A Mutation, a Blood Disease, Two Cancers, and Many Questions
By Joan Nambuba
Advisor: Karel Pacak, MD, PhD, DSc
Neuroendocrine tumors (NETs) are abnormal formations of tissue that originate from both the endocrine (hormone-secreting) and nervous systems. Except in cases where there is a known family history, it is very rare and unlikely that an individual will develop more than one type of NET. But that is not the case in a syndrome that Drs. Karel Pacak and Zhengping Zhuang, along with their inquisitive team of collaborators, recently identified.
In this syndrome, recently suggested as the Pacak-Zhuang syndrome, patients are found to have genetic mutations that overactivate hypoxia-inducible factor 2α (HIF2A), a transcription factor that turns on oxygen related genes. Beginning from an early age, patients are found to have secondary polycythemia and usually experience flushing and itching from abnormally high levels of a hormone that affects red blood cell production, requiring frequent phlebotomies. Patients then develop paragangliomas, NETs arising from the adrenal gland that affect multiple parts of the body. Patients next develop somatostatinomas—NETs arising from the lining of the digestive tract. While somatostatinomas are known to affect both the pancreas and gastrointestinal tract, individuals suffering from this syndrome only develop tumors in the second portion of the duodenum.
This syndrome was initially described in two patients in The New England Journal of Medicine in 2012 and was later expanded with newer findings reported on an additional two patients in the Journal of Clinical Oncology. Due to its novelty, many questions are still unanswered. With a larger cohort of patients, our group is currently looking into how to better characterize this syndrome. Some questions we are curious to answer are how mutations in HIF2A arise, how these tumors evolve over time, and if unique therapies exist that can be personalized to patients suffering from this particular set of disease entities.