Research Highlights

Patricia Dahia
Patricia Dahia, M.D., Ph.D.

Discovery of novel cancer genes is important to shed light on the genetic underpinnings of cancer and can offer opportunities for diagnosis and development of new treatments, which can specifically target the cancer vulnerabilities.

We recently found a novel tumor predisposing gene, TMEM127, by studying families affected by pheochromocytoma, a tumor of brain-derived cells known as neural crest cells. Mutations of TMEM127, a gene of previously unknown function, were detected in various individuals and families with this tumor. All the mutations were inherited. While genetic mutations associated with pheochromocytomas are rare, family members of individuals who carry a mutation are at a higher risk of having the mutation and also developing tumors. Defining the frequency of mutations and the clinical features of mutation carriers is important for diagnostic purposes and may impact on patient follow up and identification of carriers at early stages of disease, where the chances of cure and control are highest.

The genetic pattern of the tumors in patients with mutations suggested that TMEM127 functions as a tumor suppressor gene, i.e, mutations are likely to lead to loss of TMEM127 function, which prompts tumor growth.

This study also showed that the TMEM127 protein is located in many structures within the cell that have a membrane, namely endosomes, Golgi complex and lysosomes. This finding suggests that TMEM127 shuttles between these locations within the cell and thus might function in trafficking and/or sorting of proteins. In addition, we found that when TMEM127 function is reduced, cells turn on the mTOR pathway, which suggests that under normal circumstances TMEM127 works by restraining mTOR. mTOR is an enzyme that controls many important functions of the cell, including growth, survival, protein production, response to nutrients and various stresses. Many cancers have abnormally increased mTOR function. Thus, understanding the function of genes and proteins that control mTOR can have an impact on a variety of cancer types. Furthermore, excess mTOR has also been linked to other disorders such as diabetes, obesity and has also been implicated in aging. Current treatments that target excessive mTOR activation have limited efficacy. Hence, development of novel drugs that exploit less known aspects of mTOR function may offer opportunities for new therapies in the future.

The team is broadening its study to determine if other tumors have TMEM127 mutations and is also developing a mouse model where the TMEM127 gene is absent to get a more detailed view of the exact function of TMEM127 in cells and possible ways to modify its action.

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