Data from <i>MAX</i> Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma
Authors: 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 Álvaro , 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 
Published: April 2023

<div>Abstract<p><b>Purpose:</b> Pheochromocytomas (PCC) and paragangliomas (PGL) are genetically heterogeneous neural crest–derived neoplasms. Recently we identified germline mutations in a new tumor suppressor susceptibility gene, <i>MAX</i> (MYC-associated factor X), which predisposes carriers to PCC. How <i>MAX</i> 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 <i>MAX</i> mutations in PCC/PGL.</p><p><b>Design:</b> We sequenced <i>MAX</i> 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 <i>MAX</i> mutation was assessed overall and by clinical characteristics.</p><p><b>Results:</b> Sixteen <i>MAX</i> pathogenic mutations were identified in 23 index patients. All had adrenal tumors, including 13 bilateral or multiple PCCs within the same gland (<i>P</i> < 0.001), 15.8% developed additional tumors at thoracoabdominal sites, and 37% had familial antecedents. Age at diagnosis was lower (<i>P</i> = 0.001) in <i>MAX</i> mutation carriers compared with nonmutated cases. Two patients (10.5%) developed metastatic disease. A mutation affecting <i>MAX</i> 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.</p><p><b>Conclusions:</b> Germline mutations in <i>MAX</i> 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. <i>Clin Cancer Res; 18(10); 2828–37. ©2012 AACR.</i></p></div>