Abstract
Ewing sarcoma (EWS), the second most common primary bone tumor in pediatric age, is known for its paucity of recurrent somatic abnormalities. Apart from the chimeric oncoprotein that derives from the fusion of EWS and FLI genes, recent genome-wide association studies have identified susceptibility variants near the EGR2 gene that regulate DNA binding of EWS-FLI. However, to induce transformation, EWS-FLI requires the presence of additional molecular events, including the expression of CD99, a cell surface molecule with critical relevance for the pathogenesis of EWS. High expression of CD99 is a common and distinctive feature of EWS cells, and it has largely been used for the differential diagnosis of the disease. The present study first links CD99 germline genetic variants to the susceptibility of EWS development and its progression. In particular, a panel of 25 single nucleotide polymorphisms has been genotyped in a case-control study. The CD99 rs311059 T variant was found to be significantly associated [P value = 0.0029; ORhet = 3.9 (95% CI 1.5-9.8) and ORhom = 5.3 (95% CI 1.2-23.7)] with EWS onset in patients less than 14 years old, while the CD99 rs312257-T was observed to be associated [P value = 0.0265; ORhet = 3.5 (95% CI 1.3-9.9)] with a reduced risk of relapse. Besides confirming the importance of CD99, our findings indicate that polymorphic variations in this gene may affect either development or progression of EWS, leading to further understanding of this cancer and development of better diagnostics/prognostics for children and adolescents with this devastating disease.
Highlights
Ewing's sarcoma (EWS) is a highly malignant musculoskeletal tumor that preferentially displays aggressive growth, with approximately 30% of patients harboring disseminated metastatic disease at the time of diagnosis, the most common sites being the lungs and/or bones [1]
The CD99 rs311059 T variant was found to be significantly associated [P value = 0.0029; odds ratio for heterozygote (ORhet) = 3.9 and ORhom = 5.3] with Ewing sarcoma (EWS) onset in patients less than 14 years old, while the CD99 rs312257-T was observed to be associated [P value = 0.0265; ORhet = 3.5] with a reduced risk of relapse
We examined the genetic influence of CD99 polymorphisms on EWS susceptibility in a representative sample of the Italian population
Summary
Ewing's sarcoma (EWS) is a highly malignant musculoskeletal tumor that preferentially displays aggressive growth, with approximately 30% of patients harboring disseminated metastatic disease at the time of diagnosis, the most common sites being the lungs and/or bones [1]. The tumor is more common in Caucasians while it rarely appears in individuals of African or Asian heritage [2,3,4,5,6]. This observation together with reports indicating EWS in siblings or cousins [7, 8], suggests that genetic susceptibility factors may exist for this tumor, among European population. Genome-wide scan for EWS susceptibility loci identified two common variants associated with higher susceptibility to EWS in French population [9]: a variant mapping in 1p36.22 and located proximal to the TARDBP gene
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