title: Reduced MUTYH, MTH1, and OGG1 expression and TP53 mutation in diffuse-type adenocarcinoma of gastric cardia.
abstract: 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 inducible nitric oxide synthase; 8-hydroxy-deoxyguanosine; and the base excision repair enzymes such as MUTYH, MTH1, and OGG1, and TP53 mutational status. Sixty-three cases of AGC were characterized by younger patient age (P = .0227) and more frequent venous invasion (P = .0106) compared with the adenocarcinomas of pylorus (APs). 8-hydroxy-deoxyguanosine was accumulated (P = .0011), whereas MUTYH (P = .0325) and OGG1 (P = .0007) were decreased, in the AGCs compared with the adjacent mucosa, but these differences were not detected in the APs. Among the AGCs, lower expressions of MUTYH (P = .0013) and MTH1 (P = .0059) were each significantly associated with diffuse-type histology. A lower expression of OGG1 was correlated with higher T-stage (P = .0011), lymphatic invasion (P = .004), and lymph node metastasis (P = .0094). In addition, the presence of TP53 mutation was associated with diffuse-type histology (P = .0153) and a lower level of MUTYH (P = .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 62years or older (P = .0073), diffuse-type histology (P = .0020), and TP53 mutation (P = .0066) were each associated with worse survival in the AGC patients. Our results indicate that oxidative stress accumulation and a downregulation of base excision repair 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.
authors.affiliation: Department of Anatomic Pathology, Graduate of School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Kohno
authors.affiliation: Department of Anatomic Pathology, Graduate of School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Yamamoto
authors.affiliation: Department of Anatomic Pathology, Graduate of School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Hirahashi
authors.affiliation: Department of Anatomic Pathology, Graduate of School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Kumagae
authors.affiliation: Department of Surgery and Oncology, Graduate of School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Nakamura
authors.affiliation: Department of Surgery and Science, Graduate of School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
authors.forename: Eiji
authors.initials: E
authors.lastname: Oki
authors.affiliation: Department of Anatomic Pathology, Graduate of School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan. Electronic address: oda@surgpath.med.kyushu-u.ac.jp.
authors.forename: Yoshinao
authors.initials: Y
authors.lastname: Oda
mesh_terms: D000080242:8-Hydroxy-2'-Deoxyguanosine; D000230:Adenocarcinoma / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality / Q000556:secondary; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics; D002299:Cardia / Q000201:enzymology* / Q000473:pathology; D045647:DNA Glycosylases / Q000032:analysis*; D004252:DNA Mutational Analysis; D004260:DNA Repair; D045643:DNA Repair Enzymes / Q000032:analysis*; D003849:Deoxyguanosine / Q000031:analogs & derivatives / Q000032:analysis; D018572:Disease-Free Survival; D015536:Down-Regulation; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D052247:Nitric Oxide Synthase Type II / Q000032:analysis; D018384:Oxidative Stress; D010641:Phenotype; D010744:Phosphoric Monoester Hydrolases / Q000032:analysis*; D012189:Retrospective Studies; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D000080242:8-Hydroxy-2'-Deoxyguanosine; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II; D010744:Phosphoric Monoester Hydrolases; D045647:DNA Glycosylases; C061738:mutY adenine glycosylase; C479058:oxoguanine glycosylase 1, human; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes; D003849:Deoxyguanosine
keywords: Adenocarcinoma; Base excision repair enzymes; Cardia; Oxidative stress; Stomach