Abstract 5668: DNA damage response gene mutations and their association with PD-L1 expression in sarcoma and bone tumor
Authors: Meng Fanfei , Zhang Qing , Pang Fei , Shi Xiaoliang 
Published: June 2022

Abstract
Background For a long time, the use of immune checkpoint inhibitors(ICIs)has been limited in sarcomas and bone tumors, and is only recommended as second or later line therapy for patients who meet specific requirements such as dMMR/MSI-H. DNA damage response (DDR) pathways aim to protect cells against some acquired genome changes and monitor exogenous or endogenous DNA damage. Studies have reported that genomic instability caused by DDR gene mutations effects on the immune system, and may benefit from ICI treatment. Although some studies have reported that DDR gene mutations in solid tumors such as non-small cell lung cancer and bladder cancer predicted response to ICI and correlated with patient prognosis, reports are lacking in sarcomas and bone tumors.
Methods Formalin-fixed, paraffin-embedded tissues and matched blood samples were collected from patients with sarcoma or bone tumor for targeted next-generation sequencing assay at OrigiMed (Shanghai, China), a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. PD-L1 expression was detected by immunohistochemistry using 22C3 antibody.
Results Fifteen patients including 12 male and 3 female with a median age of 22 years were recruited. Among them, 9 patients had bone tumors with a median age of 17 years. PD-L1 was tested in 13 patients and 10 patients were positive.Genetic testing showed that TP53, BRCA1, and CCND3 were the most frequently mutated genes. The analysis of pathways showed that DDR (11/15), cell cycle (7/15), NOTCH (4/15), RTK.RAS (4\15) were the most affected pathways. The median TMB was 1.6 muts/Mb. In DDR genes, TP53 mutations occurred in 8 patients including 2 soft tissue sarcomas and 6 bone tumors. BRCA1 gene fusions occurred in 2 osteosarcoma patients, one is 7-year-old boy who carried 3 BRCA1 fusions with ASIC2, LUZP6 and OXCT1 fusion partners. The boy also carried TP53 germline pathogenic mutations. Another 17-year-old boy carried a BRCA1-TMEM271 fusion, and PTEN and STK11 DDR gene mutations. Among the 11 sarcoma patients with DDR mutations, 8 were PD-L1 positive and 1 was PD-L1 negative. PD-L1 testing was not performed in other 2 cases.
Conclusion Our results showed that a proportion of sarcoma and bone tumor patients carried DDR gene mutations, especially in pediatric and adolescent osteosarcoma patients.The majority of sarcoma and bone tumor patients with DDR gene mutations in this cohort were PD-L1 positive. Since DDR gene mutation was associated with favorable response rate to ICIs, patients with DDR gene mutated sarcoma and bone tumor may benefit from ICIs therapy.
Citation Format: Fanfei Meng, Qing Zhang, Fei Pang, Xiaoliang Shi. DNA damage response gene mutations and their association with PD-L1 expression in sarcoma and bone tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5668.