University Of Iowa Researchers Identify A Genetic Cause Of Juvenile Polyposis

The research team, which also included researchers from the Johns Hopkins Oncology Center in Baltimore, Md., and the Mayo Clinic in Rochester, Minn., was led by James R. Howe, M.D., UI associate professor of surgery. The findings are published in the June issue of the journal Nature Genetics.

The gene, which codes for a protein called bone morphogenetic protein receptor 1A (BMPR1A) is the second gene identified as causing JP. The other gene was also discovered by Howe and his colleagues three years ago. Taken together, mutations in either of these genes account for nearly half of the cases of JP.

BMPR1A is a receptor protein in cellular processes mediated by bone morphogenetic proteins (BMPs), molecules that stimulate bone growth. This study provides evidence of a new role for BMPs and is the first to demonstrate a BMP pathway's specific effect on cells in the intestine.

"I think this report will lead to increased interest in this particular pathway and how it mediates gastrointestinal and other cancers," Howe said.

Most polyps of the colon are abnormalities in the cells that line the colon. In JP polyps, the abnormal cells lie just below the cells lining the colon. A more complete understanding of how JP works could lead to a better understanding of a new mechanism of cancer formation where cancers develop because of abnormalities in an adjacent tissue layer.

"If we can understand how these polyps and cancers develop in JP, it may expose a whole new mechanism by which a subset of colon cancer in the rest of the population might form," Howe said. "This understanding might also suggest new targets for therapy and for diagnosis."

Identifying genetic causes of a disease also provides physicians with a better way to screen patients who have a family history of the disease before telltale symptoms appear.

"It is very helpful to be able to pay more attention to those people with the genetic mutation for JP who are at high risk for developing cancer," Howe said. "Also, it is reasonable to substantially reduce expensive and uncomfortable screening for those people who don't have the mutation."

"In this condition, colorectal cancer can be prevented by screening and aggressive removal of polyps," Howe added.

Howe also emphasized the important role of genetic counselors, both in referring the patients to his study and for providing genetic counseling to patients with JP.

"We work closely with the genetic counselors to inform the family members of our findings, to provide information about the disease and to provide genetic testing for those who want to know if they have the mutation."

Howe and his colleagues tracked down the gene using genetic linkage studies, which compare the inheritance of specific DNA markers from different chromosomes with the inheritance of the disease among families. The researchers looked at many markers and zeroed in on a region on chromosome 10 as the home of the gene they were chasing.

"These studies are impossible to do unless you have large families," Howe said. "We had four families that were large enough to study by genetic linkage."

Howe and his colleagues were further aided in their search by the work of the Human Genome Project, which has identified the location of many human genes within the human genome.

"This enormous undertaking has allowed us to be able to examine lists of genes mapping to a region and see if there are candidates which could be likely culprits," Howe said.

In fact, that is what happened in this case. One of the genes listed was BMPR1A, which is a cousin of the gene that Howe had identified three years earlier as a cause of JP.

The researchers sequenced the new gene from each of the family members and discovered mutations in those people who had JP and no mutations in those who did not have the disease. Each family had a different mutation but the end result was the same, a shortened protein that could not do its job in the BMP biochemical pathway.

However, mutations in this gene and in the gene identified in 1998 do not cover all the cases of JP. Howe plans to continue searching for genes that cause this disease.

"There is another Iowa family that is large enough for linkage analysis who don’t have mutations in either of the two identified genes," Howe said. "They might represent the large group of JP patients who just have polyps in the colon. If we're lucky, a single gene will explain these remaining cases."

The researchers also plan to develop a mouse model for JP. The mice will be used to pursue genetic linkage studies and look at gene expression patterns. The mouse model could also provide a useful system to test pharmacological agents designed to treat JP or even colon cancer.

Howe is a surgical oncologist as well as a bench scientist studying the genetics of JP. He believes that treating patients with JP gives him a unique insight into this disease. Not only does it spur him to find effective treatments, but it also leads him to new ideas about how the disease works, ideas that can be tested and pursued in the lab.

UI researchers in Howe's lab who were authors on the study included Jennifer A. Bair, Mohamed G. Sayed, M.D., Mary E. Anderson, and Frank A. Mitros, M.D., UI professor of pathology. Howe's external collaborators were Gloria M. Petersen, Ph.D., Mayo Clinic, Rochester, Minn., and Bert Vogelstein, M.D., professor of oncology, Johns Hopkins Oncology Center, Baltimore, Md. Victor E. Velculescu, M.D., Ph.D., and Giovanni Traverso, researchers in Vogelstein's lab were also authors on the paper.

The research was funded in part by grants from the Roy J. Carver Charitable Trust, the American College of Surgeons Owen H. Wangensteen Faculty Research Fellowship, the National Institutes of Health and the Clayton Fund.