MAX Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma
MAX Mutations Cause Hereditary and Sporadic Pheochromocytoma and Paraganglioma
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DOI：
10.1158/1078-0432.ccr-12-0160
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发表时间：
2012-05-15
影响因子：
11.5
通讯作者：
Robledo, Mercedes
中科院分区：
文献类型：
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作者：
Burnichon, Nelly;Cascon, Alberto;Robledo, Mercedes
目的：嗜铬细胞瘤（PCC）和副神经节瘤（PGL）是遗传异质性神经嵴源性肿瘤。最近，我们发现了一个新的肿瘤抑制易感基因MAX（MYC相关因子X）的种系突变，该基因使携带者易患PCC。MAX突变如何促成PCC/PGL和相关表型仍不清楚。本研究的目的是检查生殖细胞和体细胞MAX突变在PCC/PGL.Design的患病率和相关的表型特征：我们测序了MAX在1,694例患者PCC或PGL（没有突变的其他主要易感基因）从17个独立的转诊中心。我们使用基于多重PCR的方法在1，535例患者中筛选大缺失/重复。在另外245名患者的肿瘤中搜索体细胞突变。MAX突变的频率和类型进行了评估的整体和临床feature.Results：16 MAX致病突变被确定在23个索引患者。所有患者均患有肾上腺肿瘤，包括13例双侧或同一腺体内的多个PCC（P < 0.001），15.8%的患者在胸腹部位发生了额外的肿瘤，37%的患者有家族病史。MAX突变携带者诊断时的年龄低于非突变病例（P = 0.001）。2例患者（10.5%）发生转移性疾病。在5个肿瘤中发现了影响MAX的突变，其中4个被证实为体细胞（1.65%）。MAX肿瘤的特点是显着增加normetaneastasis，与正常或轻微增加metaneastasis.Conclusions：生殖系突变MAX负责1.12%的PCC/PGL的患者没有其他已知的突变的证据，并应考虑在这些患者的遗传检查。临床癌症研究; 18（10）; 2828-37。（C）2012年AACR。
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. Clin Cancer Res; 18(10); 2828-37. (C)2012 AACR.