Breast Cancer Gene Investigators Prepare For The Next Showdown

The researchers who found BRCA1, and the 'also-rans,' have many remaining avenues for ground-breaking studies When the public was informed that a team of scientists led by University of Utah geneticist Mark Skolnick had found a breast cancer susceptibility gene, it indeed appeared to be what Science called in a news report "a fitting finale to one of the most riveting of the fierce and grueling gene hunts that have come to epitomize life in the fast lane of genetics research" (R. Nowak, 265:1796-9, 1994). The theatrical aspect of the long-anticipated discovery was highlighted by the fact that the story was broken by NBC News nearly a month before the papers were published. Following that September 13 television report, Science decided to print its news story in its September 23 edition, although the articles themselves did not appear in the journal until October 7. By now, the champagne corks have all been popped. The researchers not fortunate enough to have been among the discoverers have had time to regroup and move on. And life in the fast lane continues. Neither the Skolnick team nor the other gene-seekers have had much chance to rest. After the gene--dubbed BRCA1--was discovered (Y. Miki et al., Science, 266:66-71, 1994; P.A. Futreal et al., Science, 266:120-2, 1994), researchers wasted no time in confirming the result. Three reports in the December 1994 issue of Nature Genetics (L.H. Castilla et al., 8[4]:387-91; J. Simard et al., 8[4]:392-8; L.S. Friedman et al., 8[4]:399-404) verified the gene's link to breast or ovarian cancer--or, in some families, both. The reports also point out how difficult it will be to devise a reliable screening test for BRCA1, largely because the gene can be defective in so many ways. The four-year race to find BRCA1 was a high-stakes competition marked by spirited rivalries and tenuous collaborations. The successful Skolnick team was made up of more than 40 colleagues from five institutions. In all, 12 teams vied for the elusive prize, including a 15- member group led by three elite researchers: geneticist Mary- Claire King of the University of California, Berkeley, who began the race by announcing the gene's approximate location in 1990; Francis Collins, the director of the National Center for Human Genome Research (NCHGR) at the National Institutes of Health and a leader of the groups that found genes for cystic fibrosis, Huntington's disease, and neurofibromatosis; and breast cancer specialist Barbara Weber, an associate professor of medicine and genetics and director of the breast cancer program at the University of Pennsylvania Cancer Center. Another high-powered team was headed by pioneering geneticist Raymond White of the University of Utah, who helped find the neurofibromatosis gene and genes involved in colon cancer. The medical and economic stakes of the competition were unusually high. The goal--a gene for breast cancer--has enormous implications in developing potential tests for identifying women at high risk for contracting a devastating disease. For the scientists themselves, a big discovery in such a high-profile area of cancer research can mean new opportunities for collaborations, grants, lectures at scientific meetings, even promotions. Many of the teams have since folded or traded players, which, according to Collins, isn't very unusual. Once a major project has been completed, he notes, "each group has its own ideas of where it wants to go in its research." Take Weber, for example. She has now joined Skolnick's team, following a new avenue in her work: the quest for another breast cancer gene, BRCA2. Like most of the other also-rans in the search for BRCA1, she is relieved that the gene has finally been found but disappointed in not being the one who found it. "What helped get over any sense of loss was the Nature Genetics work and the BRCA2 project," says Weber, a coauthor of one of the Nature Genetics papers. "It drew everyone back together to a new project and goal. "I would have loved to have been the first to have found the gene," she acknowledges. "But our work was part of a huge consortium, and it became less of a personal thing. I never felt a sense of defeat." Comments Weber's Penn coworker Jeff Boyd, who specializes in ovarian cancer genetics: "[After] you put two years of effort into something and come up short, you have to be disappointed. It was tough getting back to it after the announcement [that the gene had been found]; you wonder if there is anything important left to do." However, he adds, "you reflect a little, and realize it's just beginning. You're pleased that this advance was made; there's still a lot to be done to apply the work clinically." "No one's licking his wounds," says Collins. "There's plenty of interesting biology to get on with. The point is to understand this disease that devastates so many. Once you get over the natural disappointment that you didn't experience that 'aha,' you move on." The Nature Genetics reports clarified the unwieldy nature of a long gene prone to many different mutations--perhaps as many as 100, though only about 40 have been identified so far, according to NCHGR senior staff fellow Lawrence Brody, a member of the Weber-Collins-King consortium. "It's not like the cystic fibrosis gene, where 70 percent of the cases have a certain mutation," he adds. "The issues are: How many mutations are there, and what are the best ways to find them?" notes Weber, who spent the last three years collecting and analyzing genetic mutations in DNA samples from women in so-called breast cancer families. But, according to Boyd, "large-scale screening may be problematic because it is a large gene with many mutations scattered throughout. You'll probably have to continue to look at the entire gene for mutations, and coming up with a cost- effective way to do that will be difficult." Other findings have been equally confounding. Why, for example, hasn't anyone found BRCA1 mutations in the tumors of patients with the sporadic, or nonhereditary, form of breast cancer, which accounts for 90 percent of the 180,000 cases annually diagnosed in the United States? No one knows how common BRCA1 may be in the normal population, though it's believed to be about 5 percent. Until now, scientists have focused only on women with a strong family history of the disease. And, according to Weber, not all mutations are created equal: "Now when we tell a woman she has a mutation, we can tell her that she has an 85 percent chance of getting cancer in her lifetime. But these are severely affected families. Some families may have different mutations that give only a 50 percent chance of getting cancer." The research groups are now facing head-on the question confronting them all: What next? Collins and his coworkers remain hot on the trail of BRCA1. "We're focusing on better ways of mutation detection," Collins says. "Virtually every family has different mutations. If you want to sample a high- risk individual to see if she has a particular mutation, you have to have a robust method of detection." Among other goals, Collins's team is planning to make a knockout mouse model with which to study BRCA1, and to better characterize the gene's protein. "We think it might be a transcription factor. If so, what genes does it regulate?" he asks. "Most of these questions will probably be answered in the next year or two." Collins is especially concerned about the ethical implications of the research. For one thing, no one's sure about the link between a particular mutation and the risk of developing cancer at a certain age. "What do we recommend to someone to reduce her risk? Mammograms? Prophylactic breast surgery?" he asks. The National Cancer Institute and NCHGR have funded 11 pilot studies that are already under way to look at the best methods of counseling women and families about issues of testing and cancer risk. Weber's Holy Grail has also been to get a clearer grasp of BRCA1--what it does normally, why mutations make it malfunction, and how it causes breast cancer. Penn and several institutions have begun clinics for women who may be at risk to develop breast cancer based on a family history of the disease. At Penn, for example, risk assessment, genetic testing, and counseling may be provided. Two years ago, Weber began thinking about what might happen when BRCA1 was found. She had been collecting blood samples from women who were at high risk to develop breast cancer, and was analyzing their DNA. Even before BRCA1 was discovered, she was able to tell one woman in an affected family that she did not possess the same genetic flaw as her sisters, and that she was not at the same risk to develop breast cancer. "You have to be careful that you're educating people about what they're going to find out so that they can make an informed decision about whether they want that knowledge or not," she points out. "We're talking about something that might happen in the future--it's a new way of looking at medical testing." That's why Weber and others won't recommend widespread screening--scientists are still searching for and analyzing mutations, attempting to figure out what they may mean in terms of cancer risk. "We're doing cutting-edge research at the same time [that] we're trying to bring information into the clinic. Women don't want a screening test that doesn't help." Members of the heralded Skolnick team have been busy, as well. Roger Wiseman, a molecular geneticist at the National Institute of Environmental Health Sciences in Re-search Triangle Park, N.C., is attempting to create another knockout mouse model, which entails halting the BRCA1 gene from working and watching the effects. "Ideally, the mice develop breast and ovarian cancers and we can study how the gene is functioning during carcinogenesis," he explains. "If we can understand the process and the biochemical pathways, perhaps it will lead to developing therapeutic options." He and postdoctoral fellow Andrew Futreal are attempting to track down what the BRCA1 protein controls, what DNA sequences it recognizes, and how the gene functions at the molecular level. The gene finders, of course, have been basking in the limelight. Prestige aside, says genetic epidemiologist David Goldgar of the University of Utah, winning the BRCA1 race has provided new opportunities for collaborations and meeting presentations. Says Goldgar: "It means that people think that you're suddenly a lot smarter than they thought you were." Goldgar is busy categorizing all known BRCA1 mutations, and is attempting to "estimate the frequency of mutations in different families and populations." He echoes a common view: "The real question is, what are the risks associated with particular mutations? Some mutations may have greater or lower risks for a disease, and it may differ for breast vs. ovarian cancer." Goldgar attributes the group's success to a large intense, collaborative effort, as well as the "size of our team, the strategy we used, plus some good fortune." Steven Benowitz is a science writer for Penn State University's Milton S. Hershey Medical Center in Hershey, Pa.

Breast Cancer Gene Investigators Prepare For The Next Showdown

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