2nd Gene Causing Inherited Breast Cancer Is Identified
A British-American team has apparently wrapped up the mystery of inherited breast cancer, isolating a second gene that causes the disorder and thereby opening the door for increased screening in susceptible families.
Like the first breast cancer gene, identified in September 1994, the newly discovered gene is thought to be responsible for about half of all inherited cases of breast cancer, which total as many as 18,000 cases a year in the United States.
Women who inherit the gene, called BRCA2, have an 85% risk of developing breast cancer--the same risk as with BRCA1. Family members who carry the gene also have an increased risk of male breast cancer, prostate cancer and ocular melanoma--but, unlike BRCA1, no significantly greater risk of developing ovarian cancer.
The discovery is reported today in the British journal Nature.
“This is a really tremendous finding that is going to profoundly change how we approach cancer and how we think about the idea of who is at risk,” said Dr. Richard Klausner, director of the National Cancer Institute. The two breast cancer genes are “extraordinary windows into the nature of cancer.”
“This is probably just as significant as the isolation of BRCA1,” said Dawn Willis, director of research promotion and marketing for the American Cancer Society. “It looks as if the two genes have similar structure and function. Now we need to know what that function is.”
The inherited mutations appear to damage the cell’s ability to suppress the abnormal growth that characterizes cancer. “Like BRCA1, the [new] gene appears to function as a tumor suppressor gene,” said geneticist P. Andrew Futreal of Duke University, a co-leader of the team that made the discovery.
Susceptible individuals have one healthy copy of the BRCA2 gene and one mutated copy. If an individual has a damaged copy of the gene, “every cell in your breast is already primed” for cancer because the healthy copy can be easily damaged by radiation or chemicals in the environment, he said.
Breast cancer is the most common form of cancer in women, striking 182,000 U.S. women and 1,000 men each year. It is estimated that one in 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 within the breast region at the time of diagnosis and is 18% if it has spread to other parts of the body.
The disease annually kills about 46,000 women and 300 men.
Researchers have known for 100 years that breast cancer runs in families. The inherited form is physically indistinguishable from sporadic (non-inherited) breast cancer, but it strikes at an earlier age, with a large proportion of cases occurring in women under 30.
BRCA1 was found on chromosome 17, one of the 23 pairs of chromosomes that contain every person’s genetic blueprint. BRCA2 was found on chromosome 13.
Screening for breast cancer can tell a susceptible woman that she must be alert to the presence of early tumors, which can be effectively treated. But screening also presents a thorny ethical problem, primarily because there is no preventive method available, short of removing a healthy breast.
Researchers are screening for BRCA1 on a very limited basis. “It’s taking place in special research centers because they want to be sure they can offer counseling,” Willis said. “It’s sometimes difficult news for people to take because there is nothing that can be done about it now. . . . Some women [with the gene] have opted for prophylactic mastectomies, but that doesn’t remove all of the breast tissue, so it doesn’t remove all of the risk.”
Knowing that a woman has a mutated copy of BRCA1 or BRCA2 also could make it very difficult for her to obtain employment or insurance, said Dr. Eric Winer, co-director of Duke’s breast cancer program. He emphasized that it is important to couple testing with counseling and support services.
“This finding . . . makes it more important than ever that we learn how to counsel women about their options and how to develop clinics to provide support services for the women who may carry breast cancer genes,” said Barbara Rimer, chairwoman of the National Cancer Advisory Board.
And the cost and ethical quandaries associated with the test mean that it is unlikely that testing will expand to women without family histories any time soon. “Mass screening of the entire population is certainly impractical for the foreseeable future,” Willis said.
The next big question that scientists face is the possible role of BRCA1 and BRCA2 in sporadic breast tumors, which account for the vast majority of cases. Previous studies have been unable to find evidence of a mutated version of BRCA1 in women with breast cancer. Researchers have not yet had the time to look for BRCA2 in such patients.
The most suggestive evidence was reported last month by researchers at the University of Texas at San Antonio, who found that the protein produced from the BRCA1 gene occurs in the wrong place in cells from sporadic breast cancers. Instead of being in the nucleus of the cell where it belongs, the protein was found in the cytoplasm, the fluid-filled area that makes up the rest of the cell.
But, Willis said, the presence of the BRCA1 protein in the cytoplasm could be a simple side effect of the tumor process rather than its cause. Researchers must carry out a great deal more research, she said, before they can fully understand what is going on in the malignant breast cell.
