Rationalization of Genetic Testing in Patients with Apparently Sporadic Pheochromocytoma/Paraganglioma

Abstract

Hereditary susceptibility to pheochromocytoma (PCC) and paraganglioma (PGL) represents a very complex genetic scenario. It has been reported that the absence of familial antecedents of the disease does not preclude the existence of a mutation affecting any of the five major susceptibility genes. In fact, 11–24% of apparently sporadic cases (without familial or syndromic antecedents) harbor an unexpected germline mutation, but we do not know what is happening in “truly apparently” sporadic patients (i.e., apparently sporadic cases diagnosed with only one tumor). In the present study, we have analyzed 135 apparently sporadic patients developing a single tumor for the five major susceptibility genes: VHL, RET, SDHB, SDHC, and SDHD. Fourteen percent of cases were found to harbor a germline mutation, and only 2.2% of patients were older than 45 years at onset. By taking into account the tumor location and a threshold age at onset of 45 years, we propose a rational scheme for genetic testing. Analyzing VHL and RET genes would be recommended only in young patients developing a single PCC. On the other hand, genetic testing of SDHD should be done in all patients developing an extra-adrenal tumor before the age of 45, and SDHC could be the responsible gene in cases developing a single head and neck tumor, independently of age. Finally, the analysis of SDHB should always be performed because of its association to malignancy and the low penetrance of mutations affecting this gene.

Key words

paraganglioma - pheochromocytoma - SDHB - apparently sporadic

References

• 1 Peczkowska M, Cascon A, Prejbisz A, Kubaszek A, Cwikla BJ, Furmanek M, Erlic Z, Eng C, Januszewicz A, Neumann HP. Extra-adrenal and adrenal pheochromocytomas associated with a germline SDHC mutation.  Nat Clin Pract Endocrinol Metab. 2008;  4 111-115
• 2 Mannelli M, Castellano M, Schiavi F, Filetti S, Giacchè V, Mori L, Pignataro V, Bernini G, Giachè V, Bacca A, Biondi B, Corona G, Di Trapani G, Grossrubatscher E, Reimondo G, Arnaldi G, Giacchetti G, Veglio F, Loli P, Colao A, Ambrosio MR, Terzolo M, Letizia C, Ercolino T, Opocher G. the Italian Pheochromocytoma/Paraganglioma Network. Clinically guided genetic screening in a large cohort of Italian patients with pheochromocytomas and/or functional or non-functional paragangliomas.  J Clin Endocrinol Metab. 2009 Feb 17;  , [Epub ahead of print]
• 3 Dahia PL, Hao K, Rogus J, Colin C, Pujana MA, Ross K, Magoffin D, Aronin N, Cascon A, Hayashida CY, Li C, Toledo SP, Stiles CD. Novel pheochromocytoma susceptibility loci identified by integrative genomics.  Cancer Res. 2005;  65 9651-9658
• 4 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
• 5 Daly PA. Hereditary cancer: guidelines in clinical practice – general overview.  Ann Oncol. 2004;  15 ((Suppl 4)) iv121-125
• 6 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
• 7 Neumann HP, Pawlu C, Peczkowska M, Bausch B, MacWhinney SR, Muresan M, Buchta M, Franke G, Klisch J, Bley TA, Hoegerle S, Boedeker CC, Opocher G, Schipper J, Januszewicz A, Eng C. Distinct clinical features of paraganglioma syndromes associated with SDHB and SDHD gene mutations.  JAMA. 2004;  292 943-951
• 8 Schiavi F, Boedeker CC, Bausch B, Peczkowska M, Gomez CF, Strassburg T, Pawlu C, Buchta M, Salzmann M, Hoffmann MM, Berlis A, Brink I, Cybulla M, Muresan M, Walter MA, Forrer F, Valimaki M, Kawecki A, Szutkowski Z, Schipper J, Walz MK, Pigny P, Bauters C, Willet-Brozick JE, Baysal BE, Januszewicz A, Eng C, Opocher G, Neumann HP. Predictors and prevalence of paraganglioma syndrome associated with mutations of the SDHC gene.  JAMA. 2005;  294 2057-2063
• 9 Benn DE, Gimenez-Roqueplo AP, Reilly JR, Bertherat J, Burgess J, Byth K, Croxson M, Dahia PL, Elston M, Gimm O, Henley D, Herman P, Murday V, Niccoli-Sire P, Pasieka JL, Rohmer V, Tucker K, Jeunemaitre X, Marsh DJ, Plouin PF, Robinson BG. Clinical presentation and penetrance of pheochromocytoma/paraganglioma syndromes.  J Clin Endocrinol Metab. 2006;  91 827-836
• 10 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. Germ-line mutations in nonsyndromic pheochromocytoma.  N Engl J Med. 2002;  346 1459-1466
• 11 Sambrook J, Maniatis T, Fritsch EF. Molecular cloning: a laboratory manual, 2nd ed. Cold Spring Harbor, N.Y.: Cold Spring Harbor Laboratory 1989
• 12 Cascon A, Montero-Conde C, Ruiz-Llorente S, Mercadillo F, Leton R, Rodriguez-Antona C, Martinez-Delgado B, Delgado M, Diez A, Rovira A, Diaz JA, Robledo M. Gross SDHB deletions in patients with paraganglioma detected by multiplex PCR: A possible hot spot?.  Genes Chromosomes Cancer. 2006;  45 213-219
• 13 Cascon A, Ruiz-Llorente S, Cebrian A, Telleria D, Rivero JC, Diez JJ, Lopez-Ibarra PJ, Jaunsolo MA, Benitez J, Robledo M. Identification of novel SDHD mutations in patients with phaeochromocytoma and/or paraganglioma.  Eur J Hum Genet. 2002;  10 457-461
• 14 Cascon A, Cebrian A, Ruiz-Llorente S, Telleria D, Benitez J, Robledo M. SDHB mutation analysis in familial and sporadic phaeochromocytoma identifies a novel mutation.  J Med Genet. 2002;  39 E64
• 15 Ruiz-Llorente S, Bravo J, Cebrian A, Cascon A, Pollan M, Telleria D, Leton R, Urioste M, Rodriguez-Lopez R, de Campos JM, Munoz MJ, Lacambra C, Benitez J, Robledo M. Genetic characterization and structural analysis of VHL Spanish families to define genotype-phenotype correlations.  Hum Mutat. 2004;  23 160-169
• 16 Robledo M, Gil L, Pollan M, Cebrian A, Ruiz S, Azanedo M, Benitez J, Menarguez J, Rojas JM. Polymorphisms G691S/S904S of RET as genetic modifiers of MEN 2A.  Cancer Res. 2003;  63 1814-1817
• 17 Lopez-Jimenez E, de Campos JM, Kusak EM, Landa I, Leskela S, Montero-Conde C, Leandro-Garcia LJ, Vallejo LA, Madrigal B, Rodriguez-Antona C, Robledo M, Cascon A. SDHC mutation in an elderly patient without familial antecedents.  Clin Endocrinol (Oxf). 2008;  69 906-910

Correspondence