Genetic study could bring early warning for T2D patients

A raised cancer incidence in type 2 diabetes (T2D) patients has been partly explained, scientists say, by a new study identifying a strong association between a set of genetic anomalies known to be strong pre-cancer markers and T2D¹.

These anomalies, known as large chromosomal mosaic events (CMEs), are aberrations that occur due to errant distribution of genetic material during cell division. Instead of each daughter cell receiving one copy of each chromosome, sometimes one receives two copies of a certain chromosome, or parts of it, leaving the other cell deficient. This results in a "mosaic" of different non-identical clonal populations of cells within the same individual.

Philippe Froguel of the Qatar Biomedical Research Institute, and the study's lead author, said a simple genetic test could be developed to help identify those T2D patients with a greater propensity to develop CMEs. These patients would be monitored for early signs of leukemia and could start undergoing mild chemotherapy, he said.

Froguel's team built on the established link between T2D and accelerated ageing. They reasoned that CMEs may be more abundant in T2D patients, and may be predictive of cancer. The researchers collected blood samples from 2,208 T2D patients and 5,451 healthy controls of European origin. Using DNA arrays, they found that CMEs were much more likely to be found in T2D patients, especially those with vascular complications, than in healthy individuals. Their results are published in Nature Genetics1.

"This means that some patients with the most severe forms of T2D carry in their blood two different genomes, one being their normal germ-line genome (shared by all their normal cells), and the other a genome specific to a clone of blood cells that has developed [CMEs due to errant cell division]," says Froguel.

The researchers monitored the participants for six years and found that CME carriers had a significantly higher percentage of abnormal cells with the potential to develop into blood cancers.

"To our knowledge, there aren't any current specific diagnostic measures to predict cancer risk in T2D patients." says Froguel. This finding may make it possible, for the first time, to screen T2D patients for genetic markers of cancer risk. CMEs found in blood are not only predictive of blood cancers, he says, but may indicate other types of solid cancers as well.

Two 2012 studies^2,3, conducted by the National Cancer Institute (NCI), and the Gene Environment Associations Studies (GENEVA) consortium have linked CMEs to ageing and cancer. They found that CMEs appear in higher proportion in older individuals, and that people carrying a large number of CMEs in their blood cells were more likely to develop blood cancers.

Mohamed Gad, a clinical biochemistry researcher at the German University in Cairo, contends that the value of the results may be limited because samples were only taken from blood and not from other tissues. "The study did not reveal whether CMEs may be found in tissues other than blood cells, and that CMEs may be associated with solid cancers in these tissues, which are more prevalent in individuals with T2D." he says.

Gad says that the clinical implications of these results are noteworthy, but that further studies are required to investigate the possible mechanisms (either direct or indirect) and to provide the clinical evidence that T2D is actually accelerating the process of cancer, rather than just aging events.

Froguel says his team plans to address this test next. "We would like to better understand the mechanisms involved, in particular the triggers of these CMEs," he says. "We are thinking of using models of diabetic mice and to investigate all tissues, under various conditions.

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