Study focuses on role of BRCA in cancer

Yale research increases understanding of gene in DNA repair

NEW HAVEN — A mutation in one of two genes, BRCA1 and BRCA2, is a significant predictor of someone developing cancer, most notably breast cancer. However, little has been known about how BRCA performs its functions in the body’s cells.

Now, a Yale University-led study has increased knowledge about how the BRCA genes repair DNA and suppress tumors and why their mutation poses such a threat.

“They’re most wellknown to be genes that prevent breast cancer, but they also suppress ovarian, prostate, pancreatic (cancer), and it goes on and on,” said

Patrick Sung of the

Yale Cancer Center, senior author of the paper published Wednesday in the journal Nature. “By the time a woman reaches the age of 70, there’s a 1-in-8, 1-in-9 chance of a woman getting breast cancer. But if a woman has BRCA1 (mutation), the chance of getting breast cancer goes up to 80 percent.”

Sung is professor of molecular biophysics and biochemistry and also of therapeutic radiology.

It wasn’t until 1990 that a geneticist at

“... if a woman has BRCA1 (mutation), the chance of getting breast cancer goes up to 80 percent.” Patrick Sung, Yale University professor

the University of CaliforniaBerkeley discovered the BRCA1 gene had a role in breast cancer. Mary-Claire King “was the first person to propose that breast cancer could be inherited and people thought she was crazy, but she was right,” Sung said.

It was known that BRCA1 has a role in repairing broken DNA strands, which can be damaged by radiation, exposure to chemicals or other environmental effects. “Cells deficient in BRCA are very sensitive to radiation,” Sung said.

However, “they have not been able to figure out mechanistically what BRCA1 and BRCA2 are doing in DNA repair,” he said. “The only way to find out is to purify the proteins, study its properties … and reconstitute the DNArepair reaction.” Sung was able to show in the test tube how BRCA expresses itself in the body.

“It’s really the first report pinpointing the biochemical function of BRCA1 in DNA repair,” he said.

Repairing the cell’s DNA is a multi-step process, and BRCA1 has a distinct role in that process. Sung’s research determined where along the biological pathway the gene comes into play. That knowledge will help doctors find out how harmful a patient’s BRCA1 mutation is. “We can study the mutant protein. … Then we can inform [the patient] in terms of treatment,” Sung said.

By examining the mutation, “I should be able to tell you what it means,” he said. “We should be able to tell whether it affects the DNA-repair process or not.”

An “even more important aspect, I believe, is down the line,” when drugs can be developed, not only to treat cancer but to prevent its occurrence.

“Having the power to predict is pretty important, Sung said.

There is still much research still to do, however, he said.

“These proteins don’t do just one thing. They perform multiple functions … So I’m not going to claim that we solved the whole puzzle, but we solved a big part of it.”