Researchers Identify Gene Associated

with Cancer

It’s probably fair to say that there aren’t many MD/PhD students who have a righteous “Eureka moment” — a flash of scientific discovery. But David Solomon experienced one so strongly that he wrote “EUREKA!” in his lab notebook and then got back to work.

David Solomon and Todd Waldman, MD, PhDDavid Solomon and Todd Waldman, MD, PhD

Now, his insight has been published in Science, arguably the top research journal in the United States and the world. Solomon is the lead author, and the senior author, cancer geneticist Todd Waldman, MD, PhD, is both Solomon’s research mentor and director of the MD/PhD program at Georgetown University School of Medicine.

In the August 19, 2011 issue of Science, Waldman, Solomon and a team of researchers from Georgetown University Medical Center report that they have identified a gene that is commonly mutated in human cancers that directly causes aneuploidy, an abnormal number of chromosomes.

Cells with too few or too many chromosomes have long been known to be a hallmark of cancer, but the cause of chromosomal instability has been little understood. Now, Waldman and Solomon can explain how this occurs in three different tumor types they examined — the deadly brain cancer glioblastoma multiforme, the aggressive skin cancer melanoma, and the childhood bone cancer Ewing’s sarcoma.

Genetic Mutation Under Scrutiny

They found that 20 percent of these cancers had no STAG2 protein, often due to a missing or mutated STAG2 gene. The STAG2 gene encodes a component of a protein structure known as the “cohesin complex” which regulates the separation of replicated chromosomes during cell division.

What this means is that if the STAG2 gene has been inactivated by a mutation, chances increase that a cell undergoing division will distribute an uneven number of chromosomes to the two new “daughter” cells being created. These cells, which now have too few or too many genes, are significantly more likely to develop into cancer.

“Scientists have long been searching for the genetic basis of aneuploidy in cancer cells, and our study provides substantial new insight into that process,” says Waldman. “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,” he says.

The study may also provide a new direction for cancer therapy, says Solomon, who earned his PhD in May 2010, and will receive his MD in 2012. “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.”

The Eureka moment for Solomon was that he “had first identified mutations of STAG2 in a few brain tumors but was unsure of its importance as a broad spectrum cancer gene in tumor types other than brain,” he says. “The day that I did a Western blot on 10 Ewing's sarcoma tumors, a bone tumor most common in adolescents, and found that 6 out of 10 of these tumors had mutations or deletions of STAG2, 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.”

The Search for ‘Future Solomons’

The study was a product of Solomon’s work on his doctoral thesis, which was to search for genes that are mutated in glioblastoma multiforme, the most common and lethal form of brain cancer.

Solomon is “a superstar,” says Waldman. “He is unbelievably smart, he loves science, and he is passionate about biomedical research in ways one almost never sees,” says Waldman. “He will send me an email at 2 am at least once a week about research.”

Solomon is now starting his fourth year of medical school. He says his MD/PhD degree will be more than the sum of the two parts. Obtaining an MD at Georgetown “provides great clinical training” and earning a PhD in the Tumor Biology Training Program “has given me the opportunity to perform exciting cancer genetics research in an excellent training environment at a comprehensive cancer center.”

He envisions a future as a surgical pathologist and cancer researcher. “I am very interested in the future of molecular diagnostics for cancer pathology and the prospect of personalized targeted therapeutics based on the genetic profile of individual tumor specimens,” he says.

Says Waldman: “Every door will be open to David — he can do whatever he wants to do.”

By Renee Twombly, GUMC Communications