Georgetown University scientists have identified a unique gene mutation that leads to cancer. Researchers know that cancer occurs when cells have too many or too few chromosomes, but they haven't understood what triggers uneven numbers of chromosomes.
In the finding, published in the August 19th issue of Science, the researchers report they've identified missing or mutated STAG2 gene, which encodes part of an essential protein that regulates chromosomes in several types of cancer. The new discovery may mean new hope for eradicating some types of cancer.
Twenty percent of glioblastoma multiforme, malignant melanoma and Ewing's sarcoma examined by the researchers had either a missing or mutated STAG2 gene, which means during cell division an uneven number of chromosomes are likely to appear in offspring, or “daughter” cells.
Todd Waldman, M.D., Ph.D., an associate professor at Georgetown Lombardi said, "In the cancers we studied, mutations in STAG2 appear to be a first step in the transformation of a normal cell into a cancer cell. We are now looking at whether STAG2 might be mutated in breast, colon, lung, and other common human cancers."
New cancer treatments possible
Study lead author, David Solomon, Ph.D., a student in the M.D. Ph.D. program at Georgetown University School of Medicine says, "We are now attempting to identify a drug that specifically kills cancer cells with STAG2 mutations. Such a drug would be of clinical benefit to the many patients whose tumors have inactivation of STAG2."
Solomon says he had a “eureka" moment during the study when he found mutations of STAG2 in a few brain cancer cells.
“The day that I did a Western blot of 10 Ewing's sarcoma tumors, a bone tumor most common in adolescents, and found that 6 out of 10 Ewing's sarcoma tumors had mutations or deletions of STAG2," he says. "I knew then that STAG2 was indeed an important tumor suppressor gene in several tumor types. That day I wrote EUREKA! in my lab notebook."
He also notes the STAG2 gene mutation is only the second to be found on the human sex chromosome. The gene lies on the X chromosome. Men have two copies, and women have one which is active; the other is dormant. What that means is the gene has to undergo just one mutation to lead to cancer, unlike most genes that require two mutations to become inactivated.
The gene is different in other ways too, says Solomon. "It's not like most tumor suppressor genes, which when mutated lead to either enhanced cell proliferation or decreased cell death. Instead it's a tumor suppressor gene with a different function — maintaining normal chromosome number and structure."
The finding lends new insight about the genetic basis for cancer. Identifying cancer tumors with the STAG2 gene mutation might lead to a new approach to eradicating cancer tumors. The Georgetown researchers are now working on finding a drug that specifically kills tumors caused by the newly identified STAG2 gene mutation.
"Science": DOI: 10.1126/science.1203619
"Mutational Inactivation of STAG2 Causes Aneuploidy in Human Cancer"
David Solomon, et al.
August 19, 2011
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