Neuroblastoma (neuroblastoma) - Genes ALK, KIF1B, MYCN and PHOX2B.  

Neuroblastoma is a cancer that most often affects children. This alteration occurs when neuroblasts multiply uncontrollably forming a tumor. Most often, the tumor originates in nerve tissue of the adrenal gland located above each kidney. Other common areas in which the tumor forms include nervous tissue in the abdomen, chest, neck or pelvis. Moreover, the neuroblastoma can spread to other parts of the body with bone metastases, liver or skin.

Affected individuals may develop signs and general symptoms such as irritability, fever, fatigue, pain, loss of appetite, weight loss and diarrhea. Other signs and symptoms depend on the specific location of the tumor and where it has spread. A tumor in the abdomen can cause bloating. A tumor in the chest can cause respiratory distress. A tumor neck may cause nerve damage known as Horner 's syndrome, causing drooping eyelids, small pupils, decreased sweating, skin and red. A bone metastases can cause pain in the bones, bruises, pale skin or dark circles around the eyes. Tumors in the spine can put pressure on the spinal cord, causing weakness, numbness or paralysis of the arms or legs. The appearance of blue or violet areas indicates that neuroblastoma has spread to the skin.

Furthermore, neuroblastoma tumors can release hormones that can lead to other signs and symptoms such as high blood pressure, palpitation, redness, and sweating. Rarely, people with neuroblastoma may develop opsoclonus myoclonus syndrome, characterized by rapid eye movement, jerky muscle movements. This alteration occurs as a result of malfunction of the immune system attacks the nerve tissue. Neuroblastoma is most common in children before age 5 rarely occurs in adults.

Neuroblastoma and other cancers occur when an accumulation of genetic mutations in critical genes that control growth, proliferation and cell differentiation occurs, allowing the cells to grow and divide uncontrollably forming a tumor. It has been shown that mutations in the ALK and PHOX2B genes increase the risk of sporadic and familial neuroblastoma. Furthermore, the deletion of certain regions in the KIF1B gene are associated with the development of neuroblastoma. On the other hand, genetic changes in the MYCN gene is associated with the severity of the disease, but it is believed that it is not the cause.

ALK gene, located on the short arm of chromosome 2 (2p23), encodes a protein called anaplastic lymphoma kinase, part of receptor tyrosine kinases (RTKs). The receptor tyrosine kinases transmit signals from the cell surface into the cell through signal transduction. Although the specific function of this protein is unknown, it appears to play an important role in cell proliferation. They have identified at least 16 mutations in the ALK gene in some people with neuroblastoma. Mutations in ALK change amino acids in the anaplastic lymphoma kinase. The most common mutation replaces the amino acid arginine for glutamine at amino acid position 1275 (Arg1275Gln or R1275Q). This mutation has been identified both in the family and sporadic neuroblastoma. Changes in the ALK gene lead to an abnormal version of the protein that is constitutively active, which induces abnormal proliferation of immature nerve cells and leads to neuroblastoma.

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 kinesin proteins. These proteins are essential for transporting material within cells. In addition to their transport function, the kinesin protein 1B appears to be involved in apoptosis. Deletion of a region containing the KIF1B gene has been identified in some individuals with neuroblastoma. These mutations change individual amino acids in the protein 1B kinesin family member. It is likely that deletion or mutation of the gene may interrupt KIF1B apoptosis, allowing the cells to grow and divide too fast or uncontrolled. This type of regulated cell growth may not lead to tumor formation.

MYCN gene, located on the short arm of chromosome 2 (2p24.3), encodes a protein that plays an important role in the formation of tissues and organs during embryonic development. It is believed that this protein is required for normal development of the limbs, heart, kidneys, nervous system, digestive system and lungs. MYCN protein regulates the activity of other genes by binding to specific DNA regions. MYCN gene belongs to a class of genes known as oncogenes. When mutations in oncogenes, they have the potential to cause normal cells to become cancerous occur. The MYCN gene is a member of the MYC oncogene family. These genes play an important role in regulating the growth, proliferation and apoptosis. About 25% of people with neuroblastoma have extra copies of the MYCN gene, a phenomenon known as gene amplification. However, it is not clear how the amplification of this gene contributes to the aggressive nature of neuroblastoma.

The PHOX2B gene, located on the short arm of chromosome 4 (4p12), encodes a protein that acts in early development to help promote the formation of neurons and regulate the differentiation of neurons. The protein is active in the neural crest. The cells migrate from the neural crest to form part of the autonomic nervous system which controls some body functions such as breathing, blood pressure, heart rate and digestion. The neural crest cells also give rise to many tissues of the face and skull, and other cell types and tissues. The protein encoded by the gene PHOX2B contains two areas in which the amino acid alanine is repeated several times. These sections are known as alanine or polyalanine extensions poly (A). Several mutations have been identified in the PHOX2B gene in people with neuroblastoma. Some of these mutations change the amino acids in protein PHOX2B. Other mutations involve the addition or deletion of nucleotides in the gene PHOX2B. It is considered that mutations interfere with the function of the protein PHOX2B, leading to an excess of immature nerve cells and neuroblastoma.

Most people with neuroblastoma have sporadic neuroblastoma, ie, the disease arises from somatic mutations in body cells and not inherited. However, about 1% to 2% of affected individuals have familial neuroblastoma. This form of the disease is an autosomal dominant inheritance, which means that a copy of the altered gene in each cell increases the risk of developing the disease. However, heredity is considered to have incomplete penetrance because not all people who inherit the altered gene develops neuroblastoma. Have the altered gene predisposes an individual to develop neuroblastoma, but probably an additional somatic mutation would be needed for the disease to be expressed.

Tests in IVAMI: in IVAMI perform detection of mutations associated with neuroblastoma, by complete PCR amplification of the exons of ALK, KIF1B, MYCN and PHOX2B 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).