GermlineNF1Mutational Spectra and Loss-of-Heterozygosity Analyses in Patients with Pheochromocytoma and Neurofibromatosis Type 1
| Autor: | Hartmut P. H. Neumann, Martin K. Walz, Giorgio Arnaldi, Ann Cathrin Koschker, Mercedes Robledo, Oliver Gimm, Birke Bausch, Giuseppe Opocher, Georg Brabant, Jürgen Kohlhase, Tomas Harenberg, Charis Eng, Detlef Boehm, Roland Pfäffle, Felix Lohoefner, Sarah R. McWhinney, Bernhard Kremens, Graham A. MacGregor, Marta Barontini, Nicole Reisch, Michael M. Hoffmann, Stefano Calvieri, Markus G. Mohaupt, Massimo Mannelli, Barbara Jarzab, Alberto Cascón, Victor F. Mautner, Francesca Schiavi, Fausto Palazzo, Andrzej Januszewicz, Rolf D. Klingenberg-Noftz, Wiktor Borozdin, Claudio Letizia, Christian Pawlu, Laurent Brunaud, Ambrogio Fassina, Martin A. Walter, Mariola Pęczkowska |
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| Rok vydání: | 2007 |
| Předmět: |
Adult
Male congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Neurofibromatosis 1 Adolescent Genotype endocrine system diseases Endocrinology Diabetes and Metabolism Clinical Biochemistry Medizin Loss of Heterozygosity Pheochromocytoma Severity of Illness Index Biochemistry Germline Loss of heterozygosity Endocrinology Germline mutation Internal medicine medicine Humans Genetic Predisposition to Disease Allele Neurofibromatosis neoplasms Germ-Line Mutation Aged Genetics Neurofibromin 1 biology business.industry Biochemistry (medical) Middle Aged medicine.disease eye diseases nervous system diseases biology.protein Female business |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 92:2784-2792 |
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/jc.2006-2833 |
| Popis: | BACKGROUND: Neurofibromatosis type 1 (NF1) is a pheochromocytoma-associated syndrome. Because of the low prevalence of pheochromocytoma in NF1, we ascertained subjects by pheochromocytoma that also had NF1 in the hope of describing the germline NF1 mutational spectra of NF1-related pheochromocytoma. MATERIALS AND METHODS: An international registry for NF1-pheochromocytomas was established. Mutation scanning was performed using denaturing HPLC for intragenic variation and quantitative PCR for large deletions. Loss-of-heterozygosity analysis using markers in and around NF1 was performed. RESULTS: There were 37 eligible subjects (ages 14-70 yr). Of 21 patients with corresponding tumor available, 67% showed somatic loss of the nonmutated allele at the NF1 locus vs. 0 of 12 sporadic tumors (P = 0.0002). Overall, 86% of the 37 patients had exonic or splice site mutations, 14% large deletions or duplications; 79% of the mutations are novel. The cysteine-serine rich domain (CSR) was affected in 35% but the RAS GTPase activating protein domain (RGD) in only 13%. There did not appear to be an association between any clinical features, particularly pheochromocytoma presentation and severity, and NF1 mutation genotype. CONCLUSIONS: The germline NF1 mutational spectra comprise intragenic mutations and deletions in individuals with pheochromocytoma and NF1. NF1 mutations tended to cluster in the CSR over the RAS-GAP domain, suggesting that CSR plays a more prominent role in individuals with NF1-pheochromocytoma than in NF1 individuals without this tumor. Loss-of-heterozygosity of NF1 markers in NF1-related pheochromocytoma was significantly more frequent than in sporadic pheochromocytoma, providing further molecular evidence that pheochromocytoma is a true component of NF1. |
| Databáze: | OpenAIRE |
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