Nelly Burnichon 1 , Alberto Cascón , Francesca Schiavi , Nicole Paes Morales , Iñaki Comino-Méndez , Nasséra Abermil , Lucía Inglada-Pérez , Aguirre A de Cubas , Laurence Amar , Marta Barontini , Sandra Bernaldo de Quirós , Jérôme Bertherat , Yves-Jean Bignon , Marinus J Blok , Sara Bobisse , Salud Borrego , Maurizio Castellano , Philippe Chanson , María-Dolores Chiara , Eleonora P M Corssmit , Mara Giacchè , Ronald R de Krijger , Tonino Ercolino , Xavier Girerd , Encarna B Gómez-García , Alvaro Gómez-Graña , Isabelle Guilhem , Frederik J Hes , Emiliano Honrado , Esther Korpershoek , Jacques W M Lenders , Rocío Letón , Arjen R Mensenkamp , Anna Merlo , Luigi Mori , Arnaud Murat , Peggy Pierre , Pierre-François Plouin , Tamara Prodanov , Miguel Quesada-Charneco , 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 Show Affiliations »
Abstract
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. ©2012 AACR.
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 . ©2012 AACR.
Entities: Chemical
Disease
Gene
Mutation
Species
Mesh： See more »
Substances： See more »
Year: 2012
PMID： 22452945 DOI： 10.1158/1078-0432.CCR-12-0160
Source DB: PubMed Journal: Clin Cancer Res ISSN： 1078-0432 Impact factor: 12.531