An Approach to Measuring Somatic Mosaicism in Solid Tissues
Researchers here report on an approach to quantifying somatic mosaicism in a tissue sample. Mutational damage to nuclear DNA occurs constantly, but specific mutations only spread through a tissue over time to a sizable degree when they occur in one of the stem cells or progenitor cells that support that tissue by generating a supply of new daughter somatic cells. Somatic mosaicism has been shown to correlate with an increased risk of a few age-related conditions, particularly cancers, but it remains unclear as to how greatly it contributes to the overall progression of aging. Better ways to measure and catalog the extent of somatic mosaicism seem likely to help increase our understanding of its role.
The extensive presence of mutation-containing cells alongside normal cells, typically with no obvious difference between them, is known as somatic mosaicism. Now recognized as a common feature of human aging, it arises when a DNA "driver" mutation occurs in a cell, giving the cell and its progeny a slight but not yet cancerous growth or survival advantage. Researchers developed a technology called single-cell Genotype-to-Phenotype sequencing (scG2P), which allowed them to study somatic mosaicism in solid tissues - prior studies focused mostly on mosaicism in blood cells. Solid tissue samples are stored in ways that make mutational and gene activity information more challenging to access. Moreover, obtaining an accurate picture of solid tissue mosaicism typically requires profiling larger numbers of cells.
The team used scG2P to study esophageal tissue samples from six older adults. They found that more than half of the 10,000+ sampled cells contained clonal driver mutations and most had a single driver mutation in a gene called NOTCH1, which normally controls cell maturation, identity, division, and survival in the lining of the esophagus and other epithelial tissues in the body. The gene-activity readouts suggested that these NOTCH1 driver mutations induce clonal overgrowth by impairing normal cell development. The next most common driver-mutation gene in the samples was TP53, which makes the p53 protein, a crucial tumor suppressor that is inactivated in many cancers. TP53-mutant clones in the samples showed impaired maturation and also more frequent cell division compared to normal cells.
The findings are consistent with one of the central ideas of cancer biology: a single mutation is usually insufficient for malignancy and cancers arise from a series of mutations, which is increasingly common as we age.