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Oral Cancer Program

Research Activities

Genetic causes of hereditary paraganglioma
Why are we interested in further research in hereditary paraganglioma and how will this benefit the patients?
Recruitment of paraganglioma patients into a research study led by Dr. Bora E. Baysal.

Genetic Causes of Hereditary Paraganglioma

Hereditary paraganglioma (PGL) is characterized by the development of slow-growing and vascularized tumors anywhere from the skull base to the pelvic floor. The tumors derive from paraganglia, a diffuse neuroectodermal system distributed throughout the body. Paraganglia normally function in protecting our body against reduced oxygen tension (hypoxia), bleeding, cold and reduced blood sugar levels. The carotid body (CB), a small organ located at the bifurcation of the common carotid artery in the neck is one of the most common locations for PGL. The CB functions as an oxygen-sensor and stimulates the cardiopulmonary system in acute hypoxia. The head and neck and abdominal paraganglia represent the major locations for PGL.

Mutations in three genes, SDHB, SDHC and SDHD, which encode three of the four subunits of mitochondrial complex II (succinate dehydrogenase, SDH) have been linked to the pathogenesis of PGL (Figure 5). Mitochondrial complex II is involved both in the Krebs cycle and in the aerobic electron transport chain. SDHD (PGL1), which encodes the small subunit of cytochrome b in mitochondrial complex II was the first gene identified by a positional-candidate approach by our group. Subsequently mutations in two other complex II subunits, SDHC (PGL3) and SDHB (PGL4) were discovered in familial paragangliomas by direct candidate gene analyses. Mutations in SDHB and SDHD were also detected in subjects who primarily present with pheochromocytomas. Although genotype-phenotype correlations in PGL are not completely clear yet, recent studies suggest that mutations in SDHD may primarily predispose to mostly benign head and neck paragangliomas and those in SDHB may predispose to abdominal paragangliomas (pheochromocytomas), that may be malignant. Interestingly, SDHD mutations caused PGL1 only if the transmission occurs through fathers, whereas if the gene is transmitted from mother, no tumor development is seen. This peculiar transmission pattern is consistent with a phenomenon called genomic imprinting.

Figure 5. Mechanism of paraganglioma formation

The oxygen-sensing role of the carotid body was implicated in paraganglioma tumor development under certain conditions. It was observed that humans and other mammals (including cattle, dogs, rabbits, and guinea pigs) living at high altitudes have heavier and larger carotid bodies and an increased incidence of carotid body tumors than those living at sea level. Carotid body enlargement was also observed in certain medical conditions with chronic arterial hypoxemia (i.e. reduced levels of oxygen in the blood), including some chronic heart and lung diseases such as emphysema and cystic fibrosis. Thus, chronic hypoxic stimulation was the common underlying factor leading to carotid body enlargement. The physiological role of the carotid body in oxygen sensing and the recurrent observations linking paraganglioma tumor development to chronic hypoxic stress gave us some clues in interpreting the genetic basis of PGL tumors.

The phenotypic features of PGL tumors, including their benign biological behavior, limited organ involvement, and microscopic structure, were markedly similar to those developed when normal CBs were challenged by chronic hypoxic stimulation. This phenotypic similarity led us to hypothesize that a critical component of oxygen-sensing system of the paraganglionic tissues was rendered inactive by genetic mutations in an oxygen-sensing gene, leading to defective oxygen sensing and cellular proliferation (Figure 6).

Figure 6. Mechanism of paraganglioma formation

Since we proposed this hypothesis, several lines of supporting evidence have emerged. First, the paraganglioma tumors caused by complex II subunit mutations showed overexpression of hypoxia-inducible genes. Second, we showed that PGL patients with SDHD mutations have an increased likelihood of tumor development if they live in higher altitudes, whereas mutation carriers who live in lower elevations, such as close to sea level, had reduced risk of tumor development.

Why are we interested in further research in hereditary paraganglioma and how will this benefit the patients?

Identification of the paraganglioma genes was a major turning point in understanding and ultimately developing better management tools for these insidious tumors. However, there are many unanswered questions regarding the development and inheritance of these tumors:

What is the basis of clinical variation observed among mutation carriers (i.e., why some carriers develop tumors at earlier ages, at multiple sites?)
Why do we see malignant transformation in some tumors?
What causes the imprinted genetic transmission pattern and how is this mechanism involved in tumor development?
What is the relative contribution of PGL genes among the patient population?
Do the paraganglioma genes play a role in other types of tumors?

Answering these questions will be possible only by continuing our work in collaboration with PGL patients and their families. The development of potential therapeutic tools may ultimately be possible after answering some or all of these questions.

Our research plan to address these questions builds upon our previous discovery of SDHD as the PGL1 gene at 11q23. More specifically, we plan to:

elucidate molecular mechanisms responsible for imprinting
test if PGL1 tumors are caused by genetic defects in oxygen sensing and affected by environmental oxygen

Thus, our study requires:

recruitment of families with hereditary paraganglioma
establishing cell lines (from PGL tumors, white blood cells and skin) from PGL patients
isolation of DNA from contributing family members and mutation analysis
isolation of DNA and RNA from paraganglioma tumors to search for mutations at SDHD that occurred in the tumor, and to assess molecular mechanisms of imprinting
genetic linkage analysis to assign families to PGL loci.

Findings from clinical testing and advanced studies done in the clinical laboratory on patient samples are an additional source of useful new information on paraganglioma. The program's Genetic Screening activities collect such samples.

About the Paraganglioma Program Screening Study

Recruitment of Subjects with Paraganglioma Into a Research Study Led by Bora E. Baysal, PhD

A research study led by Dr. Baysal seeks recruitment of new subjects with hereditary paragangliomas. This study aims in part to address mechanisms that predispose certain individuals to develop paraganglioma tumors. The patients potentially eligible for this study are:

patients diagnosed with multiple paraganglioma tumors
patients diagnosed with a single paraganglioma tumor and have a relative who was also diagnosed with paraganglioma.

Patients who meet at least one of these two criteria should contact Dr. Baysal to discuss potential participation in this study.

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