ARID1A deficiency associated with MMR deficiency and a high abundance of tumor-infiltrating lymphocytes predicts a good prognosis of endometrial carcinoma

Abstract

• ARID1A alterations are common in EC patients, and their presence is related to a good prognosis as an independent prognostic factor. • ARID1A alterations were found to co-occur with mutations in MMR-related genes, and patients concomitantly harboring alterations of ARID1A and MMR-related gene mutations achieved the best prognosis. • ARID1A expression loss is also an independent prognostic factor and is related to good prognosis. • Low expression of ARID1A is associated with a tendency for MSI. • Both ARID1A alterations and expression loss could function as modulators of the TME and might thereby play a role in the prognosis of EC patients and the outcome of cancer immunotherapy. ARID1A alterations have been detected in 40% of endometrial carcinomas (ECs) and are associated with loss of its expression. The role of ARID1A in tumorigenesis and development is complex, and the prognostic role in EC remains controversial. Hence, it is of great significance to confirm the role of ARID1A in EC. A total of 549 EC patients (cohort A) from TCGA were evaluated to explore the prognostic role of ARID1A. NGS was performed for 13 EC patients (cohort B), and expression of ARID1A, CD3, CD8 and mismatch repair (MMR) proteins in 52 patients (cohort C) from our center was determined by immunohistochemistry (IHC). The Kaplan–Meier method was used to perform survival analyses. ARID1A alterations were detected in 32% of EC patients and correlated with good disease-free survival (DFS, P = 0.004) and overall survival (OS, P = 0.0353). ARID1A alterations were found to co-occur with MMR-related gene mutations and correlated with higher PD-L1 expression. Patients concomitantly harboring ARID1A alterations and MMR-related gene mutations had the best prognosis (DFS: P = 0.0488; OS: P = 0.0024). A cohort from our center showed that ARID1A deficiency was an independent prognostic factor and predicted longer recurrence-free survival ( P = 0.0476). ARID1A loss was associated with a tendency toward MSI-H ( P = 0.0060). ARID1A alterations and expression loss were associated with a higher abundance of CD3+ ( P = 0.0406) and CD8+ ( P = 0.0387) T cells. ARID1A alterations and expression loss are tightly associated with MMR deficiency and a high abundance of tumor-infiltrating lymphocytes, which might contribute to the good prognosis of EC.

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