Reporter: Venkat Karra, Ph.D,
Recently studies on structural abnormalities of chromosomes (Mosaicism) were conducted by two consortia, one led by scientists at the National Cancer Institute (NCI), and one by Gene Environment Association Studies (GENEVA). This study was sponsored by the National Human Genome Research Institute (NHGRI). These studies have found that mosaicism can be detected in a small fraction of people without a prior history of cancer. Mosaicism results from a DNA alteration that is present in some of the body’s cells but not in others. A person with mosaicism has a mixture of normal and mutated cells. “These two studies provide large population-based evidence that genetic mosaicism increases with age and could be a risk factor for cancer” which may mean that detection of genetic mosaicism could be an early marker for detecting cancer, or perhaps other chronic diseases,” said Stephen Chanock, M.D., co-author and chief, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI.
Scientists began observing an unexpected frequency of structural abnormalities in chromosomes during quality control checks of data from genome-wide association studies (GWAS) conducted in the GENEVA consortium and similar programs at NCI. These studies involve comparing hundreds of thousands of common differences across individual patients’ DNA to see if any of those variants are associated with a known trait, such as cancer. At first, these abnormalities were thought to be errors or outcomes of laboratory procedures. But they were found consistently at a low frequency, so the scientists wondered with what frequency these structural abnormalities occurred in the general population.
The NCI-led study observed that genetic mosaic abnormalities were more frequent in individuals with solid tumors (0.97 percent vs. 0.74 percent in cancer-free individuals). The NCI study also observed mosaic chromosomal abnormalities in slightly less than 1 percent of the study participants, but noted that the frequency of detectable genetic mosaicism increased with age. This was consistent with GENEVA results that found genetic mosaicism increased in those over the age of 50.
In both studies, scientists observed an increase in the detection of genetic mosaicism in patients with hematological cancers (leukemia, lymphoma and myeloma), for which DNA was collected at least one year prior to diagnosis, compared to cancer-free individuals. Results from the NCI study showed that risk of leukemia was also substantially higher among people with these chromosomal alterations while the GENEVA study showed that the risk of acquiring a hematological cancer diagnosis was 10 times higher for people who had mosaic chromosomal abnormalities. The results of both studies suggest that mosaicism, observed in older people, may be an asymptomatic condition — not often causing overt illness — that may predispose them to hematological cancer. However, GENEVA and NCI scientists stress that the event numbers analyzed are small, and additional studies are needed across a broader diversity of populations to establish the clinical significance of these findings.
NIH scientists say these findings will have important implications for the design and analysis of molecular studies of cancer, as well as ongoing studies looking at the characterization of cancer genomes, such as NIH’s The Cancer Genome Atlas and the International Cancer Genome Consortium.
NIH scientists recommended that additional analyses be conducted in groups of currently healthy people so that investigators may follow them over time for health outcomes.
The results of the studies were published online May 6, 2012, in Nature Genetics.