GENETICS COULD PLAY KEY ROLE IN DEVELOPMENT OF ENDOCRINE TUMORS

UMC researchers may have helped discover a genetic link that predisposes individuals to developing pituitary abnormalities. That scientific discovery has come while UMC researchers participate in an international collaboration to determine which genes make some people more susceptible to problems with the pituitary gland.

Dr. Christian A. Koch, professor and director of the Division of Endocrinology at UMC, and Dr. Andrew Parent, UMC chairman of neurosurgery, began a study last year to understand the origin and development of endocrine tumors, including those of the pituitary, thyroid, adrenal, and other glands. 

The multinational effort is between Finland, the Netherlands, Germany, Turkey, the United Kingdom, Canada, Italy, and the U.S., represented exclusively by UMC.  

The approach is to identify families with endocrine tumors and then characterize them. In 2006, Koch was the first to elucidate the pathogenesis of a Mississippi family with pituitary tumors. He said he received invaluable assistance from Prof. Lauri Aaltonen of the Finnish Academy of Sciences.

“There is so little known about how genetics play into the pituitary gland,” Koch said. “And although many families across the country have been willing to participate in this study over the last year, we still need more.

“To unlock the key to any medical mystery, we must have multiple individuals participating in research to quantify our results; to discover any genetic links that cause abnormalities.”

Research on disorders of the endocrine system is vital because the system affects many organs. Endocrine disease is often overlooked and under diagnosed.

“Therefore, it is one of UMC’s directives to train students and doctors in this field to better serve our state,” Koch said.

Abnormal growth and tumorous lesions do not always represent cancer. However, if such abnormal growths lead to overproduction or underproduction of certain hormones, severe health impairment can occur.

Hyperthyroidism can be the result of excessive production of thyroid hormone from a thyroid nodule and can lead to endocrine hypertension, stroke, myocardial infarction, and heart failure. 

On the other hand, hypothyroidism can cause fatigue, weight gain, decreased physical activity, and coma as a result of lacking thyroid hormone. The cause for both hyperthyroidism and hypothyroidism can be an inflammation of the thyroid gland, but they also can be related to the higher control center: the pituitary gland.

This gland produces TSH, thyroid stimulating hormone. TSH production can be impaired by abnormal growth of pituitary cells in the setting of a pituitary tumor. Tumors located in the pituitary are quite common, according to autopsy reports.

“In fact, approximately 22 percent of the population may have them,” Koch said. This represents approximately 61 million Americans.

Endocrine tumors are heterogeneous, develop from a variety of tissues and can be difficult to diagnose. Modern imaging modalities have led to the detection of so-called incidentalomas in various organs and glands, including the pituitary, thyroid and adrenal gland.

“Pituitary and thyroid tumors are quite frequent,” Koch said. “Only a minority of these tumor types are malignant, although they can clinically ‘act’ malignant when someone experiences an excess of hormone production or lack thereof.”

However, endocrine tumors of other organs, including the lungs and gastrointestinal tract, are often difficult to characterize as malignant upon presentation without the clinical manifestation of metastases. Even completely resected tumors can spread clinically visible metastases within a few months after initial therapy. 

“Therefore, a fruitful avenue for the elucidation of tumorigenesis has been the study of endocrine tumors that are manifestations of hereditary or postzygotic genetic syndromes when one knows of the ‘first hit,’ or the primary gene defect,” Koch said. In contrast, in sporadic endocrine tumors, the first hit, possibly a somatic mutation of a tumor-related gene, is unknown, and therefore the sequence of genetic alteration is difficult to establish.

Molecular-targeted therapies, including targeted kinase inhibitors, deacetylase inhibitors, multiligand somatostatin analogs, and others have shown that understanding the pathogenesis of endocrine tumors may eventually offer patients better treatment options.

Koch coauthored a paper on the topic of multiple endocrine neoplasia published in the Journal of Clinical Endocrinology & Metabolism. Koch’s endocrine group, with Shema Ahmad, an endocrine fellow, presenting, won the Southern Society of Clinical Investigation Trainee Travel Award at last year’s SSCI meeting in New Orleans, on the topic of pituitary tumor pathogenesis.

—Dani Edmonson (7-23-07)

2007-07-20 00:00:00 17136