The first study, led by the Lombardi Comprehensive Cancer Center at Georgetown University School of Medicine (GUSM) in Washington, DC, has identified that STAG2 - a commonly mutated gene in cancer - is directly involved in causing aneuploidy. The second study, led by the researchers at the Massachusetts Institute of Technology (MIT), has shown that aneuploidy causes genetic instability that can pave the way for malignant tumour growth and other cancerous defects. Together the studies have opened up an avenue for research that could lead to new drugs for people with cancer, which target cells containing the mutation.
Aneuploidy is found in almost all cancers, but the phenomenon was poorly understood because it was unclear whether it was a cause or effect of cancer. The studies, reported in Science, show that it is a bit of both.
The STAG2 gene influences the production of a protein structure called the 'cohesin complex', which regulates how chromosomes are separated during cell division. Mutations in STAG2 mean that cells are more likely to have uneven numbers of chromosomes after division, leading to an increased risk that they will develop into cancer cells.
The GUSM study found that in 20 percent of the cancer cells they studied, including types of brain, skin and bone cancer, the STAG2 gene was missing or mutated. The team then manipulated tumour cell lines to repair and induce STAG2 mutations, with the number of chromosomes becoming more stable when it was repaired and less stable when it was mutated. The findings suggest the mutation is a 'first step' toward normal cells transforming into cancer cells.
The MIT study examined the effects of aneuploidy on the functioning of the cell. The team was able to determine that the mutation increases the chances of disruption in genome repair and maintenance, because the cell struggles to maintain genome function when there are extra chromosomes.
Associate Professor Todd Waldman, senior author on the GUSM study, said: 'When cells are in a state of aneuploidy, their mitotic machinery gets somewhat confused by the abnormal chromosome count and that perpetuates the instability'.
The latter findings are based on yeast cells and it is not yet clear whether human cells respond in the same way to genomic instability. But the study, if replicated in human cells, could have huge implications. 'The grand implication is that mutation of one single gene can be responsible for all sorts of instability seen in tumors', said Duane Compton, Professor of Biochemistry at Dartmouth Medical School in New Hampshire who was not involved in the study.