Almost all cancer cells have gained or lost entire chromosomes. Despite the genetic turmoil this causes, scientists have disagreed for nearly a century about whether this abnormality and other types of genomic instability are the starting gun for cancer or merely collateral damage. A study published online 10 October in Nature Genetics provides the strongest evidence yet for the starting gun theory by showing that mutations in a gene involved in ensuring proper numbers of chromosomes result in childhood cancer.
In 1914, German biologist Theodor Boveri postulated that abnormal chromosome number, or aneuploidy, might be a root cause of cancer. But the idea fell out of fashion as researchers began to discover that mutations in specific oncogenes and tumor-suppressor genes could set cancer in motion. A series of studies in the mid-1990s rekindled the theory. This work suggested that mutations in DNA repair proteins can lead to genomic instability and cancer by making cells more vulnerable to future genetic defects, but scientists still disagree about whether genomic instability causes cancer.
In the new study, a team led by cancer geneticist Nazneen Rahman of the Institute of Cancer Research in Sutton, U.K., screened the DNA of eight families with mosaic variegated aneuploidy (MVA)--a genetic disorder in which more than 25% of a patient's cells are aneuploid and childhood cancers occur much more frequently than normal. The group identified five children with mutations in both copies of a gene called BUB1B. All five had a high percentage of aneuploid cells, and two already have cancer. The BUB1B gene encodes a protein that helps guarantee that the right number of chromosomes are passed from cell to cell. "This indicates that aneuploidy has a direct causal role in cancer," says Rahman.
"This is a giant step forward for those who believe early instability predisposes to cancer," says Bert Vogelstein, an oncologist at Johns Hopkins University School of Medicine in Baltimore, Maryland. But William Dove, a geneticist at the University of Wisconsin, Madison, has been unable to detect early genomic instability in a mouse model of intestinal cancer, and says the theory may not apply to all cancers.