Characterization of the entire spectrum of cancer-associated genetic disruptions is an overarching goal of contemporary and future oncology and can inform on patient diagnosis, treatment, and surveillance. Hereditary endocrine tumors, by having the potential to reveal the cancer's primary molecular defect, have been especially informative in this realm. Within this group, pheochromocytomas and paragangliomas, neural crest-derived, catecholamine- secreting tumors have come to represent true conduits for gene discovery. About one-third of pheochromocytomas and paragangliomas are now known to result from germline mutations in one of at least eight genes that belong to a variety of functional classes. Greater understanding of the molecular signals transduced by these genes and their respective mutants has advanced our understanding of kinase signaling pathways, hypoxia regulation, and the link between metabolic disruptions and cell growth. A new susceptibility gene without homology to other functional classes has been recently identified and encodes for a three-spanner transmembrane protein, transmembrane protein 127 (TMEM127). Initial insights from in vitro and patient data suggest that this candidate tumor suppressor is linked to the endosomal system and the mechanistic target of rapamycin [formerly mammalian target of rapamycin (mTOR)] pathway, and that mutation carriers often have clinical features that are typically associated with sporadic forms of pheochromocytoma. Functional characterization of transmembrane protein 127 (TMEM127) and discovery of additional pheochromocytoma/ paraganglioma susceptibility genes is likely to shed light on our understanding of these tumors and extend these insights to other cancers.
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