FP/MEM127 MUTATIONS ASSOCIATED WITH PHEOCHROMOCYTOMAS

December 16, 2010 — An international collaborative study investigating the prevalence and genetic association of FP/TMEM127 mutations with chromaffin cell tumors has found an association with pheochromocytomas, but not with paragangliomas. The mutations cause abnormal intracellular distribution of the protein encoded by the gene.

The report, published online December 15 in the Journal of the American Medical Association, also noted that germline mutations of FP/TMEM127 are present in patients in their 40s — an age not commonly included in genetic screenings associated with the diagnosis.

"Fortunately, the tumors are benign, in most cases, and can be cured by surgical removal of the adrenal when appropriately identified," said senior author Patricia L.M. Dahia, MD, PhD, from the Department of Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, in an email to Medscape Medical News.

The tumors are easily found using the appropriate tests, but they often may not be considered as a likely diagnosis. "Many cases still go undiagnosed for years, and patients suffer the harmful effects of high adrenaline (which can affect heart and kidney function if left undetected) before they get appropriate treatment," said Dr. Dahia.

"The tumors can also be malignant in 10% to 15% of the cases, and those spread to other organs," Dr. Dahia added. "Although these cases can be treated, cure rates are very limited with the current methods of treatment."

Both pheochromocytomas and paragangliomas involve chromaffin cells (which develop from neural crest cells) and affect the adrenal medulla or other sympathetic paraganglia, respectively. Tumors of both types also often secrete catecholamines. Several genetic associations have already been identified but did not explain the molecular causes of most of these tumors.

The new study grew from previous work showing that TMEM127 was the gene of interest in a chromosome 2 locus associated with familial pheochromocytoma (FP). Germline mutations of FP/TMEM127 were present in patients with familial pheochromocytomas and in patients with sporadic pheochromocytomas, suggesting a tumor-suppressor role for the wild-type gene.

The investigators obtained samples from international sources from 990 patients with pheochromocytomas and paragangliomas who lacked mutations in other genes associated with these diseases. Diagnoses had been made by "conventional procedures" and were confirmed by histology. DNA was isolated from blood samples or from tumor tissue. Control samples were obtained from similarly international, multiethnic populations.

Analysis identified 44 variants of FP/TMEM127. Germline mutations were found only in patients with pheochromocytomas, with mutated tumors arising only from the adrenal medulla; subsequent statistical studies involved only this population.

In vitro studies were also performed, using clones that carried some of the novel substitution mutations found, to assess their effects on intracellular distribution of the mutant protein. Distribution patterns were classified as wild-type (punctate) or diffuse. In addition, 3 types of prediction software were used to evaluate variants' potential for pathogenicity, based on the effect of amino acid substitutions or sites for initiation of translation on protein structure and function. Overall, 19 mutations were regarded as potentially pathogenic.

The mean age at which tumors withFP/TMEM127 mutations developed was 42.8 years (range, from 20 years to the mid-70s). The age of onset is similar to that of patients with pheochromocytoma with nonmutated or sporadic occurrence of the disease (43.2 years and 47.01 years, respectively). However, patients with hereditary pheochromocytomas caused by other genes typically develop the disease earlier.

"Our study suggests that patients who were considered either due to their age (40s or older) or clinical presentation (single tumor, as opposed to bilateral tumors) to carry a sporadic, nonfamilial tumor, may in fact have a hereditary form of the disease," observed Dr. Dahia. "This suggests that any individual with pheochromocytoma could potentially be a mutation carrier, and this has implications for family members also."

Asked about the clinical application of the study: "We propose that sporadic-appearing cases should also be screened," Dr. Dahia said. "This is likely to require independent confirmation by other groups and patients series, but our findings are a strong indicator that genetic screening will need to become routine in these tumors."

Support for the study came from University of Texas Health Science Center at San Antonio, the National Cancer Institute, the National Institute of Aging, and the Fundacão Faculdade de Medicina, Division of Endocrinology. Study authors received grant funding from São Paulo State Research Foundation, Cancer Research United Kingdom, Interuniversity Attraction Poles of the Belgian Federal Science Policy, the Italian University and Research Ministry, Fondazione della Comunita Bresciana, Conselho Nacional de Desenyolyimento Científico e Tecnológico, Fondo do Investigaciones Sanitarias, Fundacion Mutua Madrilena, the Voelcker Fund, Alex’s Lemonade Stand Foundation, Concern Foundation, and National Institutes of Health Clinical Translational and Sciences Award; otherwise, the authors have disclosed no relevant financial relationships.

JAMA. 2010;304:2611-2619. Abstract