Ataxia-telangiectasia-mutated protein expression with microsatellite instability in gastric cancer as prognostic marker

Abstract

The prognostic significance of ataxia-telangiectasia-mutated (ATM) expression in gastric cancer remains unclear. The functional loss of ATM gene exhibits a biologic correlation with microsatellite instability (MSI). In this study, we investigated the significance of ATM expression with MSI by evaluating gastric cancer patients who had underwent curative resection. ATM expression was classified into low ATM expression (-, , +) and high ATM expression (++, +++) using immunohistochemistry analysis. MSI status was classified as MSI-negative (MSS, MSI-low) and MSI-positive (MSI-high). Of 321 patients, 205 (63.9%) exhibited low ATM expression and 116 (36.1%) exhibited high ATM expression. Low ATM expression was more frequently identified in patients of older age, more advanced stage and with MSI-positive tumor (p=0.025, p=0.001 and p=0.014, respectively). The probability of 5-year disease-free survival (DFS) and overall survival (OS) was lower in low ATM expression group compared with the high ATM expression group (DFS: 62.5%, 76.4%, p=0.017, OS: 65.9%, 78.5%, p=0.027, respectively). According to MSI status, a subgroup of MSI-negative and low ATM expression cases exhibited the worst prognosis for DFS and OS; this subgroup also exhibited poorer DFS according to multivariable analysis (hazard radio=1.8, 95% confidence interval, 1.2-2.8, p=0.010), although prognostic value of ATM expression alone did not remain in the multivariable analysis. Taken together, these findings indicate that ATM expression with MSI status is an independent factor for gastric cancer prognosis in gastric cancer patients who received curative surgery. What's new? ATM is a protein kinase that controls the repair of double-stranded breaks in DNA. Defective ATM has been reported in several types of tumors. Defects in a different type of DNA-repair, mismatch repair, have been associated with microsatellite instability (MSI). In this study, however, the authors confirmed that MSI can also be associated with defective ATM function. In addition, they found that ATM expression plus MSI status may be a useful prognostic biomarker in gastric cancer. These results may be beneficial for further studies of agents that target the DNA-repair pathways controlled by ATM.