Exome sequencing identifies MAX mutations as a cause of hereditary pheochromocytoma

• Published in: Nature genetics Vol. 43; no. 7; pp. 663 - 667
• Main Authors: Comino-Méndez, Iñaki, Gracia-Aznárez, Francisco J, Schiavi, Francesca, Landa, Iñigo, Leandro-García, Luis J, Letón, Rocío, Honrado, Emiliano, Ramos-Medina, Rocío, Caronia, Daniela, Pita, Guillermo, Gómez-Graña, Álvaro, de Cubas, Aguirre A, Inglada-Pérez, Lucía, Maliszewska, Agnieszka, Taschin, Elisa, Bobisse, Sara, Pica, Giuseppe, Loli, Paola, Hernández-Lavado, Rafael, Díaz, José A, Gómez-Morales, Mercedes, González-Neira, Anna, Roncador, Giovanna, Rodríguez-Antona, Cristina, Benítez, Javier, Mannelli, Massimo, Opocher, Giuseppe, Robledo, Mercedes, Cascón, Alberto
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.07.2011; Nature Publishing Group
• Subjects: 631/208/2489/144; 631/208/2489/144/68; Adolescent; Adrenal Gland Neoplasms - genetics; Adrenals. Adrenal axis. Renin-angiotensin system (diseases); Adult; Aged; Aged, 80 and over; Agriculture; Amino Acid Sequence; Animal Genetics and Genomics; Base Sequence; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors - genetics; Basic-Leucine Zipper Transcription Factors; Biological and medical sciences; Biomedical and Life Sciences; Biomedical research; Biomedicine; Cancer Research; Child; Child, Preschool; Chromosomes; Diagnosis; DNA methylation; DNA sequencing; Endocrinopathies; Exons - genetics; Female; Follow-Up Studies; Fundamental and applied biological sciences. Psychology; Gene Function; Gene mutations; Genetic aspects; Genetic counseling; Genetic Predisposition to Disease; Genetic testing; Genetics; Genetics of eukaryotes. Biological and molecular evolution; Genomes; Germ-Line Mutation - genetics; Human Genetics; Humans; Kinases; letter; Loss of Heterozygosity; Male; Medical sciences; Methods; Middle Aged; Molecular Sequence Data; Mutation; Neuroblastoma - genetics; Non tumoral diseases. Target tissue resistance. Benign neoplasms; Nucleotide sequencing; Pheochromocytoma; Pheochromocytoma - genetics; Physiological aspects; Polymerase Chain Reaction; Polymorphism, Single Nucleotide - genetics; Proteins; Risk factors; Sequence Homology, Amino Acid; Studies; Tumors; Uniparental Disomy; Young Adult; Italy; Spain; Endocrinopathy; Secretory tumor; Pheochromocytoma; Identification; Mutation; Hereditary; Sequencing
• ISSN: 1061-4036; 1546-1718; 1546-1718
• DOI: 10.1038/ng.861

Alberto Cascón, Mercedes Robledo and colleagues show that MAX germline mutations confer susceptibility to hereditary pheochromocytoma. This finding supports a key role for MAX and its interaction partners in tumors of neural crest cell origin. Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date 1 , 2 , 3 , 4 , 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 5 and by the amplification of MYCN in neuroblastoma 6 and suggests that loss of MAX function is correlated with metastatic potential.