Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France.
Clin Cancer Res. 2012 May 15;18(10):2828-37. doi: 10.1158/1078-0432.CCR-12-0160. Epub 2012 Mar 27.
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.
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.
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.
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.
嗜铬细胞瘤（PCC）和副神经节瘤（PGL）是遗传异质性的神经嵴衍生肿瘤。最近，我们在一个新的肿瘤抑制基因易感基因 MAX（MYC 相关因子 X）中发现了种系突变，该基因突变使携带者易患 PCC。MAX 突变如何导致 PCC/PGL 及相关表型尚不清楚。本研究旨在研究 PCC/PGL 中种系和体细胞 MAX 突变的流行率及相关表型特征。
我们对来自 17 个独立转诊中心的 1694 名 PCC 或 PGL 患者（无其他主要易感性基因突变）进行了 MAX 测序。我们使用基于多重 PCR 的方法对 1535 名患者进行了大片段缺失/重复的筛查。另外 245 名患者的肿瘤中寻找了体细胞突变。总体上和根据临床特征评估了 MAX 突变的频率和类型。
在 23 名索引患者中发现了 16 个 MAX 致病性突变。所有患者均有肾上腺肿瘤，包括 13 例同一腺体的双侧或多发性 PCC（P < 0.001），15.8%在胸腹部发生额外肿瘤，37%有家族史。与未突变病例相比，携带 MAX 突变的患者诊断时年龄较低（P = 0.001）。两名患者（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 个被确认为体细胞突变（1.65%）。MAX 肿瘤的特征是去甲肾上腺素显著增加，同时伴有正常或轻度增加的去甲肾上腺素。
MAX 中的种系突变导致了 1.12%无其他已知突变证据的 PCC/PGL 患者，应在这些患者的遗传分析中考虑。
