title: Differential clinicopathologic features in microsatellite-unstable gastric cancers with and without MLH1 methylation.
abstract: Key clinicopathologic features of microsatellite instability-positive (MSI+) gastric cancers (GCs) are that they tend to be located in the antrum and have an intestinal phenotype and an expanding-type growth pattern. They are also associated with a better prognosis. Although MSI occurs mainly as a result of promoter CpG island hypermethylation in the mismatch repair gene MLH1, only a minority of MSI+ GCs develop from genetic mutations of mismatch repair enzymes, including MLH1 and MSH2. Furthermore, it is unknown whether there are differences in the clinicopathologic features of MSI+ GCs with and without MLH1 methylation. The methylation status of 17 genes (including MLH1) was assessed in 102 cases of MSI+ GC to determine whether there was a correlation between the clinicopathologic/molecular features of MSI+ GC and MLH1 methylation status. Compared with MSI+ GCs without MLH1 methylation (n = 22), MSI+ GCs with MLH1 methylation (n = 80) had an older age of onset (66.9 versus 60.9 years, P = .018), were more frequently located in the antrum (86.3% versus 50%, P = .001), exhibited an ulcerofungating gross type of tumor morphology (50.0% versus 9.1 %, P < .001), and had a higher number of unstable microsatellite loci (4.7 versus 3.8, P < .001) and a higher number of methylated genes (11.4 versus 6.2, P < .001). In addition, MLH1-deficient tumors without MLH1 methylation were associated with a better clinical outcome than MLH1-deficient tumors with MLH1 methylation or tumors that retained expression of both MLH1 and MSH2 (P = .002). These findings suggest that MSI+ GCs with and without MLH1 methylation may have different clinicopathologic features. Furthermore, some of the known clinicopathologic features of MSI+ GC, including older age of onset, ulcerofungating gross morphology, and antral location, are not typical of MSI+ GC without MLH1 methylation.
authors.affiliation: Department of Pathology, and Seoul National University College of Medicine, Chongno-gu, Seoul 110-744, South Korea.
authors.forename: Kyung-Ju
authors.initials: KJ
authors.lastname: Kim
authors.forename: Tae-Hun
authors.initials: TH
authors.lastname: Lee
authors.forename: Nam-Yun
authors.initials: NY
authors.lastname: Cho
authors.forename: Han Kwang
authors.initials: HK
authors.lastname: Yang
authors.forename: Woo Ho
authors.initials: WH
authors.lastname: Kim
authors.forename: Gyeong-Hoon
authors.initials: GH
authors.lastname: Kang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000368:Aged; D019175:DNA Methylation / Q000235:genetics*; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics*; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein