Discovery of Breast Cancer Gene Called Major Advance : Medicine: Researchers locate defect that causes half of inherited cases. Early detection may save many lives.
Utah researchers have identified the defective gene believed to cause about half of all inherited cases of breast cancer, a discovery that should make it possible within a year to identify the estimated 600,000 American women who carry the gene.
These women have an 85% risk of developing breast cancer by age 65 and an unusually high risk of developing ovarian cancer. Identifying the women at risk could save many lives by allowing intensive monitoring and early detection of the tumors, which substantially increases the cure rate.
The discovery is the result of a massive effort triggered four years ago when geneticist Mary-Claire King of UC Berkeley showed that the gene, commonly called BRCA1, is located on a small region of chromosome 17, one of the 23 pairs of chromosomes that contain every person’s genetic blueprint. The race to locate the gene was ultimately won by a team of more than 45 scientists headed by geneticist Mark H. Skolnick of the University of Utah and Myriad Genetics Inc. of Salt Lake City.
Another team also has identified the approximate location of a second gene, BRCA2, that is believed responsible for most of the remaining cases of inherited breast cancer in women, possibly many sporadic cases of the disease, as well as male breast cancers.
The discovery of BRCA1 is a “major advance (that) will enable us to identify women, particularly younger women, who have an increased risk of developing breast cancer,” said molecular biologist Harold Varmus, director of the National Institutes of Health.
Perhaps even more important, however, will be the new understanding the genes provide about how breast cancer occurs, according to Dr. Harmon Eyre, chief medical officer of the American Cancer Society.
“We actually know very little about what causes breast cancer,” Eyre said. “This is a real first step in getting to the bottom of what it is all about.”
Breast cancer activists were delighted by the discovery, particularly because of its potential implications for understanding the biology of the disease, said Michelle Rakoff, co-chair of the Los Angeles Breast Cancer Alliance. “What we have now is early detection,” she said. “What we really want is prevention, and for that we need to know what causes it.”
Reports on the breakthrough were scheduled to be published next month in the journal Science, but they were released Wednesday after NBC News revealed their contents.
Breast cancer is the most common form of cancer in women, striking an estimated 182,000 U.S. women and 1,000 men each year. It is estimated that one in every nine women will develop the disease sometime in their lives. The five-year-survival rate after treatment for localized breast cancer is 93%, but the rate dips to 72% if the disease has spread in the breast region at the time of diagnosis and to 18% if the disease has spread to other parts of the body.
The disease annually kills about 46,000 women and 300 men.
Researchers have known for more than 100 years that breast cancer runs in families, with this form of the disease accounting for about 5% of all cases. The inherited form is physically indistinguishable from sporadic breast cancer, but it strikes at an earlier age, with a large proportion of cases occurring in women under the age of 30.
Previous studies of more than 200 families with the BRCA1 gene have revealed that the gene is linked not only to breast and ovarian cancer, but perhaps to colon and prostate cancer as well. Both women and men in these families have an above-normal rate of colon cancer and men have an excessive amount of prostate cancer.
The newly identified gene, Skolnick said, is a very large gene “that had no similarities to any other gene that we know of until the last segment that we found.” The structure of that segment suggests that the protein produced from the gene binds to DNA within the cell, but the researchers as yet have no idea what it does after it binds.
Most researchers, however, believe that BRCA1 is a tumor suppressor gene--one that normally keeps the replication of cells in check. Skolnick’s group is working overtime to pinpoint its function when healthy.
“It is going to be difficult, to say the least, to understand how this gene predisposes some women to breast and ovarian cancer,” King said. “But no one ever said breast or ovarian cancer would be easy to solve.”
Skolnick said it would require at least a year to develop a test for the defective gene because researchers need to be sure which mutations cause cancer, which are harmless and which are more likely to cause ovarian cancer rather than breast tumors. “We want to make sure that if you tell a woman she has an elevated risk, it is true,” he said.
Based on the size of the gene, a test to detect its presence could cost as much as $1,000, he said.
Eyre noted that the test will also make it possible to determine when the defective gene is not present. In any family with many women, he said, there is a significant chance that several will develop breast cancer even though they do not carry the gene. In such families, the test should reduce anxiety by showing that unaffected members have no unusual risk for breast cancer, he said.
Currently, some women in families with a history of the disease undergo prophylactic mastectomies to reduce their risk. If the gene is not present, such mastectomies would clearly be unnecessary.
Skolnick’s group has also looked for the gene in several patients with sporadic forms of the disease and, to everyone’s surprise, was unable to find it. “That’s completely unexpected,” Eyre said. Generally, he said, a gene that plays a major role in an inherited form of a disease is also important in sporadic cases.
Researchers have higher hopes that the other gene under study, BRCA2 , will be linked to sporadic cases once it has been isolated.
The approximate location of BRCA2 on chromosome 13 was determined by a team headed by molecular biologist Douglas F. Easton of the Institute of Cancer Research in London, who studied 15 breast cancer families that do not have BRCA1. “We think that BRCA1 accounts for perhaps half of the inherited cases and BRCA2 accounts for a good fraction of the rest,” he said. “But we think there is still another gene to be found.”
Easton and his colleagues--a team that includes Skolnick’s group--are now using the same techniques used in Utah to isolate BRCA2 from among the approximately 65 genes located in the small segment of chromosome 13 they identified.
* INNOVATION: Gene mapping is changing biology, farming and medicine. D1
