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Mismatched Gene Pair May Lead to Cancer

One defective copy may permit certain cancers in mice, study finds

WEDNESDAY, Nov. 14, 2001 (HealthDayNews) -- The mutation of even a single copy of one of a pair of genes at the beginning of the chemical cascade that leads to lymph cancer may be enough to permit various forms of the disease to start, at least in mice, says a new study.

When one of the Dmp1 genes is inactivated, it leads to B-cell lymphoma, even if the other of the pair is normal, and even if a common pair of genes that suppress tumors is normal, say researchers in Tennessee. B-cells come from bone marrow and are one of two antibody-making lymphocytes; 90 percent of cancers of the lymph systems involve B-cells.

The latest study looked at B-cell lymphoma in a strain of mice genetically engineered to make too much of a gene (Myc) that can cause lymphomas and leukemia.

In humans, this Myc gene is linked to a rare and aggressive type of non-Hodgkin's lymphoma. Non-Hodgkin's lymphoma is a group of roughly 30 types of cancers of the lymphatic system that, along with Hodgkin's lymphoma, affects about 87,000 Americans every year.

Half of all human cancers have mutations in a certain gene that suppresses tumors, and the experimental mice often had mutations in this same gene, as well as in another tumor suppressor gene that controls the first gene.

However, these suppressor genes are normal in about a quarter of human lymphomas, and scientists have been searching for what could be responsible for the unchecked growth of these cancers.

Now, a study in the Nov. 15 issue of Genes & Development says a mutation in even a single copy of the Dmp1 gene could be enough to allow lymphoma to develop.

Normally, Dmp1 triggers the gene that sets in motion the tumor-suppressing process.

Senior researcher Dr. Charles Sherr, Howard Hughes medical investigator and tumor cell biologist at St. Jude Children's Research Hospital, in Memphis, says when Dmp1 is mutated, neither tumor suppressing gene is triggered, and that allows cancer cells to flourish.

Sherr says, "The loss of Dmp1 in mice results in the spontaneous appearance of cancers of different types. It shows that Dmp1 is a tumor suppressor."

Sherr says the surprise was that the mice didn't have to lose both copies of the Dmp1 gene to run into problems. "The loss of one copy is sufficient to give you a result," which scientists call haplo-insufficiency, he says.

"It means the probability of losing these genes is higher," says Sherr, since only one copy must be inactivated.

Sherr says several other cancer-related genes have been found to be haplo-insufficient.

In 1998, for example, Dr. James Roberts, another Howard Hughes medical investigator in Seattle, showed that the p27 gene was haplo-insufficient for tumor suppression. P27 appears to be linked to human colon, breast, skin and brain cancers, says Roberts, who is familiar with Sherr's new study

In theory, Roberts says restoring the function of a tumor suppression gene should reverse the cancerous properties of tumor cells. But, in at least in the case of the lymphoma-suppressing genes, it would take gene therapy to reintroduce the normal gene. "There's no good way to do that," he says.

But with haplo-insufficient genes like Dmp1, "the cell still has one normal copy of the gene," says Roberts.

"You can think about ways of using drugs to increase expression of that one normal gene to get the levels back up to where they should be," he says. "That opens new therapeutics avenues and possibilities that aren't available with classic tumor suppressors."

But Roberts says if these findings in mice translate to human genetics, it could be five to 10 years before a drug candidate could be developed and 10 to 15 years before a drug could be clinically available.

Sherr says his team doesn't yet know what triggers the loss of the Dmp1 gene copy.

To better understand Dmp1's role in cancer, Sherr's team is trying to figure out what regulates the gene's activity, and how Dmp1 works under normal circumstances.

What To Do

For a glimpse into the genetics of Burkitt's lymphoma, visit the National Center for Biotechnology Information Web site.

CancerNet, the Lymphoma Research Foundation of America and the American Cancer Society provide information on adult non-Hodgkin's lymphoma. The Lymphoma Information Network also has a fact sheet on B-cell cancers.

SOURCES: Interviews with Charles J. Sherr, M.D., Ph.D., Howard Hughes Medical Investigator, chairman, department of tumor cell biology, St. Jude Children's Research Hospital, Memphis, Tenn.; James M. Roberts, M.D., Ph.D., Howard Hughes Medical Investigator, member, Basic Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, Wash.; Nov. 15, 2001, Genes & Development
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