title: Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma.
abstract: Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.
authors.affiliation: Hereditary Endocrine Cancer Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
authors.forename: Iñaki
authors.initials: I
authors.lastname: Comino-Méndez
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Gracia-Aznárez
authors.forename: Francesca
authors.initials: F
authors.lastname: Schiavi
authors.forename: Iñigo
authors.initials: I
authors.lastname: Landa
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Leandro-García
authors.forename: Rocío
authors.initials: R
authors.lastname: Letón
authors.forename: Emiliano
authors.initials: E
authors.lastname: Honrado
authors.forename: Rocío
authors.initials: R
authors.lastname: Ramos-Medina
authors.forename: Daniela
authors.initials: D
authors.lastname: Caronia
authors.forename: Guillermo
authors.initials: G
authors.lastname: Pita
authors.forename: Alvaro
authors.initials: A
authors.lastname: Gómez-Graña
authors.forename: Aguirre A
authors.initials: AA
authors.lastname: de Cubas
authors.forename: Lucía
authors.initials: L
authors.lastname: Inglada-Pérez
authors.forename: Agnieszka
authors.initials: A
authors.lastname: Maliszewska
authors.forename: Elisa
authors.initials: E
authors.lastname: Taschin
authors.forename: Sara
authors.initials: S
authors.lastname: Bobisse
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pica
authors.forename: Paola
authors.initials: P
authors.lastname: Loli
authors.forename: Rafael
authors.initials: R
authors.lastname: Hernández-Lavado
authors.forename: José A
authors.initials: JA
authors.lastname: Díaz
authors.forename: Mercedes
authors.initials: M
authors.lastname: Gómez-Morales
authors.forename: Anna
authors.initials: A
authors.lastname: González-Neira
authors.forename: Giovanna
authors.initials: G
authors.lastname: Roncador
authors.forename: Cristina
authors.initials: C
authors.lastname: Rodríguez-Antona
authors.forename: Javier
authors.initials: J
authors.lastname: Benítez
authors.forename: Massimo
authors.initials: M
authors.lastname: Mannelli
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Opocher
authors.forename: Mercedes
authors.initials: M
authors.lastname: Robledo
authors.forename: Alberto
authors.initials: A
authors.lastname: Cascón
mesh_terms: D000293:Adolescent; D000310:Adrenal Gland Neoplasms / Q000235:genetics*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D001483:Base Sequence; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics*; D050976:Basic-Leucine Zipper Transcription Factors; D002648:Child; D002675:Child, Preschool; D005091:Exons / Q000235:genetics*; D005260:Female; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D019656:Loss of Heterozygosity; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009447:Neuroblastoma / Q000235:genetics; D010673:Pheochromocytoma / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D024182:Uniparental Disomy; D055815:Young Adult
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; D050976:Basic-Leucine Zipper Transcription Factors; C499330:MAX protein, human; C067850:Myc associated factor X