May 9, 2002 New research suggests inherited genetic mutations play a larger role than previously thought in the development of a rare form of adrenal cancer - findings that offer important implications for clinical practice management in the future.
Pheochromocytomas are unusual cancers of the adrenal gland that are popularly referred to as “10 percent tumors” because it is widely believed they have several characteristics that show up about 10 percent of the time. For example, only about 10 percent of pheochromocytomas are malignant. About 10 percent of them occur in children. In roughly 10 percent of cases, the tumors will appear in both adrenal glands. Ten percent of pheochromocytoma patients will have a family member who has the same type of tumor, and, in 10 percent of patients, pheochromocytomas are hereditary, occurring in conjunction with unusual endocrine disease syndromes.
“Not so fast,” says Dr. Charis Eng, director of the Clinical Cancer Genetics Program at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute. Eng, leading a large team of researchers, just completed a study of 271 patients with pheochromocytomas or related tumors called paragangliomas, and concluded that the inherited fraction of pheochromocytoma patients may be a lot closer to 25-30 percent than 10 percent.
The findings appear in the May 9 issue of the New England Journal of Medicine.
The study involved painstaking detective work over 6 years by an international team of investigators utilizing tumor registries in Poland and Germany.
Members of the research team reviewed each patient’s medical record for a complete understanding of the clinical data. They then obtained blood samples from each patient, and using two sophisticated systems of genetic identification - analysis of single strand conformation polymorphisms (SSCP) and direct sequencing – pinpointed mutations in one of four genes that had previously been found to be associated with the development of pheochromocytoma.
They discovered 24 percent of the individuals carried one or more mutations, with some mutations significantly more widespread than others. They found mutations in the VHL gene in 30 individuals, mutations in the RET gene in 13 people, mutations in the SDHB gene in 12 individuals and mutations in the SDHD gene in 11 individuals.
“This is truly significant,” says Eng. “From all outward observation, none of these patients would have been identified as having any inherited disposition toward developing pheochromocytomas because they had no family history of other tumors and no other personal medical history. More importantly, at least for the patients, our data suggest the precise gene involved affects how the patient and family should be treated and screened in the future.”
Eng says individuals with the genetic mutations tended to reveal symptoms of the disease at an earlier age. Seventy percent of the patients who had symptoms in the first 10 years of life had genetic mutations, with the percentage decreasing steadily to 0 percent after age 60. Of the 139 registrants demonstrating symptoms after age 40, only 8 percent were found to have mutations.
In addition, patients with genetic mutations tended to have more than one tumor, and it appears that multiple tumors may be linked to specific genetic mutations.
“We found, for example, that no one with SDHB mutations had tumors at multiple sites, but 40 percent of those with VHL mutations did,” says Eng.
Eng says specific genetic profiles are also associated with later development of concurrent tumors. “For example, if an individual with pheochromocytoma were found to have a mutation in SDHD instead of VHL, that tells the clinician to watch out for glomus tumors - growths that can appear on the carotid arteries, and, when large, are very difficult to treat.”
The research findings appear to add more evidence to the need for systematic gene testing for all pheochromocytoma patients because understanding the genetic component of the disease can lead to better patient management. Pheochromocytomas are difficult to diagnose, and because they often involve overproduction of adrenalin, they can cause life-threatening spikes of high blood pressure as well as strokes. “The more we find out about this disease, the better. We believe that if this data can be replicated, then the practice of clinical cancer genetics will be altered,” says Eng.
The research project is supported by grants from the Center of Clinical Research of the Albert-Ludwigs University, the Deutsche Forschungsgemeinschaft, the Polish Committee of Scientific Research and the National Institutes of Health.
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