Distinguishing Hereditary vs. Sporadic Breast Cancers
A new study published in the New England Journal of Medicine reports on a revolutionary technique that analyzes gene patterns to distinguish between hereditary breast cancers and those that have occurred spontaneously. The technique further enables physicians to distinguish between genetic cancers caused by mutations in the BRCA1 and the BRCA2 "breast cancer genes."
If the technique eventually proves as promising as early results indicate, it could have extraordinary implications for breast cancer diagnosis and treatment.
Genetic factors account for between 5 to 10 percent of all breast cancers. In the past decade, researchers have identified mutations in two genes-BRCA1 and BRCA2-that are the major causes of most hereditary forms of the disease. If a woman has one of these genetic mutations, she has a significantly greater chance of developing breast or ovarian cancer.
Writing in the New England Journal of Medicine, Dr. Jeffrey Trent of the National Institutes of Health in Bethesda, Maryland and colleagues discussed a technique called "gene expression profiling," which compares the genetic makeup of cancer cells that exhibit BRCA1 or BRCA2 mutations with those of sporadic breast cancers.
The authors contend that their new genetic test will make it possible for physicians to accurately diagnose the cause of an individual woman's disease and may ultimately guide decisions about their most effective treatment.
They wrote that traditional techniques which look at tumor sizes and shapes under a microscope make it difficult to tell which tumors are caused by BRCA1 mutations. It is also virtually impossible to distinguish between those caused by BRCA2 mutations and those from non-inherited sporadic causes. Furthermore, they noted, the BRCA1 and BRCA2 genes are very large, and searching through them for mutations is both complicated and expensive.
Trent's team examined samples of tumors that had been surgically removed from 22 breast cancer patients at the University of Lund in Sweden. Fifteen of the women were known to have hereditary breast cancer-7 with BRCA1 mutations and 8 with BRCA2 mutations. The remaining cancers were of unidentified sporadic origin.
The researchers employed a "DNA microarray," which basically involves a glass slide with tiny dots of DNA from different genes arranged in a grid-like pattern. They first isolated messenger RNA from the test breast cancer cells to see which of the estimated 30,000 cells in the microarray were "turned on" in a cell. They then tagged these active cells with a fluorescent label.
A pattern of spots eventually appeared, showing which genes were active or inactive in the tumor cells. This provided a type of fingerprint for each tumor type, they wrote, which showed the key genes involved in tumor development and progression.
They found unique patterns associated with the hereditary and nonhereditary forms of breast cancer. Importantly, they further identified a handful of critical genes that they believe are crucial to cancer progression. "These 50 or 60 genes are obvious candidates for further research to understand the molecular basis of cancer, and are potential targets for the development of new drug treatments," they concluded.
Their technique was able to accurately identify all 7 BRCA1-positive tumors and 14 of 15 BRCA1-negative tumors. Similarly, they were able to identify 5 of the 8 BRCA2-positive tumors and 13 of 14 BRCA2-negative tumors. Although not perfect, the technique represents a major first step toward understanding breast cancer at its basic genetic level.
The authors called their ability to distinguish between the BRCA1 and BRCA2 genes "perhaps the most striking finding of our study." They believe this will enable future treatments to be specifically tailored to the genetic fingerprint of each individual patient.
"Now we have entered a new phase [of breast cancer research]," wrote Dr. Todd Golub of Harvard Medical School in a related editorial, "wherein methods of analyzing thousands of genes at a time can be brought to bear on the challenges of diagnosis and treatment."
SOURCE:
New England Journal of Medicine, February 15, 2001; 344:539-548, 601-602
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