Burnichon, NellyCascon Soriano, AlbertoSchiavi, FrancescaMorales, Nicole PaesComino-Méndez, IñakiAbermil, NasséraInglada-Pérez, Lucíade Cubas, Aguirre AAmar, LaurenceBarontini, Martade Quirós, Sandra BernaldoBertherat, JérômeBignon, Yves-JeanBlok, Marinus JBobisse, SaraBorrego, SaludCastellano, MaurizioChanson, PhilippeChiara, María-DoloresCorssmit, Eleonora P MGiacchè, Marade Krijger, Ronald RErcolino, ToninoGirerd, XavierGómez-García, Encarna BGómez-Graña, AlvaroGuilhem, IsabelleHes, Frederik JHonrado, EmilianoKorpershoek, EstherLenders, Jacques W MLetón, RocíoMensenkamp, Arjen RMerlo, AnnaMori, LuigiMurat, ArnaudPierre, PeggyPlouin, Pierre-FrançoisProdanov, TamaraQuesada-Charneco, MiguelQin, NanRapizzi, ElenaRaymond, VictoriaReisch, NicoleRoncador, GiovannaRuiz-Ferrer, MacarenaSchillo, FrankStegmann, Alexander P ASuarez, CarlosTaschin, ElisaTimmers, Henri J L MTops, Carli M JUrioste, MiguelBeuschlein, FelixPacak, KarelMannelli, MassimoDahia, Patricia L MOpocher, GiuseppeEisenhofer, GraemeGimenez-Roqueplo, Anne-PauleRobledo, Mercedes2025-01-202025-01-202012-05-15Clin Cancer Res . 2012 May 15;18(10):2828-37https://hdl.handle.net/20.500.12105/26068Pheochromocytomas (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.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.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.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.The ENS@T consortium received funding from the European Union Seventh Framework Programme (ENS@T-CANCER; HEALTH-F2-2010-259735). The ENS@T registry is supported by a grant of the European Science Foundation (ESF-ENS@T). This work was supported in part by the Fondo de Investigaciones Sanitarias (projects PI11/01359, PS09/00942, PI10/01290, PI08/0531 and P108/0883), Mutua Madrilena (AP2775/2008), Consejeria de Innovacion Ciencia y Empresa de la Junta de Andalucia (CTS-2590), Red Tematica de Investigacion Cooperativa en Cancer (RD06/0020/0034). The French COMETE network is supported in part by the Programme Hospitalier de Recherche Clinique grant COMETE 3(AOM 06 179), by grants from INSERM and Ministere Delegue a la Recherche et des Nouvelles Technologies and by the Institut National du Cancer. This work was also funded by grants from the Agence Nationale de la Recherche (ANR 08 GENOPATH 029 MitOxy) and by the national program "Cartes d'Identite des Tumeurs" funded and developed by the "Ligue Nationale contre le Cancer" (http://cit.ligue-cancer.net). This research was supported, in part, by the Intramural Research Program of the NIH, NICHD. This work received funding support from the Voelcker Fund to P. L. M. Dahia. This work was also supported in part by grants from the Fondazione Comunita Bresciana and the Fondazione Guido Berlucchi.engAMhttp://creativecommons.org/licenses/by-nc-nd/4.0/Attribution-NonCommercial-NoDerivatives 4.0 International2245294518102828-2837CLINICAL CANCER RESEARCHopen access