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Publication

MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma

Journal Contribution - Journal Article

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.

Journal: Clinical Cancer Research
ISSN: 1078-0432
Issue: 10
Volume: 18
Pages: 2828-2837
Publication year:2012
Keywords:Adolescent, Adrenal Gland Neoplasms/genetics, Adult, Aged, Aged, 80 and over, Basic Helix-Loop-Helix Leucine Zipper Transcription Factors/genetics, Child, Child, Preschool, Female, Genetic Predisposition to Disease, Germ-Line Mutation, Humans, Male, Middle Aged, Paraganglioma/genetics, Pheochromocytoma/genetics, Young Adult