Most human cancers are aneuploid (containing an abnormal number of chromosomes). But the links between aneuploidy and cancer are not well understood, particularly the mechanisms driving chromosomal instability during tumorigenesis.

Scientists now have identified mutations of the STAG2 gene, whose protein normally aids in chromosome segregation during cell division, as common in several types of solid human tumors (Science 2011;6045:1039–43). Moreover, the investigators demonstrated that mutations of STAG2 can kick-start the aneuploid process.

A Georgetown University Medical Center team found that the STAG2 protein was missing in 20% of the glioblastoma, malignant melanoma, and Ewing sarcoma samples they studied. They then showed that knocking out STAG2 in a chromosomally stable human cell line could trigger aneuploidy. Conversely, when aneuploid glioblastoma cells, in which the endogenous mutant STAG2 allele had been corrected by homologous recombination, began re-expressing the protein, their collections of chromosomes began returning to normal.

STAG2 is located on the X chromosome—apparently the second cancer-related gene that has been found there. With just one functional copy for each gene on this chromosome, “it only requires a single hit to get complete inactivation, which may help to explain the mutation's prevalence in the solid tumors we examined,” notes lead author David Solomon, PhD. The Georgetown scientists are broadening their studies to analyze STAG2 in breast, colon, lung, and other cancers.