Correspondence

Somatic SDHB Mutation in an Extraadrenal Pheochromocytoma

N Engl J Med 2007; 357:306-308July 19, 2007

Article

To the Editor:

As many as 25% of pheochromocytomas — catecholamine-producing tumors located along the sympathetic nervous system, including the adrenals — occur in hereditary tumor syndromes that include von Hippel–Lindau disease (VHL gene),1 multiple endocrine neoplasia type 2 (RET gene), neurofibromatosis type 1 (NF1 gene), and the pheochromocytoma–paraganglioma syndrome (SDHB and SDHD genes). The last two genes are also associated with extraadrenal pheochromocytoma.2,3 To date, except for one sporadic SDHD mutation, only germ-line mutations in SDHB and SDHD have been described, even among reported mutations in these genes in apparently sporadic pheochromocytomas and paragangliomas.4,5

We present a case of a 25-year-old woman with an extraadrenal pheochromocytoma in the wall of her urinary bladder. Mutational analysis of the pheochromocytoma candidate genes RET, VHL, SDHB, and SDHD was performed in tumor and normal DNA present in the same tissue specimen. (The NF1 gene was not investigated, since the patient had no clinical signs of neurofibromatosis type 1 disease.) A single aberration was found: an SDHB 299C→T transition in tumor DNA but not in the patient's normal DNA (Figure 1A and 1BFigure 1Molecular and Immunohistochemical Results.). This finding was confirmed by allelotyping the DNA samples and repeating the entire procedure, starting with the isolation of DNA from tumor and normal tissue. This somatic SDHB gene mutation results in a substitution of phenylalanine for serine at position 100 (S100F). Functional consequences of the S100F mutation can be anticipated, given the large physical differences between the two amino acids: substitution of a nonpolar side chain (F) for an uncharged polar side chain (S). In addition, the region of the SDHB gene that includes the S100F mutation is highly conserved at the protein level. Moreover, an SDHB germ-line missense mutation of the S100 neighboring amino acid (C101Y) has been described in a patient with an extraadrenal pheochromocytoma.1

From the sequence analysis of the tumor DNA, it is apparent that the mutated allele is in excess of the wild-type allele (Figure 1A), indicating amplification of the mutated allele or loss of the wild-type allele. Comparative genomic hybridization, loss of heterozygosity of the SDHB locus (Figure 1C), and chromosome 1p fluorescence in situ hybridization all showed the loss of one 1p allele. These findings point to the biallelic inactivation of SDHB in this tumor: the mutation of one SDHB allele and the loss of the second SDHB allele. In addition, we found that there was an absence of SDHB expression in tumor cells, indicating complete loss of SDHB function (Figure 1D and 1E).

We think it is likely that the somatic S100F mutation played a causal role in the tumorigenesis of the extraadrenal pheochromocytoma. Our findings suggest that the SDHB gene not only plays a role in the pathogenesis of a subgroup of inherited pheochromocytomas but also can be involved in a subgroup of truly sporadic pheochromocytomas.

Francien H. van Nederveen, M.D.
Esther Korpershoek, B.Sc.
Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands

Jacques W.M. Lenders, M.D., Ph.D.
Radboud University Medical Center Nijmegen, 6525 GA Nijmegen, the Netherlands

Ronald R. de Krijger, M.D., Ph.D.
Winand N.M. Dinjens, Ph.D.
Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands
w.dinjens@erasmusmc.nl

Supported by the Netherlands Organisation for Health Research and Development, the Dutch Cancer Society, and Vanderes Foundation.

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Citing Articles (11)

Citing Articles

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   J. Welander, P. Soderkvist, O. Gimm. (2011) Genetics and clinical characteristics of hereditary pheochromocytomas and paragangliomas. Endocrine Related Cancer 18:6, R253-R276
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   Chiara Bardella, Patrick J. Pollard, Ian Tomlinson. (2011) SDH mutations in cancer. Biochimica et Biophysica Acta (BBA) - Bioenergetics 1807:11, 1432-1443
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   Christian Frezza, Patrick J Pollard, Eyal Gottlieb. (2011) Inborn and acquired metabolic defects in cancer. Journal of Molecular Medicine 89:3, 213-220
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   Despoina Alataki, A. Triantafyllidis, José Gaal, C. Rodiou, J. Vouros, A. Papathanasiou, A. Papanicolaou, V. Rombis, Ronald R. Krijger. (2010) A non-catecholamine-producing sympathetic paraganglioma of the spermatic cord: the importance of performing candidate gene mutation analysis. Virchows Archiv 457:5, 619-622
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   Anthony J. Gill, Diana E. Benn, Angela Chou, Adele Clarkson, Anita Muljono, Goswin Y. Meyer-Rochow, Anne Louise Richardson, Stan B. Sidhu, Bruce G. Robinson, Roderick J. Clifton-Bligh. (2010) Immunohistochemistry for SDHB triages genetic testing of SDHB, SDHC, and SDHD in paraganglioma-pheochromocytoma syndromes. Human Pathology 41:6, 805-814
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   Jean-Pierre Bayley, Henricus PM Kunst, Alberto Cascon, Maria Lourdes Sampietro, José Gaal, Esther Korpershoek, Adolfo Hinojar-Gutierrez, Henri JLM Timmers, Lies H Hoefsloot, Mario A Hermsen, Carlos Suárez, A Karim Hussain, Annette HJT Vriends, Frederik J Hes, Jeroen C Jansen, Carli M Tops, Eleonora P Corssmit, Peter de Knijff, Jacques WM Lenders, Cor WRJ Cremers, Peter Devilee, Winand NM Dinjens, Ronald R de Krijger, Mercedes Robledo. (2010) SDHAF2 mutations in familial and sporadic paraganglioma and phaeochromocytoma. The Lancet Oncology 11:4, 366-372
   CrossRef

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   B.-J. Petri, C. H. J. van Eijck, W. W. de Herder, A. Wagner, R. R. de Krijger. (2009) Phaeochromocytomas and sympathetic paragangliomas. British Journal of Surgery 96:12, 1381-1392
   CrossRef

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   Francien H van Nederveen, José Gaal, Judith Favier, Esther Korpershoek, Rogier A Oldenburg, Elly MCA de Bruyn, Hein FBM Sleddens, Pieter Derkx, Julie Rivière, Hilde Dannenberg, Bart-Jeroen Petri, Paul Komminoth, Karel Pacak, Wim CJ Hop, Patrick J Pollard, Massimo Mannelli, Jean-Pierre Bayley, Aurel Perren, Stephan Niemann, Albert A Verhofstad, Adriaan P de Bruïne, Eamonn R Maher, Frédérique Tissier, Tchao Méatchi, Cécile Badoual, Jérôme Bertherat, Laurence Amar, Despoina Alataki, Eric Van Marck, Francesco Ferrau, Jerney François, Wouter W de Herder, Mark-Paul FM Vrancken Peeters, Anne van Linge, Jacques WM Lenders, Anne-Paule Gimenez-Roqueplo, Ronald R de Krijger, Winand NM Dinjens. (2009) An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. The Lancet Oncology 10:8, 764-771
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   B. Pasini, C. A. Stratakis. (2009) SDH mutations in tumorigenesis and inherited endocrine tumours: lesson from the phaeochromocytoma-paraganglioma syndromes. Journal of Internal Medicine 266:1, 19-42
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    Jens Waldmann, Peter Langer, Nils Habbe, Volker Fendrich, Anette Ramaswamy, Matthias Rothmund, Detlef K. Bartsch, Emily P. Slater. (2009) Mutations and polymorphisms in the SDHB, SDHD, VHL, and RET genes in sporadic and familial pheochromocytomas. Endocrine 35:3, 347-355
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    Umasuthan Srirangalingam, Lisa Walker, Bernard Khoo, Fiona MacDonald, Daphne Gardner, Terence J. Wilkin, Robert H. Skelly, Emad George, David Spooner, John P. Monson, Ashley B. Grossman, Scott A. Akker, Patrick J. Pollard, Nick Plowman, Norbert Avril, Daniel M. Berney, Jacky M. Burrin, Rodney H. Reznek, V.K. Ajith Kumar, Eamonn R. Maher, Shern L. Chew. (2008) Clinical manifestations of familial paraganglioma and phaeochromocytomas in succinate dehydrogenase B ( SDH-B ) gene mutation carriers. Clinical Endocrinology 69:4, 587-596
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