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Somatic Mutations Widespread Across Normal Tissues, New RNA-Seq Analysis Finds

NEW YORK (GenomeWeb) – Normal cell populations contain a mosaic of mutations, including alterations found in cancer cells, according to a new study.

Researchers led by the Broad Institute's Gad Getz developed a new method dubbed RNA-MuTect to uncover somatic mutations from RNA sequencing data that arise during an individual's life before any disease develops.

When they applied this tool to analyze Genotype-Tissue Expression (GTEx) project data from 29 disease-free tissue types collected from nearly 500 individuals, they found that 95 percent of the individuals had at least one tissue that contained clonal mutations. As they reported this week in Science, some of these mutations appeared to be associated with age and sun or other environmental exposures and some affected cancer-linked genes.

"That means that everyone is going around with these mutated cells," Getz said in a statement.

The researchers developed the tool RNA-MuTect to detect somatic mutations in bulk RNA-sequencing data. Compared to previous approaches, this allowed them to analyze every expressed gene, rather than a small set of genes.

To account for mutations that are only found in RNA and not in DNA, they incorporated a number of filtering steps that, for instance, filtered out alignment errors. On a validation set of 303 samples from The Cancer Genome Atlas, the researchers reported that the approach had high sensitivity and precision and outperformed other methods for detection mutations in RNA-seq data.

Getz and his colleagues then applied RNA-MuTect to analyze RNA-seq data from 29 different tissues and matched blood DNA samples from 488 individuals from the GTEx project, a total of 6,707 RNA-seq samples.

Overall, they identified 8,870 somatic mutations in 2,519, or 37 percent, of the samples, which represented 95 percent of the individuals in the cohort. The researchers could only detect macroscopic mutational clones, suggesting there could be additional, smaller clones they were unable to catch.

Certain tissues, such as sun-exposed skin, the esophagus mucosa, and the lungs, contained higher numbers of somatic mutations, the researchers noted. This, they added, suggests a role for environmental exposures in the development of somatic mosaicism. Cancers in these tissues have been associated with environmental factors like ultraviolet light exposure, air pollution, smoking, and eating habits.

Likewise, they found a correlation between individuals' ages as well as higher cell proliferation rates and an increased number of mutations in these tissues.

Some of the mutations the researchers uncovered fall in known cancer-associated genes. For instance, they found that 3 percent of the samples and 33 percent of the individuals in their cohort had at least one nonsynonymous mutation in a Cancer Gene Census (CGC) gene. The most frequently mutated cancer genes in this cohort were TP53 and NOTCH1.

By determining the ratio of nonsynonymous and synonymous substitutions in each gene, the researchers explored whether this clonal expansion in normal tissues was in part due to natural selection. CGC genes and other cancer-linked genes, they found, had a higher rate of nonsynonymous mutations, suggesting that some of these mutations may provide a selective advantage.

"We expect that most of these clones would not ever become cancer; they grow but likely stop at some point," Getz noted.

These findings underscore that a better understanding of "what is normal and what is not" is needed, Cristian Tomasetti of Johns Hopkins University School of Medicine wrote in an accompanying commentary in Science. He added that this knowledge is needed as researchers develop new early cancer detection strategies.