Reduced MUTYH, MTH1 and OGG1 expression and TP53 mutation in diffuse-type adenocarcinoma of gastric cardia

Summary The effects of oxidative stress in adenocarcinomas of gastric cardia (AGCs) have not been fully elucidated. With a strict definition of AGC, we examined the immunohistochemical expressions of iNOS, 8-OHdG, the base excision repair (BER) enzymes such as MUTYH, MTH1 and OGG1, and TP53 mutational status. Sixty-three cases of AGC were characterized by younger patient age (p=0.0227) and more frequent venous invasion (p=0.0106) compared to the adenocarcinomas of pylorus (APs). 8-OHdG was accumulated (p=0.0011) whereas MUTYH (p=0.0325) and OGG1 (p=0.0007) were decreased in the AGCs compared to the adjacent mucosa, but these differences were not detected in the APs. Among the AGCs, lower expression of MUTYH (p=0.0013) and MTH1 (p=0.0059) were each significantly associated with diffuse-type histology. A lower expression of OGG1 was correlated with higher T-stage (p=0.0011), lymphatic invasion (p=0.004) and lymph node metastasis (p=0.0094). In addition, the presence of TP53 mutation was associated with diffuse-type histology (p=0.0153) and a lower level of MUTYH (p=0.0221). The AGCs also showed a relatively high rate of a transversion-type mutation of TP53 (50%), whereas all TP53 mutations in the APs were transition-type. Age 62 years or older (p=0.0073), diffuse-type histology (p=0.0020) and TP53 mutation (p=0.0066) were each associated with worse survival in the AGC patients. Our results indicate that oxidative stress accumulation and a down-regulation of BER enzymes may play an important role in the pathogenesis of AGC, in particular diffuse-type AGCs. Diffuse-type AGC might involve molecular pathways different from those of other subsets of gastric cancer.