N Burnichon, A Cascón, F Schiavi, NP Morales, I Comino-Méndez, N Abermil, L Inglada-Pérez, AA de Cubas, L Amar, M Barontini, SB de Quirós, J Bertherat, Y-J Bignon, MJ Blok, S Bobisse, S Borrego, M Castellano, P Chanson, M-D Chiara, EPM Corssmit, M Giacchè, RR de Krijger, T Ercolino, X Girerd, EB Gómez-García, A Gómez-Graña, I Guilhem, FJ Hes, E Honrado, E Korpershoek, JWM Lenders, R Letón, AR Mensenkamp, A Merlo, L Mori, A Murat, P Pierre, P-F Plouin, T Prodanov, M Quesada-Charneco, 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, A-P Gimenez-Roqueplo, M Robledo
Clin Cancer Res
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 somatic (1.65%). MAX tumors were characterized by substantial increases in normetanephrine, associated with normal or minor increases in metanephrine. 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.