CD99 polymorphisms significantly influence the probability to develop Ewing sarcoma in earlier age and patient disease progression

// Marcella Martinelli 1 , Alessandro Parra 2, 3 , Luca Scapoli 1 , Paola De Sanctis 1 , Valentina Chiadini 2, 3 , Claudia Hattinger 3 , Piero Picci 3 , Cinzia Zucchini 1, * , Katia Scotlandi 2, 3, * 1 Department of Experimental Diagnostics and Specialty Medicine (DIMES), University of Bologna, Bologna, Italy 2 CRS Development of Biomolecular Therapies, Oncology Laboratory, Rizzoli Orthopaedic Institute, Bologna, Italy 3 Experimental Oncology Laboratory, Rizzoli Orthopaedic Institute, Bologna, Italy * Both authors have shared senior authorship Correspondence to: Katia Scotlandi, email: katia.scotlandi@ior.it Keywords: CD99, Ewing sarcoma, polymorphisms, association analysis Received: July 11, 2016 Accepted: October 03, 2016 Published: October 25, 2016 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 CD9 9 rs311059 T variant was found to be significantly associated [ P value = 0.0029; OR het = 3.9 (95% CI 1.5-9.8) and OR hom = 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; OR het = 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.