Understanding the Role of a Novel Hereditary Cancer Gene

Cancers of neural and neuroectodermal origin are rare in incidence. However, high rates of mortality convert these infrequent tumors into the second leading cause of cancer-related death among children less than 15 years of age. Genetic analysis of familial cancers provides fundamental insights into their more common sporadic equivalents.  Using integrative genomics, we recently identified a novel cancer gene known as TMEM127. We discovered that truncating TMEM127mutations are responsible for the development of familial pheochromocytomas, highly vascular tumors of neural crest origin. Our initial studies show that TMEM127 has features of a tumor suppressor gene and functions as an inhibitor of mTOR, a pathway implicated in multiple cancers. Further, we found that TMEM127 localizes to multiple intracellular compartments involved in protein shuttling, including the plasma membrane, endosome and Golgi, a complex network for which a role in cancer has remained underexplored. In this proposal we aim to elucidate TMEM127 function by identifying binding proteins and by defining precisely the regulation of TMEM127 intraorganelle localization and movement and its effects on mTOR function. We will also examine the integrity of the TMEM127 gene in pediatric tumors of neural origin. In summary, the studies proposed in this application should provide us initial insights into the function of a novel tumor suppressor gene that impinges on mTOR. Furthermore, the unique, multicompartmental distribution of TMEM127 suggests that it might function in protein trafficking or sorting, and hints at where its interplay with mTOR occurs. In addition to defining the function of a novel cancer gene, our study will provide insights into the regulation of mTOR and will explore the emerging role of the endomembrane system in cancer. In addition, this work will also offer an initial assessment of the role of TMEM127 in pediatric tumors of neural origin.