2.1 Ewing Sarcoma

Mutations involving the FLI1 gene cause a type of cancerous tumor known as Ewing sarcoma. These tumors develop in bones or soft tissues such as nerves and cartilage. There are several types of Ewing sarcoma, including Ewing sarcoma of bone, extraosseous Ewing sarcoma, peripheral primitive neuroectodermal tumor, and Askin tumor. The mutations that cause these tumors are acquired during a person's lifetime and are present only in the tumor cells. This type of genetic change, called a somatic mutation, is not inherited. The most common mutation that causes Ewing sarcoma is a rearrangement (translocation) of genetic material between chromosome 11 and chromosome 22. This translocation, written as t(11;22), fuses part of the FLI1 gene on chromosome 11 with part of another gene called EWSR1 on chromosome 22, creating an EWSR1/FLI1 fusion gene.

The protein produced from the EWSR1/FLI1 fusion gene, called EWS/FLI, has functions of the protein products of both genes. Like the FLI protein, the EWS protein, produced from the EWSR1 gene, can regulate transcription. The EWS/FLI protein has the DNA-binding function of the FLI protein as well as the transcription regulation function of the EWS protein. It is thought that the EWS/FLI protein turns the transcription of a variety of genes on and off abnormally. This dysregulation of transcription leads to uncontrolled growth and division (proliferation) and abnormal maturation and survival of cells, causing tumor development.

The EWSR1/FLI1 fusion gene occurs in approximately 85 percent of Ewing sarcomas. The remaining tumors result from translocations that fuse the EWSR1 gene with other genes.

2.2 Jacobsen Syndrome