MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma.


  • Burnichon Nelly
  • Cascón Alberto
  • Schiavi Francesca
  • Morales Nicole Paes
  • Comino-Méndez Iñaki
  • Abermil Nasséra
  • Inglada-Pérez Lucía
  • de Cubas Aguirre A
  • Amar Laurence
  • Barontini Marta
  • de Quirós Sandra Bernaldo
  • Bertherat Jérôme
  • Bignon Yves-Jean
  • Blok Marinus J
  • Bobisse Sara
  • Borrego Salud
  • Castellano Maurizio
  • Chanson Philippe
  • Chiara María-Dolores
  • Corssmit Eleonora P M
  • Giacchè Mara
  • de Krijger Ronald R
  • Ercolino Tonino
  • Girerd Xavier
  • Gómez-García Encarna B
  • Gómez-Graña Alvaro
  • Guilhem Isabelle
  • Hes Frederik J
  • Honrado Emiliano
  • Korpershoek Esther
  • Lenders Jacques W M
  • Letón Rocío
  • Mensenkamp Arjen R
  • Merlo Anna
  • Mori Luigi
  • Murat Arnaud
  • Pierre Peggy
  • Plouin Pierre-François
  • Prodanov Tamara
  • Quesada-Charneco Miguel
  • Qin Nan
  • Rapizzi Elena
  • Raymond Victoria
  • Reisch Nicole
  • Roncador Giovanna
  • Ruiz-Ferrer Macarena
  • Schillo Frank
  • Stegmann Alexander P A
  • Suarez Carlos
  • Taschin Elisa
  • Timmers Henri J L M
  • Tops Carli M J
  • Urioste Miguel
  • Beuschlein Felix
  • Pacak Karel
  • Mannelli Massimo
  • Dahia Patricia L M
  • Opocher Giuseppe
  • Eisenhofer Graeme
  • Gimenez-Roqueplo Anne-Paule
  • Robledo Mercedes

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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 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.

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