Osteosarcoma (osteogenic sarcoma, osteosarcoma) - Genes RB1, TP53 and CHEK2.

Osteosarcomas are the most common primary bone tumors with high incidence in children and adolescents compared to other ages. These tumors appear most frequently in long bones, in areas adjacent to the growth plates, and less frequently in the axial skeleton and other bones. Signs and symptoms associated with osteosarcoma may include inflammation over a bony part, pain in a bone or joint, bone fractures without known reason and limited movement.

Osteosarcomas are characterized by a high degree of genomic instability, specifically a subset of instability called "chromosomal instability (CIN Chromosomal instability). This instability is characterized by a high proportion of acquisition or loss of chromosomes or parts of complete chromosomes, significantly in the pathogenesis of osteosarcoma, leading to highly variable structural and numerical aberrations between cells.

The first observation of an association between osteosarcoma with a hereditary predisposition, was conducted to find patients with bilateral retinoblastoma having a higher incidence of osteosarcoma, so intuited that genetic alterations retinoblastoma, could be involved in the development of osteosarcomas. Subsequently, the RB1 gene was found on chromosome 13, also showing that such mutations appear in a high percentage of osteosarcomas. Syndrome familial cancer Li-Fraumeni, which was characterized by rhabdomyosarcoma, breast tumor and other tumors, including osteosarcoma is, and its relationship with p53 (TP53), led to the conclusion the association between abnormalities this gene and development of osteosarcomas.

This process is due to mutations in the RB1, TP53 and CHEK2 gene. These genes involved in the control point cell mitosis, so that when altered by mutation or dysregulation, lead to chromosome instability (CIN). In this respect, mutations in the TP53 gene are correlated with high levels of chromosomal instability in osteosarcoma, as with the RB1 gene mutation.

RB1, located on the long arm of chromosome 13 (13q14.2), encoding the protein pRb, which acts as a tumor suppressor. Under certain conditions, the protein pRb stops other proteins that trigger DNA copying. Because the DNA copy must occur before a cell divides, the strict regulation of this process controls cell division and helps prevent tumor growth. Furthermore, PRB interacts with other proteins to influence differentiation, cell survival and apoptosis. RB1 somatic mutations in cancer cells inactivate protein pRb so can no longer regulate cell division effectively.

TP53, located on the short arm of chromosome 17 (17p13.1), encodes a protein called p53 protein which acts as a tumor suppressor. The p53 protein is found in the nuclei of cells throughout the body, where it binds directly to DNA. When DNA in a cell is damaged, this protein plays a critical role in determining whether the DNA will be repaired or damaged cell is induced to apoptosis. If DNA can be repaired, p53 activates other genes to repair the damage. If the DNA can not be repaired, this protein prevents the cell from dividing and induces apoptosis. Most TP53 mutations change the individual amino acids in the protein p53, which leads to the codification of an altered version of the protein can not effectively control growth and cell division. As c onsecuencia, cells can grow and divide in a unregulated manner, which can lead to cancerous tumors.

CHEK2 gene, located on the long arm of chromosome 22 (22q12.1), encoding the protein CHK2 (check point kinase 2) acting as a tumor suppressor, regulating cell division, preventing cells grow and divide rapidly or uncontrollably. CHK2 protein is activated when DNA is damaged or broken chains, as by the action of agents such as toxic chemicals, radiation, UV sunlight, or the exchange of genetic material. In response, the protein interacts with other proteins, including p53, stopping cell division and determining whether the cell repairs the damage or apoptosis is induced. A mutation identified in the CHEK2 gene (1100delC) leads to encoding a nonfunctional version of CHK2 protein. As a result, cells can grow and divide in a unregulated manner, which can lead to osteosarcoma and other cancerous tumors.

Genetic alterations that can be found in the osteosarcoma can be found in tumor cells (somatic mutations, not inherited), or in blood cells (germline mutations, inherited).

Tests in IVAMI: in IVAMI perform detection of mutations associated with osteosarcoma by the complete PCR amplification of the exons of RB1, TP53 and CHEK2, respectively, genes and subsequent sequencing.

Samples recommended: for detection of somatic mutations (not inherited), tissue from biopsy; detection germline mutations (inherited), 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).