Chromosomal changes after age 50 appear to indicate risk of blood cancer.
The discovery started with GWAS—genome-wide association studies—that find genetic variations that might be responsible for a trait or a disease. When researchers conduct GWAS, they use data on sequence variations in the genomes of thousands of individuals to find variants that are associated with specific characteristics such as increased risk of a disease. However, a few years ago, while conducting routine quality controls, GWAS researchers noticed occasional, unexpected chromosomal abnormalities in some genome regions. These were not the expected differences between individuals, but differences between the cells of one person. This mixture of genetically different cells in a single individual is called mosaicism.
Increasing with age
The mosaic pattern of cells with normal and abnormal chromosomes is rare, according to two studies published in Nature Genetics this year. One study detected chromosomal mosaicism in less than 0.5% of people under age 50 by looking at DNA from a global representation of more than 50,000 individuals. However, detectable mosaicism was as high as 2 or 3 per cent in older people, increasing steadily with age.
“As we get older, we’re not as capable of correcting DNA errors or maintaining our genome,” explains Bjarke Feenstra, a senior scientist at Denmark’s Statens Serum Institute and an author on the study, which also included researchers from multiple American universities.
Connection to leukemia
Looking closely at the chromosomal locations of the genetic abnormalities in cells from mosaic samples, the scientists found that many were associated with blood cancers such as leukemias. This led to an examination of cancer diagnosis records for more than 8500 people who gave DNA samples.
“A majority did not get cancer,” emphasizes Feenstra. However, people with detectable mosaicism in their DNA sample had a ten-fold higher risk of later developing a blood cancer. The companion study on chromosomal mosaicism detected mosaicism in 0.97 percent of people with cancer and 0.75 per cent of people who were cancer free.
The results from the two papers could inspire two areas of research and development. Although Feenstra says the associations of higher cancer diagnoses with mosaicism “are just first steps,” clinical and longitudinal studies in large populations might find that mosaicism can identify people at risk of developing cancer—even before they have symptoms.
Early predictor of cancer
More research is needed, but Professor Ian Hickson, at the Center for Healthy Aging at the Institute for Cellular and Molecular Medicine, University of Copenhagen, says, “It could potentially be a relatively cheap and straightforward way to screen an older population for those with a higher risk of cancer. It could be a very early predictor of cancer, and anything that detects cancer early could have an enormous impact on survival, especially in the elderly.”
Basic research is also needed to find out why mosaicism is detected more often in older people—maybe because mutations increase with age or because cells with chromosomal abnormalities proliferate more easily in older people.
Feenstra says the work is a good example of the kind of discovery that is possible by linking the comprehensive Danish health registry to the extensive biological specimens in the Danish National Biobank. In February 2012, Feenstra and colleagues reported using GWAS linked to Danish health records to find three chromosomal locations associated with infantile hypertrophic pyloric stenosis. This digestive system disorder causes severe vomiting, usually requiring surgery to correct. It affects up to 3 of 1000 infants with European ancestry. In a Nature Genetics letter, Feenstra and his research team reported that genes for cardiac muscle development, gut development and regulation of alternative splicing might be involved in infantile hypertrophic pyloric stenosis, suggesting new avenues for research into the cause of this condition.
Denmark’s National Biobank officially launched in March 2012, will contain more than 15 million biological samples including blood spots take from all newborn Danes since 1982 and a growing repository of tissue samples from biopsies and other tests. With oversight from the Danish Data Protection Agency and Scientific Ethics Committees, the biobank is a joint initiative between Statens Serum Institut and Danish research, medical, and academic institutions.
“It’s a great resource,” says Feenstra, and we have lots of studies planned.”
Laurie, CC et al. Detectable clonal mosaicism from birth to old age and its relationship to cancer. Nature Genetics 2012; 44(6):642-50.
Jacobs KB et al. Detectable clonal mosaicism and its relationship to aging and cancer. Nature Genetics 2012; 44(6):651-8.
Feenstra, B et al. Common variants near MBNL1 and NKX2-5 are associated with infantile hypertrophic pyloric stenosis. Nature Genetics 2012;44(3):334-8.