DNA damage response pathways in synovial sarcoma.
Authors: Barreto Coelho Priscila , Bialick Steven , Rose Brandon Edward , Elliot Andrew , Walker Phillip , Abraham Jim , Leu Kirsten , von Mehren Margaret , Espejo-Freire Andrea P. , Costa Philippos Apolinario , D'Amato Gina Z. , Rosenberg Andrew , Trent Jonathan C. , Dhir Aditi 
Published: June 2022

11580 Background: Synovial sarcomas (SS) harbor a specific, balanced, reciprocal translocation t(X;18) leading to the oncogenic SS18-SSX fusion. Defective DNA damage response (DDR) is a hallmark of cancer leading to genomic instability and is associated with chemosensitivity. Efforts have been made to identify a genetic signature that predicts SS progression, treatment response, and survival in order to identify more accessible and effective treatments. This investigation explores the role of DDR in pathogenesis of SS. Methods: Patients with the diagnosis of SS from 2013 to 2021 within the Caris Life Science database were included in the study. A combination of NGS of DNA and RNA at a CLIA-certified laboratory (Caris Life Sciences, Phoenix, AZ) was performed on archival tumors. Homologous recombination deficiency (HRD) scores were calculated as a composite of loss of heterozygosity, telomeric allelic imbalance, and large-scale transitions, using a positive threshold of 42. This study was approved by the University of Miami (UM)-Sylvester IRB and all the data collected was de-identified. Results: A total of 120 patients were identified with 49 of these patients from UM-Sylvester. Mean age of diagnosis on the sample was 46 years old (range of 15-86) and 45.8% were female. Among the 49 patients from UM-Sylvester, mean age was 60 years old (range of 35-84), 28 patients had a gene alteration identified (57%) and 6 of them a homologous recombination deficiency (HRD) gene (12%). A total of 63 different genes were identified with the most common TP53 (49%), LOH (12.2%), ATRX (10.2%) and RB1 (6.1%). Other HRD genes identified were MLH1 (4%) and CHEK2 (4%). There was no correlation identified between the age (15-65 vs elderly ⩾ 65 years) or the gender (female vs male) and the presence of a mutated DDR (p = 0.615; p = 0.091 respectively). Within the entire Caris database (N = 120), we identified 11 patients (N = 120, 9%) whose tumor tested positive for any DDR gene alteration. The most common were ATM (2.6%), followed by ATRX (1.6%) and CHEK2 (0.9%). The median HRD score was 22 within the sample. Conclusions: We report here the most common genes altered on molecular profile for a large cohort of SS samples. The prevalence of predicted pathogenic DDR gene mutation carriers in our cohort (9%) suggests that constitutional defects in this pathway may be associated with SS. We found higher rates of positive DDR on the UM-Sylvester cohort, and this could be associated with specifics of our population, given high frequency of Hispanic patients. Work is ongoing to associate our findings with race, ethnicity, survival and response to treatments. Work is ongoing to associate our findings with race, ethnicity, survival and response to treatments. These correlations will be reported in the final abstract. Cytotoxic therapy remains gold standard for metastatic SS, but better understanding of the molecular profile can pave way for further options, including targeted therapy and immunotherapy.