A pan-cancer analysis of ARID1A as a potential biomarker for immune checkpoint therapy.

Abstract

3540 Background: AT-rich interactive domain 1A (ARID1A), encoding a subunit of the BAF (SWI/SNF) chromatin remodeling complex, is correlated with the origination and progress of tumor. Previous research on ARID1A gene revealed that ARID1A deficiency was associated with mismatch repair (MMR) and higher tumor mutation burden (TMB) level in cancer, which might cooperate with immune checkpoint blockade therapy. Methods: Next generation sequencing (NGS) data of 10336 pan-cancer patients were obtained from the MSK-IMPACT Clinical Sequencing cohort (MSKCC). NGS data of 15849 pan-cancer patients from Chinese clinical dataset were analyzed to explore the association between ARID1A gene mutation and TMB. TMB was defined as total number of somatic non-synonymous mutations in coding region. 853 advanced NSCLC patients from two independent cohorts (OAK study cohort and POPLAR study cohort) were used to analyze the correlation between ARID1A alteration and the efficacy of immune checkpoint blockade immunotherapies (ICIs). Results: In total, 8.62% (891/10336) of pan-cancer patients in MSKCC harbored ARID1A mutation and 8.47% (3188/37628) in Chinese cohort. In MSKCC cohort, the highest ARID1A mutation frequency tumor type was endometrial cancer (31.64%, 69/218), bladder cancer (26.95%, 114/423) and hepatobiliary cancer (17.18%, 61/355) come in second and third, respectively. While in Chinese cohort, the top three ARID1A mutation frequency tumor types were endometrial cancer (39.29%, 88/224), gastric carcinoma (17.80%, 318/1787) and urothelial carcinoma (17.18%, 83/483), respectively. ARID1A gene mutation was also associated with higher TMB in the Chinese pan-cancer cohort (P < 0.0001). The highest medium TMB level of ARID1A mutation tumor type was Urothelial carcinoma with 18.63 Muts/Mb (n = 65). In addition, the TMB level and prognositic analysis were performed on patients in two independent NSCLC cohorts with ICIs, TMB level of ARID1A mutant group was higher than wild-type group with significant difference (P < 0.0001). The overall survival (OS) of ARID1A mutation group were significantly shorter than wild-type group (OS, median, 6.80 vs 10.28 months; HR, 1.47; P = 0.0474), and a decreasing trend on progression-free survival (PFS) without significant difference (median, 1.46 vs 2.99 months; HR, 1.27; P = 0.1584). Conclusions: The results indicated that ARID1A gene mutation was associated with a higher TMB level in Chinese pan-cancer patients, and patients harboring these genes mutations might easily benefit from ICIs.