January 24, 2003

esearchers have identified the genetic 'signatures' of certain cancers that could help doctors determine which tumors are most likely to spread throughout body, or metastasize. Genetic signatures are characteristic patterns of gene activity in cells.

A widely held theory of cancer is that tumors metastasize when a critical mass of mutant cells breaks from the main site. The new work challenges that theory. Some cancers, the researchers say, are genetically programmed from the start to spread.

Recognizing this genetic predisposition in patients at the time of their diagnosis could improve their chances for survival because it could help physicians make decisions about aggressive treatment.

Adenocarcinoma of the prostate. Courtesy PathWeb, University of Connecticut Health Center

"We need more accurate ways to try to determine at the time of diagnosis who is most at risk for having their cancer spread," says Sridhar Ramaswamy, an oncologist at the Dana-Farber Cancer Institute in Boston who worked on the study.

The researchers identified 128 genes whose activity correlated with the spread of cancer. Using 'gene chips', they analyzed 76 solid tumors, including both metastatic tissue and primary cancers, from the lung, breast, prostate and other organs. Gene chips, or DNA microarrays, are microchips or glass slides arrayed with DNA.

To make the test more manageable, they narrowed the roster of 128 genes to 17 that most strongly correlated with tumor movement. Profiling the activity of these genes allowed the researchers to accurately classify patients whose medical histories were known into groups at high- and low-risk for metastasis.

"The next challenge is to see whether the genetic signature we get from microarray analysis can be refined to the point of having diagnostic utility in individual patients," says Ramaswamy. At the present time, the work is too new to be used with confidence when making treatment decisions.

Isaiah J. Fidler, a cancer biologist at the M.D. Anderson Cancer Center in Houston, calls the study a "wonderful piece of work." Yet Fidler disagrees that metastases arise from genetic pre-programming in the beginning stages of disease.

"Metastases come from rare cells in early tumors," Fidler says. "With progressive disease the proportion of metastatic cells increases," which is why they so closely resemble the main mass. "That's why we advise patients: early diagnosis, early diagnosis, early diagnosis. That's the key."

Genetic signatures are a hot topic among cancer researchers. Last month, scientists in Holland and the United States reported that a cluster of 70 genes could help predict the prognosis of breast cancer patients. Certain signatures are associated with a 50 percent chance of the cancer spreading within a decade, compared to only fifteen percent chance for patients with other genetic signatures. The study appeared in the New England Journal of Medicine.

The hunt for genetic signatures of cancer is "vigorous," says Robert Strausberg, director of the National Cancer Institute's Cancer Genomics Office, in Bethesda, Maryland.

These studies are revealing patterns of gene activity as well as genomic events such as mutations and changes in chromosomes. "The key is to get an integrated view of these changes to find the most informative features of a cancer," says Strausberg.

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Ramaswamy, S. et al. A molecular signature of metastasis in primary solid tumors. Nat Genet 33, 49-54 (January 2003).

van de Vijver, M. et al. A gene-expression signature as a predictor of survival in breast cancer. N Engl J Med 347, 1999-2009 (December 19, 2002).

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