The discovery of a succession of pheochromocytoma and paraganglioma predisposing genes over the past decade challenged a long-held view that these tumors were rarely inherited. It is now recognized that well over one-third of pheochromocytomas and paragangliomas are hereditary and, with more familial forms that remain yet to be diagnosed, it is likely that the frequency of inherited tumors may be even higher. This notion, as families who carry a mutation in one of the dozen or so pheochromocytomas or paragangliomas predisposition genes can attest, has many practical implications for handling the disease.
Our search for the TMEM127 gene, which prior to its identification we had dubbed the ‘FP’ (for Familial Pheochromocytoma) gene, lasted for more than a decade and started with one single, large family. The involvement of this family and their remarkably positive attitude throughout the years was truly inspiring. Their perseverance and unwavering support were instrumental for the eventual success in our efforts to uncover the identity of the elusive FP gene.
TMEM127 may have been among the last genes to be discovered using a conventional genetic method known as linkage analysis. Through this approach, the chromosomal location of the gene was initially found and it spun an area that contained hundreds of potential ‘candidate’ genes. By using this general location as a test to find other patients that had similar profile we were able to narrow down the ‘FP’ region and eventually single out a mutation that fulfilled our requirements for the FP gene: it was present in every individual of the family that had pheochromocytoma. Next we were able to test other patients and families that had genetic features similar to ‘FP’ and found other TMEM127 mutations, thus confirming that of all the genes in that chromosomal region, TMEM127 was responsible for pheochromocytoma in these families. These studies were further validated by a collaboration involving researchers worldwide which resulted in identification of additional families with TMEM127 mutations.
This larger study allowed us to start defining features that are typical of TMEM127-associated pheochromocytomas: patients were older at diagnosis than the average patient with hereditary pheochromocytoma caused by mutations in other genes such as RET, VHL, SDHB, SDHC, SDHD and MAX. In addition, in patients with a TMEM127 mutation the tumors are predominantly adrenal (i.e. pheochromocytomas, rather than paragangliomas), in about one-third of the cases they are bilateral, and they are overwhelmingly benign. Importantly, a clear family history of pheochromocytoma is present in only one quarter of TMEM127-mutation carriers, while the remaining cases have the appearance of a ‘sporadic’ (or nonhereditary) tumor. Besides pheochromocytoma, no other tumors or clinical features have been consistently identified in patients with a TMEM127 mutation but it is important to continue to thoroughly examine and follow up these patients to ensure that, if existent, any additional conditions will be recognized. Of note, we detected TMEM127 mutations in a few patients with kidney cancers. However, these mutations were very rare, and none of these patients had pheochromocytomas. Studies of larger number of patients are needed to determine whether mutations in TMEM127 increase the risk of other tumors besides pheochromocytomas.
Another challenge as we move forward is to identify the function of TMEM127. We are making strides on that front and have learned that TMEM127 works in cells to control the trafficking of proteins through structures known as endosomes. How exactly it performs its function and how mutations in TMEM127 can turn normal cells into tumors of the adrenal gland still remain open questions and we hope that in the coming years we will continue to make advances in this area.
- Patricia L. M. Dahia, MD, PhD
- Associate Professor of Medicine Division of Hematology and Medical Oncology
- Cancer Therapy and Research Center
- University of Texas Health Science Center at San Antonio (UTHSCSA)
- San Antonio- Texas
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