can bring forward a basic unified theory on the role of these driver mutations in tumour initiation. We discuss novel findings which can be used to inform future research in this field.
© 2023. The Author(s).