TY - JOUR
T1 - MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma
AU - Burnichon, Nelly
AU - Cascoń, Alberto
AU - Schiavi, Francesca
AU - Morales, Nicole Paes
AU - Comino-Méndez, Iñaki
AU - Abermil, Nasséra
AU - Inglada-Pérez, Lucía
AU - De Cubas, Aguirre A.
AU - Amar, Laurence
AU - Barontini, Marta
AU - De Quiroś, Sandra Bernaldo
AU - Bertherat, Jérôome
AU - Bignon, Yves Jean
AU - Blok, Marinus J.
AU - Bobisse, Sara
AU - Borrego, Salud
AU - Castellano, Maurizio
AU - Chanson, Philippe
AU - Chiara, María Dolores
AU - Corssmit, Eleonora P.M.
AU - Giacchè, Mara
AU - De Krijger, Ronald R.
AU - Ercolino, Tonino
AU - Girerd, Xavier
AU - Gómez-Garćia, Encarna B.
AU - Gómez-Graña, Álvaro
AU - Guilhem, Isabelle
AU - Hes, Frederik J.
AU - Honrado, Emiliano
AU - Korpershoek, Esther
AU - Lenders, Jacques W.M.
AU - Letón, Rocío
AU - Mensenkamp, Arjen R.
AU - Merlo, Anna
AU - Mori, Luigi
AU - Murat, Arnaud
AU - Pierre, Peggy
AU - Plouin, Pierre François
AU - Prodanov, Tamara
AU - Quesada-Charneco, Miguel
AU - Qin, Nan
AU - Rapizzi, Elena
AU - Raymond, Victoria
AU - Reisch, Nicole
AU - Roncador, Giovanna
AU - Ruiz-Ferrer, Macarena
AU - Schillo, Frank
AU - Stegmann, Alexander P.A.
AU - Suarez, Carlos
AU - Taschin, Elisa
AU - Timmers, Henri J.L.M.
AU - Tops, Carli M.J.
AU - Urioste, Miguel
AU - Beuschlein, Felix
AU - Pacak, Karel
AU - Mannelli, Massimo
AU - Dahia, Patricia L.M.
AU - Opocher, Giuseppe
AU - Eisenhofer, Graeme
AU - Gimenez-Roqueplo, Anne Paule
AU - Robledo, Mercedes
N1 - Copyright:
Copyright 2012 Elsevier B.V., All rights reserved.
PY - 2012/5/15
Y1 - 2012/5/15
N2 - 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.
AB - 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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U2 - 10.1158/1078-0432.CCR-12-0160
DO - 10.1158/1078-0432.CCR-12-0160
M3 - Article
C2 - 22452945
AN - SCOPUS:84861140704
VL - 18
SP - 2828
EP - 2837
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 10
ER -