Monthly Archives: July 2014

TMEM127 mutations, by Dr Dahia

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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
  • http://gsbs.uthscsa.edu/faculty/patricia-dahia-ph.d

For information on our ongoing genetic studies and enrollment, please email: dahia@uthscsa.edu

Radiology Notes from NIH Symposium

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Erin MacBean

During the NIH pheo/para symposium, Dr. Ingo Janssen of the NIH presented slides on nuclear medicine research. Part of the presentation focused on explaining the differences in the scans patients undergo. This wonderful comparison presentation helped us all understand how specific scans can miss tumors for some people yet shows uptake for others. (Note: The following are the notes and photos I took with my phone during the presentation. The Troopers are working on getting the slides of the presentations from the symposium so that we can share the actual content in its entirety with our members.)

Radiology 1 Radiology 2 (Top image: shows the different nuclear scans of the same patient and how each scan shows different uptake. Bottom Image: shows octreo-scans of a different patient)

Genetic mutation and/or location of tumors can play key roles in the differences of scan results. The following notes are the breakdown of the positive and negative factors of each nuclear scan:

123MIBG – Has a high sensitivity for primary functioning pheo/para, and is very specific (meaning, if it shows uptake, it has a 95-98% certainty that it’s a pheo or para) but the scan is less effective for metastatic tumors and SDHB mutations.

18F-FDA PET – Is only available at NIH and is very specific. It has a high sensitivity for sympathetic para (functioning para) but has poor results for head and neck para. It’s good for metastatic tumors.

18F-DOPA PET – Excellent sensitivity for SDHx related head and neck para and a good sensitivity for adrenal pheo, but has limited sensitivity in metastatic disease.

18F-FDG PET – Unspecific tracer (which means it shows uptake in things that aren’t pheo/para. It shows other tumors and even inflammation sometimes.) It has a high sensitivity in SDHB related pheo/para metastatic disease.

Somatostatin receptor imagining (for those that show uptake with octreoscans):

Octreoscan (111In-Pentetroitide) – When researchers discovered that pheos and para overexpress mainly SSTR 2, they tried this scan and found high sensitivity in head and neck para, but a low sensitivity for primary sympathetic para.

DOTA – After figuring out the SSTR overexpression, researchers targeted DOTA peptides to deliver tracers, so DOTATOC, DOTANOC, and DOTATATE. They found a high affinity to SSTR, and labeled to the PET tracer 68Ga, for imaging.  This was also labeled to therapeutic beta-emitters like 177Lu/90Y for treatments outside of the U.S., and are now in trial stages at select hospitals in the states.

You don’t have to be a radiologist to see what the 111In-Pentetreoitide scan missed when you compare it to the 68Ga-DOTATATE. (See second image) The 68Ga-DOTATATE is a great scan for those patients who are what I call octreo-positive, and it’s understandable why treatments with the 177Lu/90Y are showing positive results.

The U.S. is working toward FDA approval for this scan and treatment (unlike other countries that already use it as a treatment, the U.S. is a bit behind on getting it here.) To help push this along the Carcinoid Cancer Foundation has awarded a grant of more than $65,000.00 to Stanford University in California to expand access to its Gallium-68 (Ga-68) DOTATATE PET/CT program for carcinoid and neuroendocrine tumor (NET) patients. See the full article here. It’s a start!

Conferences, Notes, and Research Galore!

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Erin MacBean

The end of June 2014 marked a busy and exciting time for the pheo/para community. It kicked off on June 21-24 with the 96th ICE/ENDO2014 Expo hosted by the Endocrine Society. Then the National Institutes of Health launched their Third Annual International Patient Symposium on Pheochromocytoma June 26-27. The events wrapped up with the Pheo Para Troopers patient-focused Boot Camp on June 28. A few years ago, it was difficult to find any pheo/para proceedings – well not anymore!

The ENDO expo was a huge success for the pheo/para community as all eyes were introduced to a Pheochromocytoma and Paraganglioma Clinical Practice Guideline developed by a collaboration of leading pheo/para experts from around the world. This 28-page document is a huge accomplishment as it discusses a guideline for all doctors to follow for pheo/para patients from diagnostics to treatments. Download the Guideline here.

The NIH Symposium was packed full of pheo and para discussions from medically intense presentations to patient stories. The information shared here was priceless and energizing. A huge step in genetic research has lit the way for better diagnostic and treatment options, and the expert /patient focused panels answered amazing questions, which gave great insight to advocates and patients alike.

The Trooper Boot Camp rounded out the conferences and brought the focus back to the patients. Presentations on how to cope by using tools like the Open Cancer Network mobile app and the Pillers4Life program though reimagine showed attendees that help was out there. Patient stories and discussions bonded Troopers and formed friendships, and the chance to question experts gave great insight to the Trooper membership. New alliances formed and our members became stronger advocates. All around it was a huge success!

The significance of these symposiums shows that patients are being heard. Our outcry for more information, research, and minds working together to find a cure has been answered. It left veteran advocates hopeful, energized, and full of information to share. So stay tuned and keep visiting the website! Over the next few months, the Troopers will be compiling dozens of notes and research to deliver to our members.

The Troopers send their profound gratitude to all involved in the creation of these conferences. Without your devotion, we could not make the strides we are seeing for both patients and researchers.