MAX Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma

N Burnichon, A Cascon, F Schiavi, NP Morales, I Comino-Mendez, N Abermil, L Inglada-Perez, AA de Cubas, L Amar, M Barontini, SB de Quiros, J Bertherat, YJ Bignon, MJ Blok, S Bobisse, S Borrego, M Castellano, P Chanson, MD Chiara, EPM CorssmitM Giacche, Ronald de Krijger, T Ercolino, X Girerd, EB Gomez-Garcia, A Gomez-Grana, I Guilhem, FJ Hes, E Honrado, Esther Korpershoek, JWM Lenders, R Leton, AR Mensenkamp, A Merlo, L Mori, A Murat, P Pierre, PF Plouin, T Prodanov, M Quesada-Chameco, N Qin, E Rapizzi, V Raymond, N Reisch, G Roncador, M Ruiz-Ferrer, F Schillo, APA Stegmann, C Suarez, E Taschin, HJLM Timmers, CMJ Tops, M Urioste, F Beuschlein, K Pacak, M Mannelli, PLM Dahia, G Opocher, G Eisenhofer, AP Gimenez-Roqueplo, M Robledo

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Purpose: Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest-derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, MAX (MYC-associated factor X), which predisposes carriers to PCC. How MAX mutations contribute to PCC/PGL and associated phenotypes remain unclear. This study aimed to examine the prevalence and associated phenotypic features of germline and somatic MAX mutations in PCC/PGL. Design: We sequenced MAX in 1,694 patients with PCC or PGL (without mutations in other major susceptibility genes) from 17 independent referral centers. We screened for large deletions/duplications in 1,535 patients using a multiplex PCR-based method. Somatic mutations were searched for in tumors from an additional 245 patients. The frequency and type of MAX mutation was assessed overall and by clinical characteristics. Results: Sixteen MAX pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (P < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (P = 0.001) in MAX mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting MAX was found in five tumors, four of them confirmed as so Conclusions: Germline mutations in MAX are responsible for 1.12% of PCC/PGL in patients without evidence of other known mutations and should be considered in the genetic work-up of these patients. Clin Cancer Res; 18(10); 2828-37. (C)2012 AACR.
Original languageUndefined/Unknown
Pages (from-to)2828-2837
Number of pages10
JournalClinical Cancer Research
Issue number10
Publication statusPublished - 2012

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