Two new studies have linked a condition known as genetic mosaicism to aging and cancer. They suggest presence of the condition, the risk of which increases with age, could be a biomarker for early detection of cancer and other chronic diseases.
Genetic mosaicism is where some of the body’s cells contain altered DNA, while others do not: thus a person with mosaicism has a mixture of normal and mutated cells.
One of the two studies was led by the National Cancer Institute (NCI), and the other by Gene Environment Association Studies (GENEVA) which is sponsored by the National Human Genome Research Institute (NHGRI). Both the NCI and the NHGRI are part of the National Institutes of Health in the US.
Both studies were published online in Nature Genetics on 6 May.
Previous research has shown that certain large structural abnormalities in chromosomes are linked to increased risk of cancer.
These two new studies show that mosaicism, a type of large structural abnormality in chromosomes, can be detected in a small percentage of people with no history of cancer.
They also demonstrate that these abnormalities appear to increase with age, particularly after the age of 50, and are linked to a higher risk of cancer.
Co-author Dr Stephen Chanock is chief of the Laboratory of Translational Genomics in the Division of Cancer Epidemiology and Genetics at NCI. He told the media that:
“These two studies provide large population-based evidence that genetic mosaicism increases with age and could be a risk factor for cancer.”
He added that the link with cancer raises an important point about the stability of a person’s genome: it “suggests that detection of genetic mosaicism could be an early marker for detecting cancer, or perhaps other chronic diseases”.
Researchers working in the GENEVA consortium and at NCI regularly carry out quality control checks on the data from genome-wide association studies (GWAS). It was while carrying out these checks that they began to notice an unexpected frequency of structural abnormalities in chromosomes.
At first they thought the abnormalities were errors arising in lab procedures, but then they noticed they were happening at a consistently low frequency among studies looking for links to diseases like cancer by comparing hundreds of thousands of common differences across the DNA profiles of individual patients.
This finding prompted them to wonder whether such abnormalities might be present in the general population, and if so, at what frequency?
Although NCI researchers had already found genetic mosaicism in an earlier population-based study in Spain, that had not yielded an accurate estimate of prevalence in the general population.
So to calculate the estimated frequency in the general population, first author Kevin B Jacobs of the NCI and colleagues, used data from 13 GWAS involving a total of 31,717 cancer cases and 26,136 cancer-free controls.
They found that genetic mosaic abnormalities occured more frequently in participants with solid tumors than in cancer-free participants (0.97 percent versus 0.74 percent respectively).
Meanwhile, researchers in the GENEVA consortium, working at the University of Washington, Seattle, where first author Cathy C Laurie is based, together with investigators from NHGRI and NCI, also carried out 16 similar analyses that covered groups of all ages and various different chronic diseases. However, in that study, only a small proportion of the analyses focused on cancer.
They looked at blood samples from over 50,000 participants and found genetic mosaicism abnormalities in 404 of them, most of whom were over 50 years old.
For those under 30 years of age, the prevalence was 0.2 percent, and rose steadily above that age, with a sharp increase in the over-60s to reach , reaching 2.5% in the over-75s.
The NCI-led study had also found that while mosaic chromosomal abnormalities were present in slightly less than 1 percent of the study participants, the frequency increased with age, consistent with the GENEVA results.
Previous studies have suggested that genetic mosaicism arises and accumulates over time, with descendants of mosaic cells expanding throughout the body, which may explain why the condition is seen more often in older people.
Dr Teri Manolio, director, Office of Population Genomics at NHGRI, said:
“Repeated collection of blood samples may play a major role in helping determine how genetic mosaicism rises quickly at older ages.”
The GENEVA researchers saw evidence of this in one participant whose blood was sampled twice: once at 66 years of age and then again at age 72.
“While no mosaic abnormalities where detected in the earlier sample, the later sample contained five mosaic abnormalities, each on a different chromosome,” said Manolio.
Researchers at NIH say the studies have important implications for molecular and genome studies of cancer, such as NIH’s ongoing Cancer Genome Atlas and the work of the International Cancer Genome Consortium.
They say more studies should now be done in groups of currently healthy individuals, with health outcomes followed over time, and DNA samples taken periodically to explore diseases and the effect of treatments.
We need to know more about the origin and stability of mosaic abnormalities, they urge.
Written by Catharine Paddock PhD