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Title

MAX mutations cause hereditary and sporadic pheochromocytoma and paraganglioma

AuthorsBurnichón, Nelly; Borrego, Salud ; Ruiz-Ferrer, Macarena; Robledo, Mercedes
Issue Date2012
PublisherAmerican Association for Cancer Research
CitationClinical Cancer Research 18(10): 2828-2837 (2012)
AbstractPurpose: 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.
Description11 pages, 2 figures, 2 tables.-- Burnichón, Nelly et al.
Publisher version (URL)http://dx.doi.org/10.1158/1078-0432.CCR-12-0160
URIhttp://hdl.handle.net/10261/62678
DOI10.1158/1078-0432.CCR-12-0160
Identifiersdoi: 10.1158/1078-0432.CCR-12-0160
issn: 1078-0432
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