Abstract
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.
Highlights
Gastric cancer is the fifth most common malignancy and the third leading cause of cancerrelated deaths worldwide [1]
Minute hypermethylation of MutL homolog 1 (MLH1) causes microsatellite instability (MSI) haploinsufficiency cells with MLH1 hypermethylation were accompanied by its silenced expression, while SW480 cells with no MLH1 hypermethylation exhibited its definite expression (Fig 1B)
We recently demonstrated that Cysteine dioxygenase type 1 (CDO1) hypermethylation was cancer-specific in primary gastric cancer and its hypermethylation was correlated with poor prognosis in the same patient cohort [15]
Summary
Gastric cancer is the fifth most common malignancy and the third leading cause of cancerrelated deaths worldwide [1]. A comprehensive molecular classification of gastric cancer was proposed as Epstein Barr virus (EBV)-associated (8.8%), microsatellite instability (MSI)-associated (21.7%), chromosomal instable (49.8%), and genomic stable (19.0%) gastric cancer [4]. Among these four definite molecular phenotypes, MSI-associated gastric cancer representing defective DNA mismatch repair system is intriguing, because it could be a predictive biomarker for immune checkpoint inhibitors [5,6,7] in addition to classical chemotherapy [8]. It has been reported that the clinicopathological factors in the MSI-associated gastric cancer were elderly, female, intestinal type in Lauren classification, and tumors located in the middle to lower site of the stomach [4]. MSI-associated cancers harbored frequent genomic mutations of an SWI/SNF chromatin-remodeling factor such as ARID1A [9, 10], and such tumor cells are a good candidate for synthetic lethal target for glutathione metabolism [11]
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