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In 1987, Raul Ribeiro, MD, finished his postdoctoral training at St. Jude Children’s Research Hospital and returned to his home in Brazil. During his St. Jude fellowship, Ribeiro had treated children with many types of cancer. But when he returned to Curitiba, several of his young Brazilian patients had a kind of cancer he had not encountered during the years he spent in Memphis.
The Brazilian children had adrenocortical carcinoma (ACC), a rare tumor that grows on the adrenal gland located at the top of the kidneys. “Children with ACC were coming to me in large proportions,” says Ribeiro, who has been director of the St. Jude International Outreach program since 1997. “In three years at St. Jude, I hadn’t seen any ACC cases. I was seeing six or seven in this small part of Brazil in just one year. I thought to myself, I know there is something abnormal here.”
In southern Brazil, the incidence of ACC is 10 to 15 times higher than in other parts of the world. At first, Ribeiro thought that the most likely explanation for the ACC prevalence was Li-Fraumeni syndrome. Members of families with this syndrome have an especially high risk of developing many kinds of cancer. But after conducting careful clinical histories of Brazilian patients with ACC, Ribeiro found that the families did not have histories of cancer. In 1990, he sent tumor and blood samples to St. Jude to test the function of a tumor suppressor gene called p53.
When cells grow, develop, complete their mission in the body and die, they are controlled by several proteins and genetically determined pathways. One of these regulators is the tumor suppressor gene p53, which regulates cell survival and death. “In general, p53 is present in all cells controlling growth, development and cell fate,” Ribeiro explains. A mutation in the p53 gene increases the likelihood of having ACC. The tests at St. Jude showed the p53 function was normal. “Nobody believed that we had a p53 mutation,” says Ribeiro.
“I had two strikes against me,” he continues, “but we sequenced the p53 gene in 1994 just to make sure.” They subsequently discovered that a p53 gene mutation had occurred after all, but that it had occurred on a new location on the DNA. “Ninety percent of the mutations occur in the DNA binding domain, so people have not traditionally bothered to look at the outside areas,” says Gerard Zambetti, PhD, of Biochemistry. This mutation had occurred outside of that binding domain.
With the new information, Ribeiro and Zambetti called Richard Kriwacki, PhD, of Structural Biology. In 1999 the three men began collaborating to develop a genetic explanation for the specific type of ACC occurring in the children of Curitiba. Kriwacki identified a previously unknown defect in the structure of the p53 protein that made it fall apart at certain pH levels, ultimately leading to the onset of ACC. The collaborators published their findings in the journal Nature Structural Biology in 2002, and are continuing to follow up with more studies of the p53 protein.
“One of the unique features of this particular case is that very often when people have mutations to p53, they develop a wide variety of different cancers,” Kriwacki says. “In this particular case, the mutation is associated with one type of cancer. By looking at this mutation, we have an opportunity to get clearer insights into the molecular pathways leading to the development of cancer.”
Researchers at St. Jude are closing in on a probable explanation for the tumor development. “There is a pH-dependent defect in the mutant protein,” Kriwacki explains. “So, it suggests that in adrenal cells during early development, certain changes—best described as cellular remodeling—occur in the adrenal gland. This remodeling may cause the environment to be slightly basic or may elevate temperature slightly. There has to be something special about the adrenal gland to explain why only these cells develop into tumors.”
“The p53 protein consists of 393 amino acids,” Zambetti adds. “Change just one and you get adrenal cancer. That’s what’s remarkable about this mutation.”
The p53 mutation identified by the St. Jude team increases children’s chance of developing adrenal cancer—and only adrenal cancer—by 300,000 fold, according to Zambetti. “This is the first inherited p53 mutation that gives rise to a specific tumor type,” he says. Zambetti and his colleagues are currently exploring the possibility that another p53 mutation outside of the DNA binding domain may be responsible for a rare form of brain tumor that seems to have an inherited component. “We don’t have an answer yet to this specific case, but we’re working on it,” he says.
The information gleaned from St. Jude researchers is helping clinicians already. Physicians in Curitiba are now more alert to the symptoms of ACC and can detect them earlier than they could in the past. “Now that they know there’s a genetic link, they’re tracking all of the children in these families that have the mutation,” Kriwacki says. For the past two years, children at risk for adrenocortical carcinoma in Curitiba have been screened and monitored regularly for early symptoms of the disease.
Physicians have used the new information to develop treatment plans and a screening method. They closely observe ACC patients’ siblings to see if they exhibit signs of cancer; if symptoms occur, they begin treatment immediately. “We now have more than 70 patients we are following who have tested positive for a mutation but have not developed the cancer yet,” Ribeiro says. Staff members at the clinic in Curitiba have seen more than 100 patients with ACC.
The St. Jude researchers have been working closely with Bonald Figueiredo, MD, PhD, of the Center for Molecular Genetics and Cancer Research in Brazil. The discovery linking a p53 mutation with ACC has helped Figueiredo and his staff identify the mutation in many relatives of ACC patients. “The most important contribution of this research is the possibility of a cure we can now offer to children who test positive for the mutation but do not have ACC and who are enrolled in our surveillance program,” says Figueiredo, who has tested more than 600 individuals for the mutation. Figueiredo says he believes that ACC-related deaths will decrease because of the new surveillance program.
Figueiredo says the infrastructure of his institution has improved through association with St. Jude, and he cites numerous scientific and training opportunities that have resulted from the involvement. Videoconferencing has been one important window of research communication between St. Jude and Brazilian researchers. By using video technology, the colleagues can collaborate almost as easily as if they were sitting in a room together. Ribeiro also shares his expertise in person and on the phone. He travels to Curitiba twice a year to visit the center and give lectures. And physicians from around the world frequently call him for consults about their patients who have ACC.
Ribeiro says researchers are now exploring why ACC is prevalent in such a small area of the world. “The region in Brazil in which this is frequent is not the entire Brazilian area,” Ribeiro says. “We are trying to see if we can figure out if there are environmental or other reasons for the prevalence.”
Carlos Rodriguez-Galindo, MD, of St. Jude Hematology-Oncology is also leading an effort to create a multi-institutional protocol with the Children’s Oncology Group for children in both the United States and Curitiba who have ACC. In addition to treating children with this rare tumor, researchers will study the biology of the tumors and the incidence of the different types of p53 mutations, identifying any similarities or differences that appear in patients from each country. Rodriguez-Galindo predicts that the protocol will begin sometime in 2003, and may eventually expand to include children from other areas of southern Brazil, as well.
Joining forces, saving lives
A child in Paris, France, was recently found to have the mutated p53 gene, so researchers suspect that the problem may extend far beyond the geographical boundaries of southern Brazil. As St. Jude researchers expand their focus to look outside the DNA binding domain, they may find that the mutation occurs more frequently than they had expected. To address this possibility, St. Jude has established an International Pediatric Adrenal Tumor Bank, which allows researchers to access samples from around the world and screen them for p53 mutations and other genetic alterations.
By collaborating to attack a problem, researchers in the International Outreach program, the Hartwell Center for Bioinformatics and Biotechnology and other St. Jude departments are ensuring a brighter future for Brazilian children with adrenocortical carcinoma. Zambetti is pleased that interdisciplinary teamwork can have such far-reaching consequences. “Our work is making a difference,” he says. “All through my graduate training and postdoctoral work, my research has been focused on trying to figure out how things work using cell lines we can grow in the lab. Going from growing cell lines to actually helping kids...that’s the most rewarding part.”
Translational research—the ability to move discoveries from the laboratory to the bedside—is one of the hallmarks of St. Jude. In unraveling the p53 mystery, researchers and clinicians have shown how collaborations can save the lives of children in other parts of the globe who may never even know about St. Jude Children’s Research Hospital.
“This project is sort of amazing not only in the scientific sense, but because it really exemplifies the mission of the hospital,” Kriwacki says. “The full resources of this institution have been brought to bear on the basic understanding of the origins of the disease and the effort on how to cure diseases better in the future. It’s really been an amazing opportunity.”
Reprinted from spring 2003 Promise magazine