Departments of Medicine, San Antonio, Texas, USA.
Nat Genet. 2010 Mar;42(3):229-33. doi: 10.1038/ng.533. Epub 2010 Feb 14.
Pheochromocytomas, which are catecholamine-secreting tumors of neural crest origin, are frequently hereditary. However, the molecular basis of the majority of these tumors is unknown. We identified the transmembrane-encoding gene TMEM127 on chromosome 2q11 as a new pheochromocytoma susceptibility gene. In a cohort of 103 samples, we detected truncating germline TMEM127 mutations in approximately 30% of familial tumors and about 3% of sporadic-appearing pheochromocytomas without a known genetic cause. The wild-type allele was consistently deleted in tumor DNA, suggesting a classic mechanism of tumor suppressor gene inactivation. Pheochromocytomas with mutations in TMEM127 are transcriptionally related to tumors bearing NF1 mutations and, similarly, show hyperphosphorylation of mammalian target of rapamycin (mTOR) effector proteins. Accordingly, in vitro gain-of-function and loss-of-function analyses indicate that TMEM127 is a negative regulator of mTOR. TMEM127 dynamically associates with the endomembrane system and colocalizes with perinuclear (activated) mTOR, suggesting a subcompartmental-specific effect. Our studies identify TMEM127 as a tumor suppressor gene and validate the power of hereditary tumors to elucidate cancer pathogenesis.
嗜铬细胞瘤是起源于神经嵴的儿茶酚胺分泌肿瘤，常具有遗传性。然而，这些肿瘤的大多数分子基础尚不清楚。我们鉴定了 2 号染色体 q11 上的跨膜编码基因 TMEM127 是一个新的嗜铬细胞瘤易感性基因。在一个包含 103 个样本的队列中，我们在大约 30%的家族性肿瘤和约 3%的无已知遗传病因的散发性嗜铬细胞瘤中检测到了截断的种系 TMEM127 突变。野生型等位基因在肿瘤 DNA 中始终缺失，提示存在经典的肿瘤抑制基因失活机制。携带 TMEM127 突变的嗜铬细胞瘤与携带 NF1 突变的肿瘤在转录上相关，并且同样表现出哺乳动物雷帕霉素靶蛋白 (mTOR) 效应蛋白的过度磷酸化。因此，体外功能获得和功能丧失分析表明，TMEM127 是 mTOR 的负调节剂。TMEM127 与内质网系统动态相关，并与核周（激活的）mTOR 共定位，提示存在亚区室特异性效应。我们的研究将 TMEM127 鉴定为一个肿瘤抑制基因，并验证了遗传性肿瘤阐明癌症发病机制的能力。
