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Germline NF1 Mutational Spectra and Loss-of-Heterozygosity Analyses in Patients with Pheochromocytoma and Neurofibromatosis Type 1

Departments of Nephrology (B.B., D.B., T.H., C.P., H.P.H.N.) and Laboratory Medicine (M.M.H.), University Medical Center Freiburg, D-79106 Freiburg, Germany; Institute for Human Genetics and Anthropology (W.B., J.K.), University of Freiburg, Freiburg, Germany; Center of Human Genetics (W.B., J.K.), Freiburg, Germany; Department of Maxillofacial Surgery (V.F.M.), University Hospital Eppendorf, Hamburg, Germany; Hereditary Endocrine Cancer Group (M.R., A.C.), Centro Nacional de Investigaciones Oncologicas, Madrid, Spain; Istituto Oncologico Veneto Instituto di Ricovero e Cura a Carattere Scientifico (F.S., G.O.), Padova, Italy; Department of Hypertension (M.P., A.J.), Institute of Cardiology, Warsaw, Poland; Departments of Clinical Sciences (C.L.) and Dermatology (S.C.), University of Rome La Sapienza, Rome, Italy; Department of Endocrinology (G.A.), Azienda Ospedaliero-Universitaria Ospedali Riuniti di Ancona, Ancona, Italy; Medical Clinic I (R.D.K.-N.), Universitätsklinikum Schleswig-Holstein, Campus Lübeck, Lübeck, Germany; Department of Endocrinology (N.R.), Ludwig-Maximilians-University of Munich, Munich, Germany; Department of Pathology (A.F.), University of Padova, Padova, Italy; Department of Digestive and Endocrine Surgery (L.B.), University Hospital Nancy, University of Nancy, Nancy, France; Institute of Nuclear Medicine (M.A.W.), Division of Endocrinology, University of Basel, Basel, Switzerland; Department of Clinical Pathophysiology, Endocrine Unit (M.Ma.), University of Florence, Florence, Italy; Blood Pressure Unit (G.M.), Department of Cardiovascular Sciences, St. George’s University, London, United Kingdom; Endocrine Surgery Unit (F.F.P.), Hammersmith Hospital, London, United Kingdom; Centro de Investigaciones Endocrinologicas-Consejo Nacional de Investigaciones Científicas y Técnicas (M.B.), Buenos Aires, Argentina; Department of Surgery (M.K.W.), Kliniken Essen-Mitte, Essen, Germany; Department of Pediatrics (B.K.), University of Essen, Essen, Germany; Department of Endocrinology (G.B.), Medizinische Hochschule, Hannover, Germany; Department of Pediatrics (R.P.), University of Leipzig, Leipzig, Germany; Department of Internal Medicine I-Endocrine and Diabetes (A.-C.K.), University of Wuerzburg, Wuerzburg, Germany; Department of Surgery (F.L.), Hospital of the German Red Cross, Berlin, Germany; Department of Nephrology and Hypertension (M.Mo.), University of Berne, Berne, Switzerland; Department of Visceral Surgery (O.G.), University of Halle, Halle, Germany; Department of Nuclear Medicine and Endocrine Oncology (B.J.), M. Sklodowska-Curie Memorial Cancer Centre and Institute of Oncology, Gliwice, Poland; Genomic Medicine Institute (S.R.M., C.E.), Cleveland Clinic Foundation, Cleveland, Ohio 44195; and Department of Genetics (S.R.M., C.E.), Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

Address all correspondence and requests for reprints to: Hartmut P. H. Neumann, Medizinische Universitätsklinik, Hugstetter Straße 55, D-79106 Freiburg, Germany. E-mail: neumann{at}med1.ukl.uni-freiburg.de.

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.

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