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 (2, 6, 1) and high ATM expression (11, 111) 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 5 0.025, p 5 0.001 and p 5 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 5 0.017, OS: 65.9%, 78.5%, p 5 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 5 1.8, 95% confidence interval, 1.2-2.8, p 5 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.Ataxia-telangiectasia-mutated (ATM) gene has been identified as the gene responsible for the rare genetic disorder, ataxiatelangiectasia, which is characterized by cerebellar degeneration, immunodeficiency, enhanced radiosensitivity and elevated risk of lymphoreticular malignancy. 1-3 ATM plays a pivotal role in signaling and responding to double strand breaks (DSBs). 4 A deficiency of ATM function has been reported in several tumor types, including lymphoid malignancy, colon cancer, breast cancer, gastric cancer, head and neck cancer and lung cancer. [5][6][7][8][9] The loss of function of ATM gene was also considered a predictive marker for the treatment of poly(ADPribose) polymerase (PARP)-1 inhibitor. 10-13 Therefore, a deficiency of ATM function is a potential tumor characteristic for therapies targeting DNA repair pathways. Determination of the clinicopathologic features of tumors with loss of function of ATM is necessary and important for future clinical studies targeting DNA repair pathways. Elucidation of the prognostic role of ATM expression is also essential; however, the role remains unclear, particularly in gastric cancer.Microsatellite instability (MSI) is characterized as the increased rate of uncorrected replication errors at the simple repeat sequence caused by a MMR gene defect, resulting in accelerated mutations in the oncogene and tumor suppression gene. 14,15 Some ...

Integrated analysis of long non-coding RNAs and mRNA expression profiles reveals the potential role of lncRNAs in gastric cancer pathogenesis

“…Furthermore, construction of the lncRNA-mRNA correlation network displaying differentially expressed lncRNAs and their target genes (Fig. 5) implicated three target genes ATM, RRM2 and SERPINB5 which have been previously implicated in GC development and found to have involvement in p53 signaling in the present study (34)(35)(36). These findings indicate a possible role of the p53 signaling pathway in the dysregulation of lncRNAs during GC pathogenesis.…”

“…Further analysis of this network indicated that ataxia telangiectasia mutated (ATM) was a predicted target of six lncRNAs (AK001094, AK057054, BC042436, uc003iqu.1, AK022971 and uc003tfx.1), ribonucleotide reductase M2 polypeptide (RRM2) a predicted target of three lncRNAs (AK091139, AK001094 and uc003dwf.3) and serpin peptidase inhibitor, clade B (ovalbumin), member 5 (SERPINB5) a predicted target of AF086216. These target genes participate in the p53 signaling pathway, and have been previously implicated in the development of GC (34)(35)(36). Furthermore, the result also showed that one lncRNA could target up to 5 coding genes and that one coding gene was predicted to be a target of up to 22 lncRNAs in this network.…”

High-throughput mutation profiling identifies novel molecular dysregulation in high-grade intraepithelial neoplasia and early gastric cancers

“…A recent study on a large series of sporadic GC showed that STK11 was one of the low-frequency mutated genes with a 2 % prevalence [21]. Dysregulation of the ataxia telangiectasia mutated (ATM) gene has been associated with microsatellite instability (MSI) and is an independent negative prognostic factor in gastric cancer patients after surgery [23].…”

Linking ATM Promoter Methylation to Cell Cycle Protein Expression in Brain Tumor Patients: Cellular Molecular Triangle Correlation in ATM Territory

“…The phosphorylation of DNA damage response (DDR) proteins as well as ATM was demonstrated as a major mechanism of tumor evolution in various types of cancer [6,7]. Moreover, aberrant expression of ATM has been demonstrated in gastric, adenocortical, prostate, colorectal, and breast cancers [8][9][10][11][12]. Inefficiency of cells to repair DNA damage as a consequence of defects in DDR encoding genes was described as a possible reason for inducing brain tumor development [13].…”