What causes ewing sarcoma

Overview

Ewing sarcoma is a rare but aggressive type of cancer that begins in the bones or soft tissues. It most commonly occurs in children and young adults, typically between the ages of 10 and 20. While the exact cause of most cancers remains a complex puzzle, Ewing sarcoma has a more clearly defined underlying mechanism involving specific genetic mutations. Understanding these causes is crucial for diagnosis, research, and the development of targeted therapies.

What Causes Ewing Sarcoma?

The development of Ewing sarcoma is predominantly linked to specific genetic alterations within a cell's DNA. Unlike many other cancers where the cause might be a combination of genetic predisposition and environmental factors, Ewing sarcoma is largely attributed to unique chromosomal abnormalities.

Chromosomal Translocation: The Primary Culprit

The hallmark genetic change associated with Ewing sarcoma is a type of mutation called a chromosomal translocation. In this process, two different chromosomes break and swap sections of genetic material. For Ewing sarcoma, the most common translocation, occurring in about 85% of all cases, involves chromosomes 11 and 22. This is often written as t(11;22).

This specific translocation results in the fusion of two genes: the EWSR1 gene from chromosome 22 and the FLI1 gene from chromosome 11. The resulting hybrid gene is called EWS-FLI1. This fusion gene produces an abnormal protein that acts as a transcription factor, meaning it can control the activity of other genes. The EWS-FLI1 protein is thought to be a key driver in the development of Ewing sarcoma. It interferes with normal cellular processes, leading to uncontrolled cell growth and division, which is the hallmark of cancer.

The Role of the EWS-FLI1 Fusion Protein

The EWS-FLI1 protein is an "oncoprotein," a type of protein that can cause cancer. It disrupts the normal regulation of genes involved in cell growth, differentiation (specialization), and programmed cell death (apoptosis). By altering the expression of these genes, the EWS-FLI1 protein essentially "switches on" pathways that promote tumor formation and progression. This abnormal protein is found in virtually all Ewing sarcoma tumors with the t(11;22) translocation.

Other Genetic Changes

While the EWS-FLI1 fusion is the most common genetic event, a small percentage of Ewing sarcoma cases involve different translocations that create similar fusion genes with other partners (e.g., EWS-ERG, EWS-DAT). Regardless of the specific fusion gene, the underlying mechanism involves an aberrant transcription factor driving uncontrolled cell proliferation.

What Triggers These Genetic Changes?

This is where the cause becomes less clear. For the vast majority of individuals diagnosed with Ewing sarcoma, the genetic changes are acquired, not inherited. This means the mutations occurred spontaneously in a single cell during a person's lifetime, rather than being passed down from parents. The exact event or trigger that initiates these chromosomal translocations in a specific cell is unknown. Unlike some cancers linked to specific environmental exposures (like UV radiation for skin cancer or certain viruses for others), there is no known environmental risk factor strongly associated with causing Ewing sarcoma.

Is Ewing Sarcoma Inherited?

It is important to emphasize that Ewing sarcoma is rarely an inherited condition. In the vast majority of cases, the genetic mutations are sporadic, meaning they happen by chance. There are very rare instances where families may have a slightly increased risk, possibly due to underlying genetic predispositions, but this is not the typical presentation. Genetic counseling may be recommended for individuals with a strong family history or other concerning factors.

Why Does It Affect Children and Young Adults?

The reason Ewing sarcoma predominantly affects children and adolescents is still being investigated. One theory is that the developing cells in bone and soft tissue during these growth phases might be more susceptible to the types of genetic errors that lead to this cancer. The specific cellular environment and processes occurring during rapid growth and development might play a role in the initiation or progression of the disease.

Summary of Causes

In summary, Ewing sarcoma is caused by specific genetic mutations, most commonly a chromosomal translocation leading to the EWS-FLI1 fusion gene. This abnormal protein drives uncontrolled cell growth. These genetic changes are typically acquired, not inherited, and the precise trigger remains unknown. The disease's predilection for younger individuals is likely related to developmental processes in bone and soft tissues during childhood and adolescence.