Nonsyndromic paraganglioma (nonsyndromic paraganglioma) - Genes VHL, RET, SDHB, SDHD, TMEM127, SDHA, and KIF1B.
Paraganglioma is a benign tumor that develops in Paraganglia. Paragangliomas are usually found on the head, neck or back. However, a type of paraganglioma known as pheochromocytoma develops in the adrenal glands. Most people with paraganglioma develop only a tumor in his life. Some people develop a paraganglioma or pheochromocytoma as part of an inherited syndrome that can affect other organs and tissues in the body. However, these tumors often are not associated with any syndrome, in which case the alteration is called non - syndromic paraganglioma or pheochromocytoma.
Other pheochromocytomas and paragangliomas are associated with sympathetic ganglia nervous system. While most sympathetic paragangliomas are pheochromocytomas, some are outside the adrenal glands, usually in the abdomen, and are called extra - adrenal paraganglioma. Sympathetic paragangliomas, pheochromocytomas including produce catecholamines such as epinephrine or norepinephrine. This excess catecholamines cause signs and symptoms such as hypertension, palpitations, headaches, or sweating. Most paragangliomas are associated with the nodes of the parasympathetic nervous system that controls involuntary bodily functions such as digestion and saliva formation. Parasympathetic paragangliomas, which are usually located in the head and neck, usually do not produce hormones. However, large tumors may cause signs and symptoms such as cough, loss of hearing in one ear, or difficulty swallowing. Although most paragangliomas and pheochromocytomas are benign, but some may become malignant and metastasize. The extra-adrenal paraganglioma become malignant more often than other types of paraganglioma or pheochromocytoma.
Both syndromic and non - syndromic forms of paraganglioma and pheochromocytoma are due to mutations in the VHL, RET, SDHB and SDHD genes, whereas mutations in TMEM127, SDHA, and KIF1B, gens have been identified in people with non - syndromic form . Genetic mutations increase the risk of developing paraganglioma or pheochromocytoma to affect control of growth and cell division.
The KIF1B gene, located on the short arm of chromosome 1 (1p36.2) is a tumor suppressor gene encoding a protein called kinesin 1B, part of the family of kinesins proteins. These proteins are essential for transporting material within cells. In addition to their transport functions, 1B kinesin protein appears to be involved in apoptosis. They described so far 6 missense mutations and a larger deletion in gene KIF1B. These mutations have been identified in individuals with type called pheochromocytoma paraganglioma. Pheochromocytomas specifically affect the adrenal glands. These tumors often cause no symptoms, but in some cases can produce excess hormones that cause an excessively high blood pressure. The KIF1B gene mutations are associated with nonsyndromic pheochromocytoma, meaning that the tumors occur without additional features of a hereditary syndrome. It is believed that mutations in the gene can alter KIF1B apoptosis, allowing the cells to grow and divide too fast or in an uncontrolled and potentially lead to tumor formation.
The RET gene, located on the long arm of chromosome 10 (10q11.2), encodes a protein that is involved in signaling within cells. This protein appears to be essential for normal development of various types of nerve cells, including neurons and enteric autonomic nervous system. The RET protein is also required for normal kidney development and spermatogenesis. Mutations in the RET gene increase the risk of developing pheochromocytoma. They have been described at least 316 mutations in the RET gene. The mutations described so far have been: missense mutations (230), and cutting mutations -splicing- junction (31), regulatory mutations (8), small deletions (17), small insertions (11), insertions / deletions small ( 13), deletions larger (3) and complex rearrangements (3). These mutations probably result in a protein that can trigger overactive RET cells grow and divide without control and can cause tumor formation.
The SDHA gene, located on the short arm of chromosome 5 (5p15), encoding one of the four subunits of the enzyme succinate dehydrogenase (SDH). SDH enzyme plays a critical role in mitochondria. Within the mitochondria, the enzyme SDH joining two important routes in energy conversion: the citric acid cycle (Krebs cycle) and oxidative phosphorylation. As part of the citric acid cycle, the SDH enzyme converts succinate to fumarate. During this reaction, electrons are released. SDHA active subunit protein is the enzyme that converts succinate, and also helps the electron transfer pathway of oxidative phosphorylation. In oxidative phosphorylation, electrons help create an electrical charge that provides the energy to produce adenosine triphosphate (ATP), the major source of cellular energy. Succinate, the compound in which the enzyme acts SDH, is an oxygen sensor in the cell and can help provide specific pathways that stimulate cells to grow into a low oxygen environment. In particular, succinate stabilizes a protein called hypoxia - inducible factor (HIF) by preventing a reaction would allow HIF decompose. HIF controls several important genes involved in cell division and the formation of new blood vessels in a hypoxic environment. Furthermore, SDHA gene is a tumor suppressor gene. Described so far 11 missense mutations in the gene SDHA. SDHA gene mutations are more common in people with paraganglioma, but have also been found in people with pheochromocytoma. Specifically, mutations SDHA genes associated with nonsyndromic paraganglioma or pheochromocytoma. A single mutation in the gene SDHA increases the risk that a person will develop the disease. However, an additional mutation (somatic mutation) that eliminates the normal copy of the gene to cause tumor formation is needed. Mutations in the gene result SDHA encoding SDH enzyme with little or no activity. Since mutated enzyme SDH can not convert succinate to fumarate, succinate accumulates in the cell. Excess succinate stabilizes HIF abnormally, which also accumulates in the cells. Excess HIF stimulates cells to divide and produce blood vessels is triggered when they are not needed. Rapid cell division and uncontrolled, along with the formation of new blood vessels, it can cause the development of tumors.
SDHB gene, located on the short arm of chromosome 1 (1p36.1-p35) encoding one of the four subunits of succinate dehydrogenase (SDH). As the gene SDHA, SDHB gene is a tumor suppressor. They have been described at least 161 mutations in the gene SDHB. The mutations described so far have been: missense mutations (79), and cutting mutations -splicing- connection (24), small deletions (30), small insertions (11), insertions / deletions small (3), major deletions ( 13) and insertions / higher duplications (1). These mutations reduce the activity of the enzyme SDH, that stabilizes HIF protein, causing it to accumulate in the cells. Excess protein HIF stimulates abnormal cell division and formation of blood vessels, which may lead to tumor formation.
SDHD gene, located on the long arm of chromosome 11 (11q23), encoding one of the four subunits of succinate dehydrogenase (SDH). SDHD gene, like the SDHA and SDHB is a tumor suppressor. They have been described at least 120 mutations in the SDHD gene. The mutations described so far have been: missense mutations (51), and cutting mutations -splicing- joint (11), small deletions (31), small insertions (11), insertions / deletions small (2), larger deletions ( 13) and complex rearrangements (1). Mutations in the gene have been indentificado SDHD in some cases of non - syndromic pheochromocytoma or paraganglioma. These mutations reduce the activity of the enzyme SDH, that stabilizes HIF protein, causing it to accumulate in the cells. Excess protein HIF stimulates abnormal cell division and formation of blood vessels, which can lead to tumor formation.
The TMEM127 gene, located on the long arm of chromosome 2 (2q11.2), encodes a protein that acts as a tumor suppressor. The TMEM127 protein controls a signaling pathway that guides the growth and cell survival. Although the specific action of the TMEM127 protein is unknown, this pathway regulated by the protein complex mTORC1, is blocked by the TMEM127 protein. They have been described at least 21 mutations in the gene TMEM127. The mutations described so far have been: missense mutations (13), and cutting mutations -splicing- joint (3), regulatory mutations (1), small deletions (2) and small insertions (2). Most people with paraganglioma or pheochromocytoma related to TMEM127 acquire an additional mutation (somatic mutation) that eliminates the normal copy of the gene. Mutations in this gene result in the reduction or absence of proteins TMEM127. As a result, the cell growth pathway controlled by TMEM127 protein is abnormally active, leading to tumor formation.
The VHL gene, located on the short arm of chromosome 3 (3p25.3), encodes a protein that acts as part of a complex called the complex VCB-CUL2. This complex targets other proteins for degradation by the cell when no longer needed. Protein degradation is a normal process which removes damaged or unnecessary proteins and helps maintain normal cell functions. One objective VCB-CUL2 complex of the HIF-2? is protein. HIF-2? is a subunit of HIF complex that plays a critical role in the body's ability to adapt to changes in oxygen levels. HIF controls several genes involved in cell division, formation of new blood vessels, and the production of erythrocytes. Furthermore, it is the main regulator of the hormone erythropoietin, which controls the production of erythrocytes. HIF function is particularly important when oxygen levels are lower than normal (hypoxia). However, when adequate oxygen is available, the complex VCB-CUL2 makes HIF accumulates inappropriately in cells. The VHL protein probably plays a role in other cellular functions, including regulation of other genes and control of cell division, so this protein is considered a tumor suppressor. The VHL protein is also involved in the formation of the extracellular matrix. They have been described at least 504 mutations in the VHL gene. The mutations described so far have been: missense mutations (226), and cutting mutations -splicing- junction (23), regulatory mutations (1), small deletions (80), small insertions (49), insertions / deletions small ( 10), deletions higher (113) and insertions / higher duplications (2). VHL gene mutations associated with non - syndromic paraganglioma or pheochromocytoma can be inherited or can occur spontaneously (novo or somatic mutations). These changes alter the function of the protein, which causes HIF-2? is not decomposed, and accumulated in the cells. Excess HIF stimulates cells to divide abnormally and triggers the production of blood vessels when they are not needed, which may lead to the development of paraganglioma or pheochromocytoma.
The nonsyndromic paraganglioma is inherited as an autosomal dominant, which means that a copy of the altered gene in each cell is sufficient to increase the risk of developing a paraganglioma or pheochromocytoma. People with mutations in the gene inherited an increased risk of the disease, not the disease itself. Moreover, not all persons concerned have a mutation in the gene, and not all people with a genetic mutation develop the disease. However, most cases of non - syndromic pheochromocytoma and paraganglioma are considered sporadic, meaning that tumors occur in people with no history of disease in your family.
Tests in IVAMI: in IVAMI perform the detection of mutations associated with nonsyndromic paraganglioma, by complete PCR amplification of the exons of the VHL, RET, SDHB, SDHD, TMEM127, SDHA and KIF1B genes, respectively, and subsequent sequencing .
Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).