Aneuploidy—when the cells of an organism contain more or fewer than the standard number of chromosomes for its species—is found in greater than 90 percent of all human cancers. But how exactly it relates to cancer, and whether it is a cause or merely a consequence of genomic instability, has long been a mystery. Two new studies published today (August 18) in Science show that it’s probably both, pointing to a gene defect that can cause aneuploidy, and elucidating the disastrous effects of aneuploidy on a cell’s genome.
“Aneuploidy is found in virtually all cancers, yet very little is known about its origins or its effects,” said a cancer biologist Bert Vogelstein at Johns Hopkins Medicine, who was not involved in the research. “These two papers provide some really excellent clues to what’s going on.”
The first paper, from Todd Waldman’s group at Georgetown University School of Medicine, identifies a potential cause of aneuploidy—a gene that encodes a protein subunit of the cohesin complex, which plays a key role in correctly separating sister chromatids during cell division. An MD/PhD student in Waldman's lab, David Solomon, was examining brain tumors for missing genomic regions when he stumbled upon a sample that was missing the gene STAG2. He then looked at a dozen or so other brain tumors and found that several of them were similarly not expressing STAG2.
“And then we expanded our study to a variety of other tumor types and found that inactivation of STAG2 was actually quite common in a diverse range of human cancers,” Waldman said. Specifically, the team found evidence of mutated or missing STAG2 in some 20 percent of brain tumors, 20 percent of melanomas, and 20 percent of Ewing’s sarcomas, a pediatric tumor.
To see if this gene defect could indeed lead to the aneuploidy characteristic of the tumor cells they were examining, the researchers repaired STAG2 in two brain tumor lines, and found that the cells subsequently became less aneuploid. The cell populations showed less variation in the numbers of chromosomes they carried, and in some cases, the actual chromosome number was reduced, bringing it closer to normal. Conversely, when the team induced a STAG2 mutation in otherwise normal cells, the cells almost universally gained a chromosome. “I think that this work, together with some previous work, strongly implicates the inactivation of cohesin in general as a cause of aneuploidy in cancer,” Waldman said.
The second study looked at the consequences of aneuploidy. Geneticist Angelika Amon of the Massachusetts Institute of Technology and her colleagues had already shown that aneuploidy puts stress on the protein quality control pathways of the cell. “When you now have an extra chromosome or multiple extra chromosomes, all of a sudden thousands of proteins are imbalanced, and the cell has to deal with that,” she explained. “But we wanted to know if these protein imbalances could cause stress on the genome maintenance functions of the cell.”
So Amon and her team created haploid yeast cell lines with a single additional chromosome, and examined the cells for signs of genomic instability. Sure enough, the aneuploid yeast lines showed increased chromosomal instability, increased mitotic recombination, and increased structural abnormalities, such as those caused by double-strand breaks in the DNA. “Aneuploidy impacts basically all genome replication and segregation functions,” Amon said.
Exactly how an abnormal number of chromosomes causes such instability is unclear. One possibility is that having too many copies of a particular gene or set of genes increases the chance of genomic disruption. Or, the stress that results from the imbalance of protein levels overall could somehow lead to genomic instability. Additionally, it could simply be the increased number of chromosomes that causes the problem.
“I think the Amon paper emphasizes this, that cells with grossly abnormal numbers of chromosomes have some level of chromosome instability just by virtue of their abnormal chromosome count,” Waldman 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.”
These results were obtained in haploid yeast cells, however, which is “a fairly reductionist model system,” said cell biologist Duane Compton at Dartmouth College in New Hampshire, who did not participate in the study. “So the overall implications for human cancer are really not entirely clear.” Human cells, for example, have mechanisms that guard against such genomic chaos, such as the tumor suppressor protein p53, which signals the cells to stop dividing once the genome gets to be in such disarray.
Still, “I find the observation very, very interesting,” Compton said. “Waldman is showing that there’s a single gene mutation that causes aneuploidy. Amon is saying if you’re aneuploid, you get all sorts of other genomic changes. Taken together, the grand implication is that mutation of one single gene can be responsible for all sorts of instability seen in tumors, which to me is extraordinary.” Clearly there are some holes to fill in—namely whether aneuploidy will similarly cause genomic instability in mammalian cells, he added, but “if that were true, it would be hugely powerful.”
J.M. Sheltzer et al., “Aneuploidy drives genomic instability in yeast,” Science, 333: 1026-30, 2011.
D.A. Solomon et al., “Mutational inactivation of STAG2 causes aneuploidy in human cancer,” Science, 333: 1039-43, 2011.