Multiple myeloma (multiple myeloma) - Genes BRAF, CCND1, FGFR3, IRF4, LIG4, MUM1 and chromosome 14


Multiple myeloma is a cancer that develops in the bone marrow and characterized by abnormal plasma cells. These abnormal cells divide without control, increasing and reaching between 1% and most cells of the bone marrow. Abnormal cells form tumors in the bone, causing bone pain and an increased risk of fractures. If the tumors interfere with nerves near bones, they can lead to numbness or weakness in the arms or legs. Affected individuals may also suffer a loss of bone tissue, especially in the skull, spine, ribs and pelvis. Bone deterioration can cause hypercalcemia, which can lead to nausea, loss of appetite, excessive thirst, fatigue, muscle weakness and confusion.

The abnormal plasma cells in multiple myeloma produce proteins that prevent the development of normal blood cells. As a result, affected individuals may have anemia, which can cause fatigue, weakness, pale skin; leucopenia, which can lead to a weakened immune system and frequent infections such as pneumonia; and thrombocytopenia, which can cause bleeding and bruising. In addition, affected individuals may show kidney problems due to hypercalcemia or toxic proteins produced by abnormal plasma cells.

People with multiple myeloma disease usually appear around 65 years old. Over time, affected individuals can develop life - threatening complications, but the rate at which this happens is very variable. Some affected individuals are diagnosed incidentally when tests are performed for other purposes and have no symptoms for years.

The cause of multiple myeloma is not clear. Somatic mutations have been identified in people with multiple myeloma. Some of these changes affect genes that play a critical role in the regulation of cell division through its control. Mutations in these genes can interfere with the regulation of cell growth and division, resulting in excessive proliferation of plasma cells that characterize multiple myeloma. Translocations are frequent somatic events in multiple myeloma. Most often, translocations involve an exchange between chromosome 14 and another chromosome, which probably affects genes that control growth and cell division. It is estimated that between 20 and 60 percent of multiple myeloma cases are due to a translocation which occurs in the region 14q32 chromosome 14.

Close relatives of people with multiple myeloma have an increased risk of developing the disease by themselves, suggesting that hereditary variations in certain genes may contribute to the development of the disease in some individuals. By contrast, other inherited genetic variations appear to reduce the risk of developing multiple myeloma.

There are certain non - genetic factors that increase the risk of developing multiple myeloma. These factors include radiation or other radiation exposure. Exposure to certain chemicals, including benzene has also been found to increase the risk of myeloma. Benzene, a known carcinogen, is a petroleum product used as an industrial solvent and a gasoline additive.

Some of the genes identified in the development of multiple myeloma include the BRAF gene (B-Raf proto-oncogene, serine / threonine kinase), CCND1 (cyclin D1), FGFR3 (Fibroblast Growth Factor Receptor 3), IRF4 (Interferon regulatory factor 4 ), LIG4 (DNA ligase 4) and MUM1 (melanoma associated antigen mutated 1).

BRAF (B-Raf proto-oncogene, serine / threonine kinase), located on the long arm of chromosome 7 (7q34), encodes a protein that helps transmit chemical signals from outside the cell to the cell nucleus. This protein is part of a signaling pathway known as the RAS / MAPK pathway, which controls several important cellular functions. Specifically, the RAS / MAPK pathway regulates growth and proliferation, differentiation, migration and apoptosis. Chemical signaling through this pathway is essential for normal development before birth. The BRAF gene belongs to a class of genes known as oncogenes, meaning that a mutation in them has the potential to cause normal cells to become cancerous.

The CCND1 (cyclin D1) gene, located on the long arm of chromosome 11 (11q13), encoding a protein belonging to the cyclin family. Cyclins function as regulators of CDKs. Specifically, this cyclin forms a complex acting as a regulatory subunit of CDK4 or CDK6, whose activity is required for G1 / S transition cell cycle. It has been shown that this protein interacts with the tumor suppressor protein Rb and expression of this gene is regulated positively by Rb.

FGFR3 gene (Fibroblast Growth Factor Receptor 3), located on the short arm of chromosome 4 (4p16.3), encodes a protein called receptor fibroblast growth factor 3. This protein is part of a family of receptors factor fibroblast growth that share similar structures and functions. These proteins play a role in several important cellular processes, including the regulation of growth and cell division, determining the cell type, the formation of blood vessels, wound healing and embryonic development. The FGFR3 protein across the cell membrane, so that one end of the protein remains inside the cell and the other end remains on the outer surface. This positioning of the protein allows it to interact with specific growth factors outside the cell and receive signals that control growth and development. When these growth factors bind to the FGFR3 protein, protein triggers a cascade of chemical reactions within the cell that instruct to perform certain changes, such as maturation assume specialized functions. Several isoforms of the FGFR3 protein are encoded from the FGFR3 gene. Different isoforms are found in various tissues of the body and interact with a variety of growth factors. Many isoforms are found in the cells that form bones. It is believed that bone cells, the protein FGFR3 regulates bone growth by ossification, particularly in the long bones. One particular isoform of FGFR3 protein is specifically in epithelial cells, including the cells that form the epidermis.

The IRF4 gene (Interferon regulatory factor 4), located on the short arm of chromosome 6 (6p25.3), encodes a protein belonging to the IRF family (interferon regulatory factor) transcription factors, characterized by a single domain DNA binding in repeating group of five tryptophan. The FRI are important in regulating interferons involved in the response to virus infection, and regulation of interferon-inducible genes. A chromosomal translocation involving the gene and the IgH locus, t (6; 14) (p25; q32), can be a cause of multiple myeloma.

LIG4 gene (DNA ligase 4), located on the long arm of chromosome 13 (13q33-q34), encodes a DNA ligase that binds to fragments of single strands in double stranded polydeoxynucleotide in an ATP - dependent reaction. This protein is essential for V (D) J recombination and repair of DNA double strand breaks (DSB) through non - homologous recombination (NHEJ). This protein forms a complex with the crosslinking introduced by the X - ray complementing protein 4 (XRCC4) and also interacts with the DNA - dependent protein kinase (DNA-PK). Both XRCC4 and DNA-PK soe known to be required for NHEJ.

The MUM1 gene (melanoma associated antigen mutated 1), located on the short arm of chromosome 19 (19p13.3), involved in the response pathway DNA damage, contributing to the maintenance of chromatin architecture. It is grouped in the vicinity of DNA breaks by TP53BP1 and plays a complementary role to facilitate induced changes in chromatin damage and promote relaxation of chromatin. It is required for efficient DNA repair and cell survival after DNA damage.

Multiple myeloma usually not inherited but arises from somatic mutations in plasma cells. An increased risk of developing multiple myeloma appears to occur in some families, but the pattern of inheritance is unknown.

Tests in IVAMI: in IVAMI perform the detection of mutations associated with multiple myeloma by the complete PCR amplification of the exons of BRAF, CCND1, FGFR3, IRF4, LIG4 and MUM1 genes, respectively, and the main affected regions in the region 14q32 chromosome 14, 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).