Color array reveals breast cancer types.

Breast cancer is not a single disease. Some types grow slowly; others, rapidly. Some are due to inherited mutations; others, external factors. But figuring out which type of cancer that patients have, so physicians can treat them most effectively, is difficult.

Now researchers may have found a simple way to identify two inherited forms of the disease, by literally illuminating the genes, known as BRCA1 and BRCA2, "turned on" in these cancers.

It's hard to tell whether a cancer has sprung from an inherited mutation just by looking at tumor cells. Testing gene sequences for mutations works well for this purpose, but it's costly.

Breast cancers stemming from mutations in BRCA1 and BRCA2 tend to follow two distinct and predictable paths, however. Knowing this, cancer-genetics researcher Jeffrey Trent of the National Cancer Institute in Bethesda, Md., and his colleagues hit upon an alternative test. The progression of these cancers might reflect patterns of gene activity, signaling the mutations' presence.

"We can look at the activity of genes as a surrogate" for these mutations, says Trent. "It may be easier in the long run to use this suite of genes, rather than to sequence this huge BRCA gene."

As they report in Feb. 22 NEW ENGLAND JOURNAL OF MEDICINE, the researchers sampled tumor tissue from women with hereditary BRCA1 or BRCA2 mutations, as well as from women with no family history of the disease. Then they used devices called microarrays to detect the activity of thousands of genes all at once.

With the help of fluorescent dyes, gene activity for particular cancer types showed up as patterns of green and red dots. The researchers found that these patterns were made of 176 genes from the BRCA tumors, creating two distinctive gene "profiles." Nonhereditary tumors didn't show such patterns of gene activity.

Gene profiles ought to help physicians predict how a patient's specific form of cancer might progress. This is a marked improvement over traditional diagnostic methods that use the size of the tumor and the number of lymph nodes involved to predict the future course of the cancer. Unfortunately, many cancers that have not yet spread will still kill the patient, says cancer geneticist Jeffrey R. Marks of Duke University Medical Center in Durham, N.C. Other patients survive cancers that have already spread, however.

"Five years ago we had to look at this one gene at time," says Marks. "Now we can see thousands of genes at a time, which is three orders of magnitude higher."

Differences between the BRCA1 and BRCA2 mutations have weighty consequences. For example, women with the BRCA1 mutation can have as much as a 45 percent risk of developing ovarian cancer, compared with 10 to 20 percent for women with the BRCA2 mutation.

The microarray studies validate the notion that different cascades of mutations lead to different forms of breast cancer, says Alan D'Andrea from the Dana-Farber Cancer Institute in Boston. "[The diseases] not only look different but they have different gene-expression profiles," says D'Andrea.

He and his colleagues recently found genes involved in a pathway that activates BRCA1. He adds, "The more we can break up these breast cancers into categories, the more we can find a strategy to treat them."