New research has found the gene responsible for Peutz-Jeghers syndrome, a rare inherited disorder that can lead to cancer in many different organs. Unexpectedly, the work may also have uncovered a new category of tumor-suppressor genes.

People born with Peutz-Jeghers syndrome typically develop precancerous polyps in the intestines in their teen years or later and have freckle-like spots on the lips, around the mouth, and on the fingers. These individuals are also at a higher risk for a variety of cancers, including those of the intestine, breast, pancreas, testis, and ovary, said Albert de la Chapelle, director of the Human Cancer Genetics Program at Ohio State University’s Comprehensive Cancer Center and a coauthor of the study.

The research, published in the January issue of Nature, will likely lead to a test that can be used to unequivocally diagnosis individuals with Peutz-Jeghers syndrome and detect family members who carry the gene.

In addition, it may lead to a better understanding of how some cancers develop. “The more difficult, but in many ways more interesting, part of this story relates to how changes in this gene lead to cancer,” said de la Chapelle.

“This is the way things often go when you’re looking for genes. You begin with a condition, and you have no idea what sort of a gene causes it. So you map the gene’s location on a chromosome and clone it, and then you find out what it does. Quite often, the function of the gene is very surprising.”

In this study, de la Chapelle and colleagues studied 12 individuals with Peutz-Jeghers syndrome. By examining cells from polyps removed from a single patient, the researchers were able to map the location of the gene to the tip of the short arm of chromosome 19. With the gene identified, further study revealed a number of mutations that disabled it.

New Gene Produces Protein Kinase
A gene that leads to cancer when it is disabled is known as a tumor-suppressor gene. Tumor-suppressor genes work by producing a protein that helps prevent run-away cell division. If the gene is damaged and the protein fails to work properly, uncontrolled cell proliferation—and cancer—can occur.

Initially, de la Chapelle and the other members of the research team had no idea what kind of protein the undamaged Peutz-Jeghers syndrome gene produced or what role that protein played in the cell.

By comparing the structure of the Peutz-Jeghers syndrome gene with already known genes, however, they were startled to find that the Peutz-Jeghers syndrome gene produces a type of enzyme known as a protein kinase. “This surprised us,” said de la Chapelle. “As far as we know, this is the first time a protein kinase gene has been identified as a tumor-suppressor gene.”

Cells have genes for many types of protein kinase enzymes, and some of these enzymes do play a role in causing cancer. In those cases, however, cancer rises because the genes produce too much of the enzyme.

In Peutz-Jeghers syndrome, on the other hand, cancer seems to occur because a protein kinase is not produced.

More Study Needed
“As of now,” said de la Chapelle, “we have no clue as to how the loss of this gene might lead to cancer. That work will require many experiments to learn what other proteins this protein interacts with and how this particular gene might fit into one of the cancer-producing pathways.

“The intriguing thing here is that this unusual disorder is characterized by the occurrence of polyps in the intestine that are often premalignant, and by the presence of peculiar freckle-like spots on the lips and the skin around the mouth and on the fingers. How these two relate to each other is absolutely unknown.”

Furthermore, he said, “the combination of tumors that can occur with this syndrome really gives no clue to what’s going on. That is truly intriguing.”

The work on Peutz-Jeghers syndrome continues in de la Chapelle’s laboratory with studies that he hopes will reveal how mutations in the Peutz-Jeghers syndrome gene predispose an individual to cancer.