Microsatellite instability (MSI) is a hallmark of theAlthough the incidence rate of gastric cancer has been declining steadily, gastric cancer remains the second most common malignant tumor in the world (1, 2) and contributes to significant cancer mortality, particularly in Asia (China, Japan, and Korea) and parts of Europe and Latin America. Multiple environmental factors, including Helicobacter pylori infection (3) and dietary factors (4), have been implicated in the initiation of gastric carcinogenesis. Although much has been learned recently about the molecular genetic alterations associated with the development of gastric cancers, much about them still has remained unclear. Microsatellite instability (MSI) is a form of genomic instability associated with defective DNA mismatch repair in tumors (5). The majority of cancers of the hereditary nonpolyposis colon cancer (HNPCC) syndrome (6) and about 15% of unselected colorectal cancers have MSIϩ phenotype (7). Clinicopathologic characteristics of MSIϩ colorectal cancers are proximal location, younger age, lower lymph node metastasis, and a better survival rate (7,8). The stomach is a frequent site of extracolonic cancer development in patients with HNPCC (9) and is one of the organs in which primary sporadic tumors show MSIϩ phenotype (10 -15). Defects of the mismatch repair system and MSI play an important role in early stage of gastric carcinogenesis. In the adenoma-carcinoma sequence of the stomach, gastric adenoma had a high frequency of MSI, and it persisted after malignant transformation (16). To determine the correlations between MSI status and clinicopathologic variables

Little information is available concerning the relationship between transforming viruses and microsatellite instability (MSI). We evaluated Epstein-Barr virus (EBV) using in situ hybridization for EBV-encoded small RNAs and MSI using the polymerase chain reaction in surgically resected gastric cancer. The study subjects included 298 consecutive cases of solitary gastric carcinoma, 63 gastric carcinomas in young patients (

Ataxia-telangiectasia mutated (ATM) is a Ser/Thr protein kinase that plays a critical role in DNA damage-induced signaling and initiation of cell cycle checkpoint signaling in response to DNA-damaging agents such as ionizing radiation. We have previously reported the ATM protein loss by immunohistochemistry (IHC) in 16% of human gastric cancer (GC) tissue. We hypothesized that ATM gene intron mutations targeted by microsatellite instability (MSI) cause ATM protein loss in a subset of GC. We studied mononucleotide mutations at the intron of ATM gene, ATM IHC and MSI in GC. Ten human gastric cancer cell lines were studied for the ATM gene mutation at introns, RT-PCR, direct sequencing, and immunohistochemistry. GC tissues of 839 patients were analyzed for MSI and ATM IHC. Among them, 604 cases were analyzed for the ATM mutations at introns preceding exon 6, exon 10 and exon 20. Two human GC cell lines (SNU-1 and -638) showed ATM intron mutations, deletion in RT-PCR and direct sequencing, and ATM protein loss by IHC. The frequencies of ATM mutation, MSI, and ATM protein loss were 12.9% (78/604), 9.2% (81/882) and 15.2% (134/839), respectively. Analysis of associations among MSI, ATM gene mutation, and ATM protein loss revealed highly co-existing ATM gene alterations and MSI. ATM intron mutation and ATM protein loss were detected in 69.3% (52/75) and 53.3% (40/75) of MSI positive GC. MSI positivity and ATM protein loss were present in 68.4% (52/76) and 48.7% (37/76) of GC with ATM intron mutation. ATM mutation and ATM protein loss had characteristics of old age, distal location of tumor, large tumor size, and histologic intestinal type. Our study might be interpreted as that ATM gene mutation at intron might be targeted by MSI and lead to ATM protein loss in a selected group of GC.