Pan-cancer analysis of <i>ARID1A</i> Alterations as Biomarkers for Immunotherapy Outcomes

Abstract

<i>ARID1A</i> alterations would compromise mismatch repair pathway and increase the number of tumor-infiltrating lymphocytes and PD-L1 expression in some cancers, which would cooperate with immune checkpoint inhibitors (ICIs) treatment. However, a comprehensive analysis of <i>ARID1A</i> alteration frequency and its predictive value for ICI treatment outcome in cancers has not yet been investigated. Hence, we performed this pan-cancer analysis to evaluate the prevalence and predictive value of <i>ARID1A</i> alterations across >40,000 cases in multiple cancer types. We found a high frequency (6.2%) of <i>ARID1A</i>, which were associated with significantly higher tumor mutation burden level across various cancers. Importantly, patients with <i>ARID1A</i> alterations and advanced cancers had the substantially prolonged overall survival in ICI treatment cohort, suggesting it might be used to predict a survival benefit from ICI therapy across multiple cancer types. Notably, <i>ARID1A</i> alterations were correlated with markedly high immune infiltrates in endometrial, stomach and colon cancer. However, patients with <i>ARID1A</i>-mutant renal clear cell carcinoma had dramatically lower CD8⁺ T cell infiltrations than those without, indicating the association between <i>ARID1A</i> alterations and immune infiltrates was cancer-dependent. Collectively, our findings highlight the important value of <i>ARID1A</i> alterations as pan-cancer predictive biomarkers for ICI treatment.