Li Fraumeni syndrome ... (Li Fraumeni syndrome) - Genes TP53 and CHEK2.

Li Fraumeni syndrome is a hereditary cancer syndrome associated with clinically and genetically heterogeneous. This alteration is characterized by early onset of tumors generally, multiple times in the same individual, and the condition of several members of the same family. Penetrance differs between the sexes: at age 50, the penetrance in women is 93% and men 68%. The average age of detection is 29 years for women and 40 years for men, can be detected routinely in children and adolescents (some authors claim that the penetrance before age 16 is 40%). Most hereditary cancer syndromes are characterized by the condition of a specific place, such as in breast cancer, colorectal carcinoma or melanomas, while the Li Fraumeni syndrome is associated with a variety of tumors. The most common are breast cancers, osteosarcoma and soft tissue sarcomas. In addition, leukemias and carcinomas include adrenocortical. A wide range of other malignancies, including neuroblastoma , and pancreatic tumors, also associated with this syndrome.

Li Fraumeni syndrome is caused by germline genetic alterations in tumor suppressor gene TP53, located on the short arm of chromosome 17 (17p13.1). This gene encodes a 2.8 kb mRNA encoding the p53 protein, a tumor suppressor protein, about 20 minutes of half - life which is mainly localized in the nucleus, but can also be detected in plasma in G1 phase and during DNA synthesis as p53 function is cell cycle control during G1 phase by transactivation of genes encoding proteins with growth suppressing activity. However, p53 is not necessary for growth and normal functioning of the cell, but to suppress tumor development. In hypoxia, or DNA damage, concentrations of p53 increase rapidly, paralyzing the cell cycle in the G1 phase, which allows the cell to have time to repair DNA and, if not possible, induce apoptosis.

They have identified 60 mutations in the TP53 gene in individuals with Li Fraumeni syndrome. Many of the mutations change individual amino acids in the part of the p53 protein which binds to DNA. Other mutations eliminate small amounts of DNA in the gene. These changes result in a version of p53 that can not effectively regulate growth and cell division. Specifically, the altered protein is not able to trigger apoptosis in cells with mutated or damaged DNA. As a result, DNA damage can accumulate in the cells to divide resulting in an uncontrolled manner, leading to tumor growth. Cancers most often caused by somatic mutations in the TP53 gene are, among others, ovarian cancer, colorectal, esophagus, head and neck, larynx, lung, pancreas, etc. Generally, these mutations are more common in the more aggressive subtypes.

In other cases, it is associated with the CHEK2 gene (Check Point kinase 2), which like the TP53 gene is a tumor suppressor. This gene encodes the protein CHK2 (check point kinase 2), which acts as a tumor suppressor, regulating cell division, preventing cells from growing and rapidly or uncontrollably dividing. 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 or repairs damage (apoptosis) is self - destructing. Although most cases of the disease are associated with mutations in the TP53 gene mutations in CHEK2 gene they have been identified in several families with this alteration characteristic cancers. The 1100delC mutation was identified in one of these families. There is no assurance whether mutations in the gene CHEK2 actually cause the syndrome or are simply associated with an increased risk of various cancers, including cancers that are often observed in Li Fraumeni syndrome.

This disease 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 cancer. In most cases, an affected person has a father and other family members with the disease characteristic cancers.

Tests in IVAMI: in IVAMI perform detection of mutations associated with Li Fraumeni syndrome of, by complete PCR amplification of the exons of TP53 and CHEK2, respectively, genes 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). For detection of somatic mutations, tissue from biopsy.