HEOCHROMOCYTOMA AND PARAganglioma are tumors of the autonomic nervous system. Terminology in science and clinical practice is divergent. Herein, we use the term pheochromocytoma for location in the adrenal glands, extraadrenal abdominal, and thoracic locations (eg, where nearly all tumors are endocrinologically active). In contrast, the term paraganglioma is only used for tumors in the head and neck area where most tumors are nonfunctioning. All these tumors have been described as sporadic and as hereditary entities. [1][2][3] Estimated yearly incidence of

Hereditary pheochromocytoma (PCC) is often caused by germline mutations in one of nine susceptibility genes described to date, but there are familial cases without mutations in these known genes. We sequenced the exomes of three unrelated individuals with hereditary PCC (cases) and identified mutations in MAX, the MYC associated factor X gene. Absence of MAX protein in the tumors and loss of heterozygosity caused by uniparental disomy supported the involvement of MAX alterations in the disease. A follow-up study of a selected series of 59 cases with PCC identified five additional MAX mutations and suggested an association with malignant outcome and preferential paternal transmission of MAX mutations. The involvement of the MYC-MAX-MXD1 network in the development and progression of neural crest cell tumors is further supported by the lack of functional MAX in rat PCC (PC12) cells and by the amplification of MYCN in neuroblastoma and suggests that loss of MAX function is correlated with metastatic potential.

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.