Abstract 120P
Background
Several data indicate that Ewing Sarcoma (ES) is susceptible to DNA-damaging agents. We hypothesize that the two major repair pathways that can restore double-strand breaks (DSBs), nonhomologous end joining (NHEJ) and homologous recombination (HR), are deregulated in ES.
Methods
Pre-treatment FFPE whole tissue sections from 25 ES patients were employed. The relative quantification of 6 genes involved in NHEJ (XRCC4, XRCC5, XRCC6, POLλ, POLμ, RAD51) and 9 genes involved in HR (RAD52, RAD54, BRCA1, BRCA2, FANCC, FANCD, DNTM1, BRIT1) was assessed by Real Time PCR. Survival analysis was performed using the R studio Version 1.4.1717. All statistical testing was performed using a two-sided significance level of α=0.05.
Results
High XRCC4 expression was significantly associated with shorter OS (Hazard Ratio, HR 5.57, P=0.04). In addition, statistically significant differences in expression of DSB genes were found between ES and normal tissue samples. In ES samples XRCC5 and LIG4 were upregulated (P=0.02 and P=0.001), POLλ and POLμ downregulated (P=0.001 and P=0.001). Regarding HR genes in ES, RAD51, RAD52 and FANCD were upregulated (P=0.001, P=0.001 and P=0.003 respectively) whereas RAD54 and BRCA2 were downregulated (P=0.03 and P=0.02).
Conclusions
Our study indicates that both NEHJ and HR DSB repair pathways are deregulated in ES. High XRCC4 expression is related to shorter survival in ES patients. Larger studies and prospective clinical trials with agents targeting DNA repair pathways, like Poly (ADP-ribose) polymerase (PARP) inhibitors, are required to validate these initial observations.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.