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- Patrick Grohar (United States of America)
- Anita Mahajan (United States of America)
Introduction
- Anita Mahajan (United States of America)
- Patrick Grohar (United States of America)
TELOMERE SIZE IS ASSOCIATED WITH RELAPSE IN OSTEOSARCOMA
- Thauanna A. Meira (Brazil)
Abstract
Background and Aims
Osteosarcoma is a malignant neoplasm that originates in the progenitor cells of the bone, mostly affecting long bones. It presents features of chromosomal instability, high levels of mutations and epigenetic changes. For the last 30 years there is no significant changes in the survival rates. Understanding the underlying mechanisms of osteosarcoma tumorigenesis may help to develop more effective treatments. The telomere is essential for chromosome-end protection and genomic stability.
Methods
We evaluated telomere size in osteosarcoma samples and searched for associations with clinical and pathological characteristics in 41 children and adolescents. DNA was extracted from the osteosarcoma samples and was submitted to a real time polymerase chain reaction (qPCR) with SybrGreen. Cawthon method was applied for relative measurement of telomere length and the t-test was used to compare groups. There were 21 males and 17 females aged from 6 to 28 years at diagnosis (mean 13, median 13).
Results
Telomere length was associated with relapse but not with gender, body mass index, bone locations, metastasis at diagnosis, histology or death. Patients that relapsed following end of treatment presented increased telomere length compared to those patients that did not relapse.
Conclusions
Characterization of expression of genes that controls telomere size should help to understand the mechanism associated with osteosarcoma progression. Telomere length could be used as a prognostic marker in patients with osteosarcoma.
A THREE-GENE SIGNATURE TO PREDICT SURVIVAL IN PEDIATRIC OSTEOSARCOMAS (OS) AND TO FOLLOW PATIENTS TOWARDS LIQUID BIOPSY: A COLLABORATIVE WORK IN OS2006 SFCE PROTOCOL.
- Natacha Entz-Werlé (France)
Abstract
Background and Aims
The overall survival of pediatric OS is stable worldwide since two decades. The management of OS is lacking new approaches to classify closely the patients and adapt thereafter the chemo-treatments since diagnosis. The objectives of our molecular study, using allelotyping, quantitative PCR (qPCR) and droplet digital PCR (ddPCR), were to determine the survival impact of specific genes involved in bone de-differentiation and study them in the initial tumor biopsy, in the tumor resection after neoadjuvant chemotherapy and on circulating DNA at different treatment steps. This panel was originally identified in the tumor cohort of the French protocol OS94 and demonstrated a significant prognostic impact of 3 genes MET, TWIST and APC. To go further and understand signature significance, the same study was performed in the recent OS2006 protocol.
Methods
We performed retrospectively in the cohort of OS2006 protocol (144 patients at diagnosis, 32 patients with resected tumors) the molecular targeting of those 3 genes. Allelotyping, copy number variations by qPCR and ddPCR were used. A preliminary cohort of 28 patients with liquid biopsies at diagnosis, before tumor surgery and at the end of chemotherapy was screened by ddPCR with this gene panel.
Results
We were able to determine frequent rearrangements in the 3 genes and a statistically significant correlation was made between the presence of gene rearrangements and a worst outcome. The 3-gene signature was significantly predicting the outcome of more than 70% of OS patients. Furthermore, on the tumor resection, the persistence or appearance of new clones was significantly correlated to a higher risk of relapse. This 3-gene signature was also usable for residual disease assessment on plasmatic DNA and we were able to follow closely patients' evolution.
Conclusions
This molecular signature was able to provide evidence that this approach is a powerful tool to be used in pediatric OS follow up.
EWS/FLI1 HIJACKS UHRF1 TO DRIVE THE MALIGNANCY OF EWING SARCOMA
- Busheng B. Xue (Germany)
Abstract
Background and Aims
Ewing sarcoma (EwS) is genetically characterized by a balanced chromosome translocation forming the EWS/ETS chimeric oncoprotein, most frequently EWS/FLI1. Low mutation burden raises the possibility that epigenetic alterations play a role in the malignancy of EwS. It has been suggested that the chimeric protein participates in aberrant DNA methylation of EwS while its mechanism remains elusive. UHRF1maintains the faithful inheritance of DNA methylation by taking advantage of multiple domains. We studied the interaction of EWS/FLI1 and UHRF1 in DNA methylation in EwS, as well as the mechanisms of the specific DNA methylation pattern in EwS.
Methods
Immunohistochemistry was performed to check the expression of UHRF1 in different donors including EwS. GEO datasets were used to check and correlate their expression with different statuses and prognosis. Immunofluorescence, immunoprecipitation, and GST-pulldown were performed to detect their direct interaction. In vitro and in vivo experiments were performed to study the therapeutic efficiency of targeting UHRF1 in EwS.
Results
UHRF1 is highly expressed in EwS, and high expression of UHRF1 correlates with recurrence (P<0.001) and metastasis (P<0.001). Knockdown of UHRF1 limits tumor growth in vitro (P<0.0001) and in vivo (P<0.01). Our work demonstrates EWS/FLI1 binding to the SRA domain of UHRF1 to maintain the stability of each other. DNA methylation array indicates 2/3 of the hypopethylated sites mediated by UHRF1 are overlapping with sites hypomethylated by EWS/FLI1, further confirming that EWS/FLI1 interacts with UHRF1 to drive the specific DNA methylation pattern of EwS.
Conclusions
High expression of UHRF1 correlates with a dismal prognosis in EwS; EWS/FLI1 binds to SRA domain of UHRF1 to maintain each other's stability and drive the aberrant DNA methylation pattern of EwS.
MODERN THERAPY FOR SPINAL AND PARASPINAL EWING SARCOMA: AN UPDATE OF THE UNIVERSITY OF FLORIDA EXPERIENCE
- Danny Indelicato (United States of America)
Abstract
Background and Aims
In 2009, we published a comprehensive review of our institutional outcomes treating children with spinal and paraspinal Ewing sarcoma. Multimodality therapy was associated with a fair disease control but significant toxicity, including a 37% rate of late Grade ≥3 toxicity. The objective of this study is to review children treated with modern technology and treatment regimens available since the last report.
Methods
Between 2010-2021, 32 consecutive pediatric patients with non-metastatic spinal or paraspinal Ewing sarcoma were treated at the University of Florida. The median age at the time of diagnosis was 9.8 years old (range, 2.1-21.8 years). The median maximum tumor diameter was 5 cm (range, 3-19 cm) and 30/32 tumors possessed an EWSR1 translocation. At diagnosis, 28/32 patients had significant motor, bowel, or bladder deficits. Patients were treated with chemotherapy regimens according to contemporary North American and European protocols. Prior to radiotherapy, 14 patients had a gross total resection while the other 18 underwent a biopsy or subtotal resection with cord decompression. All patients were treated with proton therapy, and 6 with hardware stabilization also received a component of intensity modulated photon therapy (IMRT/VMAT).
Results
With a median follow-up of 4.1 years (range, 0.7 – 9.4 years), the 5 year local control, progression free survival, and overall survival is 92%, 79%, and 85%, respectively. Twenty of 30 living patients recovered from their original motor, bowel, or bladder deficits. Overall, 22% of patients experienced new-onset CTCAE Grade 3 late toxicity related to multimodality treatment: kyphosis (n=4), esophagitis (n=2) and chronic kidney disease (n=1). No patients developed grade ≥4 toxicity.
Conclusions
Compared to our prior institutional experience, advances in multimodality treatment offer an improved therapeutic ratio for children with spinal and paraspinal Ewing sarcoma. With appropriate management, most patients can be cured with recovery of long-term neurologic function and modest side-effects.