News Release

Normal tissues not so normal, but instead mosaics of mutated cells

Peer-Reviewed Publication

American Association for the Advancement of Science (AAAS)

Normal cell populations may not be as "normal" as once thought; rather, tissues contain lineages of mutational mosaics developed over a lifetime, according to a comprehensive RNA sequence analysis of more than 6,700 samples across 29 different human tissues. The study finds that somatic mutations - including genes associated with cancer risk - arise in virtually every type of normal tissue in the human body. What's more, the results indicate that sun-exposed skin, throat and lung tissues develop more mutations and suggest that environmental factors may promote somatic mutations. "Even the promise offered by cancer early detection methodologies via cell-free DNA critically depends on understanding what is normal and what is not," writes Cristian Tomasetti in a related Perspective, noting the significance of Yizhak et al.'s results on future cancer research. As people get older, they accumulate mutations in the healthy cells of normal tissues. Generally, these mutations amass passively with a negligible effect on cell behavior. However, mutant cells can become growing populations of harmful mutant clones, which are thought to be the origin of several diseases. While previous research has associated clonal expansions in normal tissues with cancer, an understanding of which specific clones could eventually lead to the development and progression of the disease remains unclear. To explore the mutational diversity of normal tissues, Keren Yizhak and colleagues developed a new method to detect mutational clones in normal tissues using RNA-sequencing (RNA-seq) data - a computational pipeline named RNA-MuTect. Unlike previous methods, it identified mutational clones in normal tissues for every expressed gene, rather than for just a small subset. Applying this method to RNA-seq data from both the Cancer Genome Atlas and the Genotype-Tissue Expression (GTEx) project, the authors identified clonal expansion in 37% of the tissue samples representing nearly all (95%) donor individuals. One third of individuals harbored mutations in genomic regions or genes known to play a causal role in cancer. The results show that a tissue's mutational burden is associated with age, cell proliferation rate and exposure to external mutagenic environmental factors.

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