Pheochromocytomas, catecholamine-secreting tumors of neural crest origin, are frequently hereditary1. However, the molecular basis for the majority of these tumors is unknown2. We identified the transmembrane-encoding TMEM127 gene, on chromosome 2q11, as a novel pheochromocytoma susceptibility gene. In a cohort of 103 samples, truncating germline TMEM127 mutations were detected in one-third of familial and about 3% of sporadic-appearing tumors without a known genetic cause. The wild-type allele was consistently deleted in tumor DNA, suggesting a two-hit mechanism of inactivation. Pheochromocytomas with TMEM127 mutations are transcriptionally related to NF1-mutant tumors and, similarly, show hyperphosphorylation of mTOR targets. Accordingly, in vitro gain- 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 unveil TMEM127 as a novel tumor suppressor gene and validate the power of hereditary tumors for elucidating cancer pathogenesis.

HEOCHROMOCYTOMAS AND paragangliomas are chromaffin cell tumors of neural crest origin that arise from the adrenal medulla or extra-adrenal sympathetic paraganglia, respectively, and are frequently catecholamine secreting. 1 These tumors are usually benign and can occur as a single entity or as part of various hereditary tumor syndromes. Genetically, pheochromocytomas and paragangliomas are heterogeneous , with at least one-third of cases resulting from germline but not somatic mutations in 1 of several independent genes: RET, VHL, NF1, and succinate dehydrogenase (SDH) subunit B, C, and D genes. 2-5 More recently, other candidate susceptibil-Author Affiliations are listed at the end of this article.

Conserved residues of IDH1 and IDH2 or the SDHAF2 gene are not frequently mutated in pheochromocytomas and paragangliomas. The molecular basis for activation of a hypoxic response in the majority of tumors without VHL or SDH mutations remains to be defined.

No abstract