MAX Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma

Nelly Burnichon, Alberto Cascon, Francesca Schiavi, Nicole Paes Morales, Inaki Comino-Mendez, Nassera Abermil, Lucia Inglada-Perez, Aguirre A. de Cubas, Laurence Amar, Marta Barontini, Sandra Bernaldo de Quiros, Jerome Bertherat, Yves-Jean Bignon, Marinus J. Blok, Sara Bobisse, Salud Borrego, Maurizio Castellano, Philippe Chanson, Maria-Dolores Chiara, Eleonora P. M. CorssmitMara Giacche, Ronald R. de Krijger, Tonino Ercolino, Xavier Girerd, Encarna B. Gomez-Garcia, Alvaro Gomez-Grana, Isabelle Guilhem, Frederik J. Hes, Emiliano Honrado, Esther Korpershoek, Jacques W. M. Lenders, Rocio Leton, Arjen R. Mensenkamp, Anna Merlo, Luigi Mori, Arnaud Murat, Peggy Pierre, Pierre-Francois Plouin, Tamara Prodanov, Miguel Quesada-Chameco, Nan Qin, Elena Rapizzi, Victoria Raymond, Nicole Reisch, Giovanna Roncador, Macarena Ruiz-Ferrer, Frank Schillo, Alexander P. A. Stegmann, Carlos Suarez, Elisa Taschin, Henri J. L. M. Timmers, Carli M. J. Tops, Miguel Urioste, Felix Beuschlein, Karel Pacak, Massimo Mannelli, Patricia L. M. Dahia, Giuseppe Opocher, Graeme Eisenhofer, Anne-Paule Gimenez-Roqueplo, Mercedes Robledo*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

199 Citations (Web of Science)


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. Clin Cancer Res; 18(10); 2828-37.
Original languageEnglish
Pages (from-to)2828-2837
JournalClinical Cancer Research
Issue number10
Publication statusPublished - 15 May 2012

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