MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma

TY - JOUR

T1 - MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma

AU - Burnichon, Nelly

AU - Cascoń, Alberto

AU - Schiavi, Francesca

AU - Morales, NicolePaes

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

AU - Opocher, Giuseppe

AU - Eisenhofer, Graeme

AU - Gimenez-Roqueplo, Anne Paule

AU - Robledo, Mercedes

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.

UR - http://www.scopus.com/inward/record.url?scp=84861140704&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84861140704&partnerID=8YFLogxK

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 -