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Progress on cancer gene chip with prognostic potential
Microarray technology may help predict ‘intermediate risk’ outcomes
of diffuse large B-cell lymphoma
By Roberta Friedman

A report earlier this year in Nature detailed how an array of thousands of genes from B cells spotted on a glass microscope slide—dubbed the lymphochip—could distinguish two types of lymphoma cancers and predict their course. New findings reported this month at the meeting of the American Hematology Society suggest that another gene chip, or microarray, may also help doctors develop a prognosis for the cancer.

The genetic 'picture' created by these microarrays can indicate that a patient might benefit more from aggressive therapy than standard chemotherapy. The color-coded pattern of gene activity in tumor cells recorded on the chips can also light the path towards more precise therapies. By identifying the specific pathways involved, you can begin to understand what the problem is in the cancer, says Margaret Shipp, of the Dana Farber Cancer Institute, in Boston. The chip's readout "gets you much closer to the basic cause of the problem."

Shipp says that the technology is moving more rapidly than she anticipated, but that it will take several years before a gene chip for cancer is likely to be available for use in the clinic. National Cancer Institute investigator Lou Staudt is more optimistic. He says the tools are already available for practical use of the technology, albeit scaled down to the clinical setting.

Clinicians have been classifying lymphomas for years based on very simple clinical characteristics, says Shipp, a strategy that was "helpful, but imprecise." For diffuse large B-cell lymphoma, the most common form of non-Hodgkin's lymphoma, a high-risk and low-risk category was defined. Yet intermediate risk categories existed whose outcomes were less certain. The gene chip developed by Shipp and her colleagues has taken this intermediate-risk class and more definitively ascertained a prognosis.

Even before the human genome was completely sequenced and assembled, scientists had put to use admittedly sketchy knowledge of genes active in certain immune cells. With a gene chip incorporating arrays of genes known to function in B cells, Staudt and his collaborators at Stanford University, in California, had shown a potential way to more accurately diagnose cancers arising from these cells.

With their array tuned specifically to lymphocyte biology, the Stanford-NCI group looked at which genes are actively directing protein production in tumor samples from lymphoma patients. Two patterns of gene activity appeared. One pattern correlated with a high chance for surviving five years after treatment, and the other with a poor prognosis.

Based on gene expression, these disease entities are different. Each type of the cancer is probably derived from different normal cell types. The different entities had different clinical courses, with 75 percent of patients with diffuse large B-cell lymphoma resembling one cell type surviving five years; of patients whose cancer likely arose from the other cell type, less than 25 percent survived five years after treatment.

At the meeting, Shipp reported that microarray analysis of tumor specimens from 58 patients with the cancer, who received the chemotherapy standard for the disease, yielded two categories of patients. The patients had very different five-year survival rates—72 percent versus 9 percent. This gene chip uses a more broad-based, general set of human genes, including those implicated in cell division, cell signaling and cell death. The chip monitored the expression of nearly 7,000 genes. Importantly, the chip could separate an intermediate risk category assigned by conventional pathology into cancers that are likely to be cured and those that probably won't respond to certain therapies.

In the low risk group, says Staudt, "one would go with the combination chemotherapy that now exists. The other group, perhaps eligible for an early bone marrow transplant, might get that up front, a therapy that's usually reserved for patients who have failed chemotherapy."

The patterns of gene activity revealed by the color readouts of the chips clearly "can make distinctions...not detected routinely by the standard pathology," says David Botstein, another of the Stanford investigators working with the lymphochip and other gene chips for cancers.

Botstein cites herceptin as an example of how finding precise molecular targets can help cancer patients. Only 20 percent of breast cancers have abundant numbers of the cell surface molecule targeted by the new agent herceptin, "but for those patients, it's a big deal," he says, noting that doctors have to separate out the eligible patients. Botstein adds that gene microarrays give a list of candidate genes whose products could be addressed in the way that herceptin was developed for breast cancer.

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Alizadeh A. et al. Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling. Nature 403, 503-511 (February 03, 2000).

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