Abstract
The prevalence of germ line mutations within the RET-protooncogene and the tumor suppressor genes SDHB, SDHD, and VHL in pheochromocytomas (PC) varies in recent studies from 12 to 24%, if one look at them collectively. DNA was extracted from frozen tumor tissue as well as from blood leukocytes of 36 PC (26 sporadic/10 MEN2). Exons 1-8 of the SDHB-gene, 1-4 of the SDHD-gene, 1-3 of the VHL-gene, and exons 10, 11, 13, 14, 16 of the RET-gene were amplified by PCR and analyzed by DHPLC with the Transgenomic WAVE®-System. Samples with aberrant wave profiles were subjected to direct sequencing. Genetic aberrations were correlated to clinical characteristics. Germ line mutations in sporadic PC were identified in four patients (11%) whereas somatic mutations were observed in two (5%) patients. Nine coding polymorphisms (PM) were identified in seven (19%) patients. Intronic variants were observed in six (17%) patients and were all located in the SHDB gene. Patients with wild type alleles in all assessed genes were older (53 vs. 37 years, P = 0.007) and presented with an increased tumor size (49 vs. 32 mm, P = 0.003) compared to patients with mutations. Malignant PC revealed multiple (>2) genetic alterations more frequently than benign PC (4/7 vs. 4/29, P = 0.03). Interestingly intronic variants of the SDHB gene occur more frequently in malignant than in benign PC (3/7 vs. 2/29, P = 0.04). The frequency of germ line mutations in sporadic pheochromocytomas was lower in our cohort than previously reported. Polymorphisms of the RET gene are common (17%) and occur in familial and sporadic PC. Multiple genetic alterations including mutations, polymorphisms and intronic variants are more frequently observed in malignant PC.
Similar content being viewed by others
References
H.P. Neumann, B. Bausch, S.R. McWhinney, B.U. Bender, O. Gimm, G. Franke, J. Schipper, J. Klisch, C. Altehoefer, K. Zerres, A. Januszewicz, C. Eng, W.M. Smith, R. Munk, T. Manz, S. Glaesker, T.W. Apel, M. Treier, M. Reineke, M.K. Walz, C. Hoang-Vu, M. Brauckhoff, A. Klein-Franke, P. Klose, H. Schmidt, M. Maier-Woelfle, M. Peczkowska, C. Szmigielski, Germ-line mutations in nonsyndromic pheochromocytoma. N. Engl. J. Med. 346(19), 1459–1466 (2002)
D. Astuti, F. Latif, A. Dallol, P.L. Dahia, F. Douglas, E. George, F. Skoldberg, E.S. Husebye, C. Eng, E.R. Maher, Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am. J. Hum. Genet. 69(1), 49–54 (2001)
H. Brauch, W. Hoeppner, H. Jahnig, T. Wohl, D. Engelhardt, F. Spelsberg, M.M. Ritter, Sporadic pheochromocytomas are rarely associated with germline mutations in the VHL tumor suppressor gene or the ret protooncogene. J. Clin. Endocrinol. Metab. 82(12), 4101–4104 (1997)
M. Bar, E. Friedman, O. Jakobovitz, G. Leibowitz, I. Lerer, D. Abeliovich, D.J. Gross, Sporadic pheochromocytomas are rarely associated with germline mutations in the von Hippel-Lindau and RET genes. Clin. Endocrinol. (Oxf.) 47(6), 707–712 (1997)
R.M. Hofstra, T. Stelwagen, R.P. Stulp, D. de Jong, M. Hulsbeek, E.J. Kamsteeg, A. van den Berg, R.M. Landsvater, A. Vermey, W.M. Molenaar, C.J. Lips, C.H. Buys, Extensive mutation scanning of RET in sporadic medullary thyroid carcinoma and of RET and VHL in sporadic pheochromocytoma reveals involvement of these genes in only a minority of cases. J. Clin. Endocrinol. Metab. 81(8), 2881–2884 (1996)
A.P. Gimenez-Roqueplo, J. Favier, P. Rustin, C. Rieubland, M. Crespin, V. Nau, P. Khau Van Kien, P. Corvol, P.F. Plouin, X. Jeunemaitre, Mutations in the SDHB gene are associated with extra-adrenal and/or malignant pheochromocytomas. Cancer Res. 63(17), 5615–5621 (2003)
H. Dannenberg, R.R. De Krijger, E. van der Harst, M. Abbou, Y. IJ, P. Komminoth, W.N. Dinjens, Von Hippel-Lindau gene alterations in sporadic benign and malignant pheochromocytomas. Int. J. Cancer 105(2), 190–195 (2003)
B.U. Bender, M. Gutsche, S. Glasker, B. Muller, G. Kirste, C. Eng, H.P. Neumann, Differential genetic alterations in von Hippel-Lindau syndrome-associated and sporadic pheochromocytomas. J. Clin. Endocrinol. Metab. 85(12), 4568–4574 (2000)
C. Eng, P.A. Crossey, L.M. Mulligan, C.S. Healey, C. Houghton, A. Prowse, S.L. Chew, P.L. Dahia, J.L. O’Riordan, S.P. Toledo et al., Mutations in the RET protooncogene and the von Hippel–Lindau disease tumour suppressor gene in sporadic and syndromic pheochromocytomas. J. Med. Genet. 32(12), 934–937 (1995)
C. Beldjord, F. Desclaux-Arramond, M. Raffin-Sanson, J.C. Corvol, Y. De Keyzer, J.P. Luton, P.F. Plouin, X. Bertagna, The RET protooncogene in sporadic pheochromocytomas: frequent MEN 2-like mutations and new molecular defects. J. Clin. Endocrinol. Metab. 80(7), 2063–2068 (1995)
N.H. Cho, H.W. Lee, S.Y. Lim, S. Kang, W.Y. Jung, C.S. Park, Genetic aberrance of sporadic MEN 2A component tumours: analysis of RET. Pathology 37(1), 10–13 (2005)
R.C. Aguiar, G. Cox, S.L. Pomeroy, P.L. Dahia, Analysis of the SDHD gene, the susceptibility gene for familial paraganglioma syndrome (PGL1), in pheochromocytomas. J. Clin. Endocrinol. Metab. 86(6), 2890–2894 (2001)
D. Astuti, F. Douglas, T.W. Lennard, I.A. Aligianis, E.R. Woodward, D.G. Evans, C. Eng, F. Latif, E.R. Maher, Germline SDHD mutation in familial pheochromocytomas. Lancet 357(9263), 1181–1182 (2001)
L.M. Brunt, T.C. Lairmore, G.M. Doherty, M.A. Quasebarth, M. DeBenedetti, J.F. Moley, Adrenalectomy for familial pheochromocytoma in the laparoscopic era. Ann. Surg. 235(5), 713–720 (2002). discussion 720-1
F.H. van Nederveen, E. Korpershoek, J.W. Lenders, R.R. de Krijger, W.N. Dinjens, Somatic SDHB mutation in an extraadrenal pheochromocytoma. N. Engl. J. Med. 357(3), 306–308 (2007)
H. Dannenberg, E.J. Speel, J. Zhao, P. Saremaslani, E. r Harst, J. Roth, P.U. Heitz, H.J. Bonjer, W.N. Dinjens, W.J. Mooi, P. Komminoth, R.R. de Krijger, Losses of chromosomes 1p and 3q are early genetic events in the development of sporadic pheochromocytomas. Am. J. Pathol. 157(2), 353–359 (2000)
H. Dannenberg, P. Komminoth, W.N. Dinjens, E.J. Speel, R.R. de Krijger, Molecular genetic alterations in adrenal and extra-adrenal pheochromocytomas and paragangliomas. Endocr. Pathol. 14(4), 329–350 (2003)
D. Astuti, M. Morris, C. Krona, F. Abel, D. Gentle, T. Martinsson, P. Kogner, H.P. Neumann, R. Voutilainen, C. Eng, P. Rustin, F. Latif, E.R. Maher, Investigation of the role of SDHB inactivation in sporadic pheochromocytoma and neuroblastoma. Br. J. Cancer 91(10), 1835–1841 (2004)
W.O. Lui, J. Chen, S. Glasker, B.U. Bender, C. Madura, S.K. Khoo, E. Kort, C. Larsson, H.P. Neumann, B.T. Teh, Selective loss of chromosome 11 in pheochromocytomas associated with the VHL syndrome. Oncogene 21(7), 1117–1122 (2002)
G. Eisenhofer, S.R. Bornstein, F.M. Brouwers, N.K. Cheung, P.L. Dahia, R.R. de Krijger, T.J. Giordano, L.A. Greene, D.S. Goldstein, H. Lehnert, W.M. Manger, J.M. Maris, H.P. Neumann, K. Pacak, B.L. Shulkin, D.I. Smith, A.S. Tischler, W.F. Young Jr, Malignant pheochromocytoma: current status and initiatives for future progress. Endocr. Relat. Cancer. 11(3), 423–436 (2004)
P.L. Dahia, K.N. Ross, M.E. Wright, C.Y. Hayashida, S. Santagata, M. Barontini, A.L. Kung, G. Sanso, J.F. Powers, A.S. Tischler, R. Hodin, S. Heitritter, F. Moore, R. Dluhy, J.A. Sosa, I.T. Ocal, D.E. Benn, D.J. Marsh, B.G. Robinson, K. Schneider, J. Garber, S.M. Arum, M. Korbonits, A. Grossman, P. Pigny, S.P. Toledo, V. Nose, C. Li, C.D. Stiles, A HIF1 alpha regulatory loop links hypoxia and mitochondrial signals in pheochromocytomas. PLoS Genet. 1(1), 72–80 (2005)
W. Xiao, P.J. Oefner, Denaturing high-performance liquid chromatography: a review. Hum. Mutat. 17(6), 439–474 (2001)
P.J. Oefner, C.G. Huber, A decade of high-resolution liquid chromatography of nucleic acids on styrene-divinylbenzene copolymers. J. Chromatogr. B Analyt. Technol. Biomed. Life Sci. 782(1–2), 27–55 (2002)
P. Langer, K. Cupisti, D.K. Bartsch, C. Nies, P.E. Goretzki, M. Rothmund, H.D. Roher, Adrenal involvement in multiple endocrine neoplasia type 1. World J. Surg. 26(8), 891–896 (2002)
J. Waldmann, D.K. Bartsch, P.H. Kann, V. Fendrich, M. Rothmund, P. Langer, Adrenal involvement in multiple endocrine neoplasia type 1: results of 7 years prospective screening. Langenbecks Arch. Surg. 392(4), 437–443 (2007)
O. Gimm, M. Armanios, H. Dziema, H.P. Neumann, C. Eng, Somatic and occult germ-line mutations in SDHD, a mitochondrial complex II gene, in nonfamilial pheochromocytoma. Cancer Res. 60(24), 6822–6825 (2000)
R. Elisei, B. Cosci, C. Romei, V. Bottici, M. Sculli, R. Lari, R. Barale, F. Pacini, A. Pinchera, RET exon 11 (G691S) polymorphism is significantly more frequent in sporadic medullary thyroid carcinoma than in the general population. J. Clin. Endocrinol. Metab. 89(7), 3579–3584 (2004)
M. Robledo, L. Gil, M. Pollan, A. Cebrian, S. Ruiz, M. Azanedo, J. Benitez, J. Menarguez, J.M. Rojas, Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A. Cancer Res. 63(8), 1814–1817 (2003)
S.M. Baumgartner-Parzer, R. Lang, L. Wagner, G. Heinze, B. Niederle, K. Kaserer, W. Waldhausl, H. Vierhapper, Polymorphisms in exon 13 and intron 14 of the RET protooncogene: genetic modifiers of medullary thyroid carcinoma? J. Clin. Endocrinol. Metab. 90(11), 6232–6236 (2005)
S.R. McWhinney, G. Boru, P.K. Binkley, M. Peczkowska, A.A. Januszewicz, H.P. Neumann, C. Eng, Intronic single nucleotide polymorphisms in the RET protooncogene are associated with a subset of apparently sporadic pheochromocytoma and may modulate age of onset. J. Clin. Endocrinol. Metab. 88(10), 4911–4916 (2003)
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Waldmann, J., Langer, P., Habbe, N. et al. Mutations and polymorphisms in the SDHB, SDHD, VHL, and RET genes in sporadic and familial pheochromocytomas. Endocr 35, 347–355 (2009). https://doi.org/10.1007/s12020-009-9178-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-009-9178-y