A Decade (2001–2010) of Genetic Testing for Pheochromocytoma and Paraganglioma

 

 Buy Article Permissions and Reprints

Abstract

The identification of 9 susceptibility genes for paraganglioma/pheochromocytoma between 2001and 2010 has led to the development of routine genetic tests. To study the evolution in genetic screening for paraganglioma/pheochromocytoma over the past decade, we carried out a retrospective study on the tests performed in our laboratory from January 2001 to December 2010. A genetic test for paraganglioma/pheochromocytoma was assessed for 2 499 subjects, 1 620 index cases, and 879 presymptomatic familial genetic tests. A germline mutation in a PGL/PCC susceptibility gene was identified in 363 index cases (22.4%): 269 in SDHx genes (137 in SDHB, 100 in SDHD, 30 in SDHC, 2 in SDHA), 64 in VHL, 23 in RET, and 7 in TMEM127. A presymptomatic paraganglioma/pheochromocytoma test was positive in 427 subjects. Advances in molecular screening techniques led to an increase in the total number of mutation-carriers diagnosed each year. Overall, during the last decade, our laboratory identified a germline mutation in 44.7% of patients with a suspect hereditary PGL/PCC and in 8% of patients with an apparently sporadic PGL/PCC. During the past decade, the discoveries of new paraganglioma/pheochromocytoma susceptibility genes and the subsequent progress of molecular screening techniques have enabled us to diagnose a hereditary paraganglioma/pheochromocytoma in about 22% of patients tested in routine practice. This genetic testing is of major importance for the follow-up of affected patients and for the genetic counselling of their families.

• References

• 1 Gimenez-Roqueplo A, Dahia PL, Robledo M. Update in the Genetics of Paraganglioma and Pheochromocytoma and Hereditary syndromes. Horm Metab Res 2012; in press
  PubMedGoogle Scholar
• 2 Amar L, Bertherat J, Baudin E, Ajzenberg C, Bressac-de Paillerets B, Chabre O, Chamontin B, Delemer B, Giraud S, Murat A, Niccoli-Sire P, Richard S, Rohmer V, Sadoul JL, Strompf L, Schlumberger M, Bertagna X, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. Genetic testing in pheochromocytoma or functional paraganglioma. J Clin Oncol 2005; 23: 8812-8818
  CrossrefPubMedGoogle Scholar
• 3 Astuti D, Latif F, Dallol A, Dahia PL, Douglas F, George E, Skoldberg F, Husebye ES, Eng C, Maher ER. Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma. Am J Hum Genet 2001; 69: 49-54
  CrossrefPubMedGoogle Scholar
• 4 Baysal BE, Ferrell RE, Willett-Brozick JE, Lawrence EC, Myssiorek D, Bosch A, van der Mey A, Taschner PE, Rubinstein WS, Myers EN, Richard 3rd CW, Cornelisse CJ, Devilee P, Devlin B. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 2000; 287: 848-851
  CrossrefPubMedGoogle Scholar
• 5 Burnichon N, Briere JJ, Libe R, Vescovo L, Riviere J, Tissier F, Jouanno E, Jeunemaitre X, Benit P, Tzagoloff A, Rustin P, Bertherat J, Favier J, Gimenez-Roqueplo AP. SDHA is a tumor suppressor gene causing paraganglioma. Hum Mol Genet 2010; 19: 3011-3020
  CrossrefPubMedGoogle Scholar
• 6 Neumann HP, Bausch B, McWhinney SR, Bender BU, Gimm O, Franke G, Schipper J, Klisch J, Altehoefer C, Zerres K, Januszewicz A, Eng C, Smith WM, Munk R, Manz T, Glaesker S, Apel TW, Treier M, Reineke M, Walz MK, Hoang-Vu C, Brauckhoff M, Klein-Franke A, Klose P, Schmidt H, Maier-Woelfle M, Peczkowska M, Szmigielski C, Eng C. Germ-line mutations in nonsyndromic pheochromocytoma. N Engl J Med 2002; 346: 1459-1466
  CrossrefPubMedGoogle Scholar
• 7 Niemann S, Muller U. Mutations in SDHC cause autosomal dominant paraganglioma, type 3. Nat Genet 2000; 26: 268-270
  CrossrefPubMedGoogle Scholar
• 8 Qin Y, Yao L, King EE, Buddavarapu K, Lenci RE, Chocron ES, Lechleiter JD, Sass M, Aronin N, Schiavi F, Boaretto F, Opocher G, Toledo RA, Toledo SP, Stiles C, Aguiar RC, Dahia PL. Germline mutations in TMEM127 confer susceptibility to pheochromocytoma. Nat Genet 2010; 42: 229-233
  CrossrefPubMedGoogle Scholar
• 9 Burnichon N, Rohmer V, Amar L, Herman P, Leboulleux S, Darrouzet V, Niccoli P, Gaillard D, Chabrier G, Chabolle F, Coupier I, Thieblot P, Lecomte P, Bertherat J, Wion-Barbot N, Murat A, Venisse A, Plouin PF, Jeunemaitre X, Gimenez-Roqueplo AP. The succinate dehydrogenase genetic testing in a large prospective series of patients with paragangliomas. J Clin Endocrinol Metab 2009; 94: 2817-2827
  CrossrefPubMedGoogle Scholar
• 10 Korpershoek E, Favier J, Gaal J, Burnichon N, van Gessel B, Oudijk L, Badoual C, Gadessaud N, Venisse A, Bayley JP, van Dooren MF, de Herder WW, Tissier F, Plouin PF, van Nederveen FH, Dinjens WN, Gimenez-Roqueplo AP, de Krijger RR. SDHA Immunohistochemistry Detects Germline SDHA Gene Mutations in Apparently Sporadic Paragangliomas and Pheochromocytomas. J Clin Endocrinol Metab 2010; 96: E1472-E1476
  PubMedGoogle Scholar
• 11 van Nederveen FH, Gaal J, Favier J, Korpershoek E, Oldenburg RA, de Bruyn EM, Sleddens HF, Derkx P, Riviere J, Dannenberg H, Petri BJ, Komminoth P, Pacak K, Hop WC, Pollard PJ, Mannelli M, Bayley JP, Perren A, Niemann S, Verhofstad AA, de Bruine AP, Maher ER, Tissier F, Meatchi T, Badoual C, Bertherat J, Amar L, Alataki D, Van Marck E, Ferrau F, Francois J, de Herder WW, Peeters MP, van Linge A, Lenders JW, Gimenez-Roqueplo AP, de Krijger RR, Dinjens WN. An immunohistochemical procedure to detect patients with paraganglioma and phaeochromocytoma with germline SDHB, SDHC, or SDHD gene mutations: a retrospective and prospective analysis. Lancet Oncol 2009; 10: 764-771
  CrossrefPubMedGoogle Scholar
• 12 Abermil N, Guillaud-Bataille M, Burnichon N, Venisse A, Manivet A, Guignat L, Drui D, Chupin M, Josseaume C, Affres H, Plouin PF, Bertherat J, Jeunemaître X, Gimenez-Roqueplo AP. TMEM127 screening in a large cohort of patients with pheochromocytoma and/or paraganglioma. J Clin Endocrinol Metab 2012; in press
  PubMedGoogle Scholar
• 13 Neumann HP, Vortmeyer A, Schmidt D, Werner M, Erlic Z, Cascon A, Bausch B, Januszewicz A, Eng C. Evidence of MEN-2 in the original description of classic pheochromocytoma. N Engl J Med 2007; 357: 1311-1315
  CrossrefPubMedGoogle Scholar
• 14 Bravo EL, Gifford Jr RW. Current concepts. Pheochromocytoma: diagnosis, localization and management. N Engl J Med 1984; 311: 1298-1303
  CrossrefPubMedGoogle Scholar
• 15 Baysal BE, van Schothorst EM, Farr JE, Grashof P, Myssiorek D, Rubinstein WS, Taschner P, Cornelisse CJ, Devlin B, Devilee P, Richard 3rd CW. Repositioning the hereditary paraganglioma critical region on chromosome band 11q23. Hum Genet 1999; 104: 219-225
  CrossrefPubMedGoogle Scholar
• 16 Mariman EC, van Beersum SE, Cremers CW, Struycken PM, Ropers HH. Fine mapping of a putatively imprinted gene for familial non-chromaffin paragangliomas to chromosome 11q13.1: evidence for genetic heterogeneity. Hum Genet 1995; 95: 56-62
  PubMedGoogle Scholar
• 17 Niemann S, Becker-Follmann J, Nurnberg G, Ruschendorf F, Sieweke N, Hugens-Penzel M, Traupe H, Wienker TF, Reis A, Muller U. Assignment of PGL3 to chromosome 1 (q21-q23) in a family with autosomal dominant non-chromaffin paraganglioma. Am J Med Genet 2001; 98: 32-36
  CrossrefPubMedGoogle Scholar
• 18 Amar L, Baudin E, Burnichon N, Peyrard S, Silvera S, Bertherat J, Bertagna X, Schlumberger M, Jeunemaitre X, Gimenez-Roqueplo AP, Plouin PF. Succinate dehydrogenase B gene mutations predict survival in patients with malignant pheochromocytomas or paragangliomas. J Clin Endocrinol Metab 2007; 92: 3822-3828
  CrossrefPubMedGoogle Scholar
• 19 Comino-Mendez I, Gracia-Aznarez FJ, Schiavi F, Landa I, Leandro-Garcia LJ, Leton R, Honrado E, Ramos-Medina R, Caronia D, Pita G, Gomez-Grana A, de Cubas AA, Inglada-Perez L, Maliszewska A, Taschin E, Bobisse S, Pica G, Loli P, Hernandez-Lavado R, Diaz JA, Gomez-Morales M, Gonzalez-Neira A, Roncador G, Rodriguez-Antona C, Benitez J, Mannelli M, Opocher G, Robledo M, Cascon A. Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma. Nat Genet 2011; 43: 663-667
  CrossrefPubMedGoogle Scholar