Another article: Cancer is an accumulation of failure of repair

by Jim Muckerheide
August 14, 1998

New York Times: August 14, 1998

Study Finds How Gene's Defects Cause Breast Cancer
By JANE E. BRODY

Scientists at the University of North Carolina have made an important discovery about how defects in one of the two breast cancer genes, BRCA1, raise the risk of the disease: They leave cells without the normal ability to correct certain mistakes that commonly occur in their genetic machinery.
    Scientists and experts elsewhere say the finding has potentially important clinical implications for people known to carry the defective gene in their cells. On the one hand, it could result in more effective treatments for hereditary breast cancer. It could also lead to a test that would predict which of the women and men who carry the defective gene are most likely to develop cancer.
    On the other hand, the new understanding raises questions about the safety of starting at a young age to do regular mammograms in women who inherit the defective gene.
    The new information, reported in Friday's issue of the journal Science, will add to the understanding of how cancer starts and what might be done to prevent it. The lead author of the study, Lori Gwen, a graduate student, said, "This is the first direct evidence of a function for this tumor-suppressor gene, and it helps to explain how the gene may be involved in cancer."
    The study, done in specially altered cells derived from a mouse, showed that the BRCA1 gene directly or indirectly participates in a process called transcription-coupled repair, a rapid means of correcting mistakes that occur in the DNA of other genes.
    When people make a mistake writing with a pencil, they use an eraser, on the typewriter they use white-out and on the computer, the delete button. When an error occurs in the DNA of a gene, cells rely on an error-specific repair mechanism to knock out the errant information.
    In Friday's report, Ms. Gowen, Dr. Steven Leadon and colleagues report that the normal task of BRCA1, one of the two genes known to be involved in hereditary cancers of the breast and ovary, is to repair DNA damage caused by oxidation, a process that occurs continually in the body in the course of normal metabolism and that can also result from exposure to outside agents like radiation.
    When BRCA1 is defective, it is unable to repair oxidative DNA damage, the most common insult to the genetic material of cells throughout the body. A defective BRCA1 gene is responsible for about 5 percent of all breast cancers and can affect men as well as women in families with hereditary breast cancer.
    An accumulation of genetic damage to the DNA is how overexposure to sunlight can cause skin cancer and an overdose of radiation from X-rays can cause cancer in internal tissues like the thyroid gland. When oxidative damage occurs in genes that determine cell growth and when the mechanism that normally repairs such damage fails to work properly, the cell is no longer able to keep its growth in check and a malignant tumor results.
    There are already several other cancers that have been linked to genes that have lost their ability to repair defective DNA. Skin cancers commonly occur in people with the rare hereditary disorder, xeroderma pigmentosum, after exposure to sunlight. Another is a
rare hereditary form of colon cancer, hereditary nonpolyposis colon cancer, or Lynch syndrome, in which a defective repair gene fails to correct a mismatch in the DNA.
    Dr. Bert Vogelstein, a cancer geneticist at Johns Hopkins University who unraveled the defect involved in the colon cancer gene, said that someone who carried a defective BRCA gene started out with both a normal and a defective version of the gene in each cell. But when a particular mutation occurs in the normal BRCA gene in breast or ovarian tissue, the pace of DNA repair changes from that of a sprint to a slow crawl. This allows mistakes to accumulate that may eventually result in the uncontrolled growth of a tumor.
    But Vogelstein also suggested that an inability to rapidly repair oxidative damage might prove to be a tumor's Achilles heel and lead to new improved therapies. The defect suggests, he said, that these tumors "are likely to be extremely sensitive" to therapeutic radiation or to chemotherapy drugs that cause oxidative damage. Tumor cells would be hit harder by such treatment than normal cells, which would still have one normal copy of the BRCA gene that could correct oxidative damage induced by the therapy.
    Leadon, a molecular biologist who studies how damaged DNA is repaired, suggested another benefit: the possibility of determining who has a defect in BRCA1 that "would lead to an inability to carry out oxidative repair." He said that "BRCA1 is a very large gene that probably has multiple functions and can have mutations that are not important." Leadon added that the new finding "will help us determine which mutations are important," which could eventually lead to a test that revealed who would be most likely to get cancer.
    But Dr. Henry Lynch, an oncologist and expert on hereditary cancers at Creighton University in Omaha, Neb., suggested that the new finding could prove to be "a double-edged sword of Damocles." Lynch said that if a woman known to carry one defective BRCA1 gene was subjected to repeated mammograms, say, starting at the age of 25, the X-rays would help detect an early, more curable breast cancer, but at the same time the cumulative exposure to radiation might increase her risk of developing a cancer.