title: MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
authors.forename: Nelly
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authors.lastname: Burnichon
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authors.lastname: Prodanov
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authors.lastname: Rapizzi
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authors.lastname: Reisch
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authors.lastname: Roncador
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authors.lastname: Ruiz-Ferrer
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authors.lastname: Schillo
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authors.lastname: Stegmann
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authors.lastname: Tops
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authors.lastname: Urioste
authors.forename: Felix
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authors.lastname: Beuschlein
authors.forename: Karel
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authors.lastname: Pacak
authors.forename: Massimo
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authors.lastname: Mannelli
authors.forename: Patricia L M
authors.initials: PL
authors.lastname: Dahia
authors.forename: Giuseppe
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authors.lastname: Opocher
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authors.lastname: Eisenhofer
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authors.lastname: Gimenez-Roqueplo
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mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D010235:Paraganglioma / Q000235:genetics*; D010673:Pheochromocytoma / Q000235:genetics*; D055815:Young Adult
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C499330:MAX protein, human