Are genetic mutations more common than we thought?

Looking at data from a standard technology in a novel way, MD Anderson researchers have discovered that certain genetic aberrations are two to three times more common in healthy tissue than previously reported.

This study, published last week in the American Journal of Human Genetics, may guide future work to learn how these changes could be used as prognostic markers for cancer risk.

Genetic mosaicism is a phenomenon described by the presence of two or more distinct groups of cells within an individual, arising from non-inherited mutations during normal cell division. Cancer is a perfect example, with tumor cells having distinct genomes from that of surrounding healthy tissue.

Typically, the genomes of non-cancerous cells are thought to be stable, explains Paul Scheet, Ph.D., associate professor of Epidemiology.

“Detectable mosaicism in healthy tissue has been documented to occur in the population,” says Scheet, senior author of the study. “We show that it is substantially more frequent. Our results better characterize the level of mutation tolerated in a particular tissue and may better clarify a marker for risk.”

Scheet and lead author Selina Vattathil, Ph.D., identified a higher prevalence of these genetic changes by analyzing genetic markers — or single nucleotide polymorphisms (SNPs) — of 31,100 individuals from 10 previously published genome-wide association studies. DNA was from non-diseased blood or cheek swabs.

Their analysis was designed to uncover relatively large genetic changes such as chromosomal duplications or deletions, which are detectable in as little as a few percent of cells from the healthy tissue. These aberrations are difficult to discern from the overwhelmingly normal sample, but incorporating genetic knowledge informs how one expects these subtle signals to look, explains Scheet.

The authors use an interesting analogy to explain their unique method. Imagine trying to detect an unfair coin that periodically changes its bias from heads to tails. You cannot simply count the total number of heads but instead need to note the unusual number of consecutive heads (or tails).

In the samples analyzed, the researchers were able to detect 1,141 unique genetic changes in 901 of the 31,100 samples, representing 2.9% of the study population. A recent analysis of the same data yielded 379 changes in 30,208 samples, or 1.2%

Additionally, Vattathil and Scheet confirmed previous observations that these changes are substantially more common with increasing age, occurring in more than 5% of individuals older than 65 and more than 10% of individuals older than 80. The study raises many questions, such as whether these newly discovered mutations carry the same prognostic value.

Although the mutations cannot be directly linked to cancer incidence in this study, the authors note that the genetic changes identified were not random. Rather, certain chromosomes appear to show a preference for loss or gains. Some aberrations were linked to regions associated with hematological malignancies.

In the future, the researchers expect their method to be applied in increasingly large datasets and alternate tissues. Scheet is now collaborating with other MD Anderson researchers to investigate genetic mosaicism in tissues subjected to environmental exposures, such as the lungs, colon and skin.

Shedding light on genetic mosaicism in pre-malignant lesions of these tissues may allow researchers to identify genetic changes that drive cancer progression and could be markers of risk or targets for intervention.

“We are looking at the genome in a different way. This allows us to examine pre-malignancies in a manner not accessible by traditional methods,” says Scheet.