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Reduced MUTYH, MTH1, and OGG1 expression and TP53 mutation in diffuse-type adenocarcinoma of gastric cardia
Yukiko Kohno1, Hidetaka Yamamoto1, Minako Hirahashi1
1Department of Anatomic Pathology, Graduate of School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan.
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.
Insights
Oxidative stress and reduced base excision repair enzymes are key in gastric cardia adenocarcinoma (AGCs) pathogenesis, particularly diffuse-type AGCs. These factors, along with TP53 mutations, are linked to worse patient survival.
Area of Science:
- Oncology
- Molecular Biology
- Gastroenterology
Background:
- Oxidative stress and DNA repair mechanisms are implicated in cancer development.
- Adenocarcinomas of the gastric cardia (AGCs) are a distinct subtype of gastric cancer with unique characteristics.
- The specific role of oxidative stress and base excision repair (BER) in AGC pathogenesis remains unclear.
Purpose of the Study:
- To investigate the role of oxidative stress markers and BER enzymes in AGCs.
- To analyze the association between these molecular alterations and clinicopathological features, including TP53 mutational status.
- To determine the prognostic significance of these findings in AGC patients.
Main Methods:
- Immunohistochemical analysis of inducible nitric oxide synthase, 8-hydroxy-deoxyguanosine, MUTYH, MTH1, and OGG1 in 63 AGC cases and adjacent mucosa.
- TP53 mutational status analysis.
- Correlation of molecular findings with clinicopathological data (histology, invasion, metastasis) and patient survival.
Main Results:
- AGCs showed increased 8-hydroxy-deoxyguanosine and decreased MUTYH and OGG1 compared to adjacent mucosa.
- Lower MUTYH and MTH1 expression correlated with diffuse-type histology in AGCs.
- Lower OGG1 expression was associated with advanced T-stage, lymphatic invasion, and lymph node metastasis.
- TP53 mutations, particularly transversion types, were linked to diffuse-type histology and lower MUTYH levels.
- Older age, diffuse-type histology, and TP53 mutation were associated with worse survival in AGC patients.
Conclusions:
- Oxidative stress accumulation and downregulation of BER enzymes (MUTYH, OGG1) are significant in AGC pathogenesis, especially diffuse-type AGC.
- Diffuse-type AGC may follow distinct molecular pathways involving oxidative damage and impaired DNA repair.
- TP53 mutations and specific molecular alterations contribute to poorer prognosis in AGC.
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