Association of ATM and ARID1A in gastric carcinoma

BACKGROUND: The ataxia telangiectasia mutated (ATM) gene is involved in the repair of double-stranded DNA breaks and a component of the DNA damage repair pathway. Tumors with mutations or low expression of both ARID1A and ATM exhibit increased numbers of tumor-infiltrating lymphocytes and a favorable prognosis. However, the relationship between ATM and ARID1A in gastric carcinoma (GC) is unclear. METHODS: We used the mRNA expression data from the Asian Cancer Research Group to construct tissue microarrays (N = 249). Next-generation sequencing (NGS) databases of Samsung Medical Center (SMC) (N = 813) were used to compare genetic alterations. Tissue microarrays were used for ATM and ARID1A immunohistochemistry, and expressions were categorized as "low" and "high." NGS data from TCGA-STAD (N = 431) were used as independent cohorts for genetic alterations validation. RESULTS: In GCs, 32.1 % (80/249) of the cases showed low ATM protein expression (ATMlow) and 20.9 % (52/249) showed low ARID1A expression (ARID1Alow). ATMlow was significantly associated with older age (P <.01), gross type of tumor (P =.02), histology (P <. 01), lower incidence of perineural invasion (P =.04), lower disease stage (P <.01), microsatellite instability-high (P <.01), and ARID1Alow (P <.01). Furthermore, GCs in the SMC NGS database showed that ATM mutations were significantly correlated with ARID1A mutations (P <.01), and this finding remained significant in TCGA-STAD validation cohort (P <.01). CONCLUSION: ATMlow in GCs shows a characteristic clinicopathological feature that correlates strongly with ARID1Alow. ATM mutation was also associated with ARID1A mutations, highlighting the interactions between ATM and ARID1A in GC and suggesting a potential therapeutic target.