Ewing sarcoma, a rare type of bone cancer, is diagnosed in only about 250 children and teenagers in the United States each year. The vast majority of Ewing sarcomas are caused by a specific rearrangement of the DNA within bone cells – the EWSR1 gene on chromosome 22 becomes fused to the FLI1 gene on chromosome 11. This EWSR1-FLI1 fused gene produces a dysfunctional protein that fails to correctly regulate important cell functions, leading to extremely aggressive tumors.
Not much is known about the genetics of Ewing sarcoma but researchers have long suspected a genetic component. Children of European ancestry are affected much more frequently than children of Asian or African ancestry, and having a sibling or a cousin with Ewing sarcoma also increases a child’s risk for the condition. The rarity of the disease, however, has made genetic studies very difficult.
Last month, scientists from the Cancer Research Center of Lyon and the Institut Curie in Paris published the first genome-wide association study reporting possible genetic susceptibility factors for Ewing sarcoma. The research team, led by David Cox and Oliver Delattre, compared over 1,000 patients with Ewing sarcoma to approximately 2,000 healthy individuals and discovered several SNPs associated with the condition.
One of these SNPs, , is located near the TARDBP gene. The researchers found that each copy of a T at was associated with about 2.2 times lower odds of Ewing sarcoma. For another SNP, , the C version was associated with 1.66 times higher odds of Ewing sarcoma.
Both of these SNPs have some biological connection to the disease. The TARDBP gene turns out to be structurally similar to EWSR1 and FLI1, the two genes that are fused together in most Ewing sarcoma cells. The researchers in this study also noted that individuals with genotypes associated with higher Ewing sarcoma risk produced more TARDBP protein than individuals with the lower-risk genotypes, though how exactly this relates to the development of Ewing sarcoma is still to be determined.
Similarly, is located near another gene – EGR2 – with a link to EWSR1 and FLI1. Cox and his team found that individuals with Ewing sarcoma have higher EGR2 protein production than individuals with other types of sarcoma. They also show that the protein encoded by the EWSR1-FLI1 fused gene that is seen in so many Ewing sarcoma cells regulates the production of EGR2 protein.
This study represents the first genome-wide association study in this rare condition but it is only a first step. More research in large groups of sarcoma patients is still needed to further investigate these associations and determine whether these variants affect Ewing sarcoma risk in other populations.
Correction: This post previously contained a typo in which “FLI1″ was replaced by “FUS” in some locations. This mistake has been corrected.
Editor’s note: Pending an FDA decision, 23andMe no longer offers new customers access to health reports referred to in this post. Customers who purchased prior to November 22, 2013 will still be able to see their health reports, but those who purchased after that time will not. Those customers will have access to ancestry information as well as access to their uninterpreted raw data.