Haploinsufficiency by minute MutL homolog 1 promoter DNA methylation may represent unique phenotypes of microsatellite instability-gastric carcinogenesis

• Published in: PloS one Vol. 16; no. 12; p. e0260303
• Main Authors: Harada, Hiroki, Nie, Yusuke, Araki, Ippeita, Soeno, Takafumi, Chuman, Motohiro, Washio, Marie, Sakuraya, Mikiko, Ushiku, Hideki, Niihara, Masahiro, Hosoda, Kei, Kumamoto, Yusuke, Naitoh, Takeshi, Sangai, Takafumi, Hiki, Naoki, Yamashita, Keishi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 22-12-2021; Public Library of Science (PLoS)
• Subjects: Age Factors; Analysis; Biology and life sciences; Cancer; Carcinogenesis; Carcinogens; Cell Line, Tumor; Chemotherapy; Cloning; Colon; Deoxyribonucleic acid; Design; DNA; DNA Methylation; DNA viruses; DNA, Viral - genetics; Epstein-Barr virus; Epstein-Barr Virus Infections - genetics; Female; Gastrectomy; Gastric cancer; Gastrointestinal cancer; Gastrointestinal surgery; Genetic aspects; Haploinsufficiency; Herpesvirus 4, Human - genetics; Histology; Homology; Humans; Male; Medical prognosis; Medicine; Medicine and Health Sciences; Methylation; Microsatellite Instability; MLH1 protein; Mutation; MutL Protein Homolog 1 - genetics; Neoplasms, Multiple Primary - genetics; Neoplasms, Multiple Primary - surgery; Neoplasms, Multiple Primary - virology; Pediatrics; Phenotype; Phenotypes; Physical Sciences; Polymerase Chain Reaction; Promoter Regions, Genetic; R&D; Research & development; Research and analysis methods; Stomach cancer; Stomach Neoplasms - genetics; Stomach Neoplasms - surgery; Stomach Neoplasms - virology; Tumors; Viruses; Japan
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0260303

Promoter DNA methylation of MutL homolog 1 (MLH1) is considered to play a causative role in microsatellite instability (MSI) carcinogenesis in primary gastric cancer, and a high MSI status is associated with treatment sensitivity to human cancers. Nevertheless, clinicopathological analysis is defective for MLH1 methylation status in a quantitative manner. We newly developed quantitative methylation specific PCR using a TaqMan probe and applied it to 138 patients with primary gastric cancer who underwent gastrectomy in addition to basic molecular features such as MSI, Epstein Barr virus, and other DNA methylation status. (1) In primary gastric cancer, median methylation value was 0.055, ranging from 0 to 124.3. First, MLH1 hypermethylation was strongly correlated with MSI-High/MSI-Low status and suppressed immunostaining (P < 0.0001). (2) The MLH1 hypermethylation was associated with advanced age (P = 0.0048), antral location (P = 0.0486), synchronous multiple gastric cancer (P = 0.0001), and differentiated histology (P = 0.028). (3) Log-rank plot analysis identified the most relevant cut-off value (0.23) to reflect gentle phenotypes in MLH1 hypermethylation cases (P = 0.0019), especially in advanced gastric cancer (P = 0.0132), which are designated as haploinsufficiency of MSI (MSI-haplo) phenotype in this study. (4) In synchronous multiple gastric cancer, MLH1 hypermethylation was not necessarily confirmed as field cancerization. (5) MSI-haplo defined by MLH1 methylation status represented distinct prognostic phenotype even after molecular classifications. MLH1 hypermethylation designated as MSI-haplo may represent unique prognostic phenotype during gastric carcinogenesis.