Correlation of hMLH1 and HPP1 hypermethylation in gastric, but not in esophageal and cardiac adenocarcinoma

Abstract

1 Using methylation-specific real-time PCR, we determined the prevalence of aberrant methylation in the mismatch repair gene hMLH1 and in the recently described HPP1 gene among 50 esophageal, 50 cardiac and 50 gastric ADCs. Additionally, expression of hMLH1 protein was detected immunohistochemically and correlated with DNA MSI. Hypermethylation of hMLH1 was found in 14% of esophageal, 28% of cardiac and 32% of gastric ADCs, whereas HPP1 hypermethylation was found more frequently in the 3 tumor types (64% vs. 38% vs. 54%). In gastric ADC, HPP1 hypermethylation was found more frequently in tumors with concomitant hMLH1 hypermethylation (81%) than in those without hMLH1 hypermethylation (41%, p ‫؍‬ 0.008). Complete loss of hMLH1 protein expression, which was present in 10 carcinomas (5 cardiac and 5 gastric), was invariably correlated with hMLH1 hypermethylation and MSI. In conclusion, our data indicate that MSI and loss of the mismatch repair protein hMLH1, which is mainly caused by hMLH1 gene hypermethylation, are more prevalent in stomach and cardia carcinogenesis than in that of the esophagus. Moreover, in gastric cancer, hMLH1 hypermethylation is correlated with hypermethylation of the HPP1 ADCs of the esophagus and stomach are characterized by important differences concerning etiologic and clinical background. Chronic gastroesophageal reflux disease and subsequent intestinal metaplasia of the esophagus (Barrett's esophagus), on the one side, and Helicobacter pylori infection with subsequent atrophic gastritis, on the other side, are among the most important risk factors for esophageal or gastric ADC, respectively. 1,2 Moreover, the incidence of esophageal ADC has been rising rapidly over the last 3 decades, whereas the incidence of gastric ADC has been declining. 3 Although traditionally considered a gastric carcinoma, cardiac ADC shares a number of features with esophageal ADC, e.g., profound male predominance, rising incidence and etiologic association with chronic gastroesophageal reflux. 4,5 Hypermethylation of CpG islands represents an important epigenetic mechanism for silencing tumor-suppressor genes during carcinogenesis. 6 For example, loss of function of the DNA mismatch repair gene hMLH1 by hypermethylation of its promoter has been described in different cancer types, such as colorectal and endometrial cancers. 6,7 Lack of hMLH1 protein expression strongly decreases the fidelity of DNA replication and has been correlated with MSI, a surrogate marker for the so-called RER phenotype. 8,9 Thus, hypermethylation of hMLH1 has been detected in about 95% of RER-positive gastric ADCs but in only 5% of RER-negative cases. 8 Shibata et al. 10 found an as yet unexplained association between hypermethylation of hMLH1 and HPP1 in a series of 32 gastric ADCs. Currently, only limited data exist about the structural and functional properties of HPP1. It is thought to encode for a cell membrane receptor. The HPP1 protein shares a high grade of structural homology to regulatory proteins of the CNS (i.e., tomoregulin...

Generation and characterization of Tmeff2 mutant mice

“…Previous literatures suggested the potential roles of TMEFF2 as a tumor suppressor [2,9,10,11,12,13,14,15,16,17]. We did not observe any tumors in Tmeff2-KO mice, or in aged heterozygous mice, although we only examined limited number of heterozygous mice.…”

“…In contrast, others reported that TMEFF2 exhibited anti-proliferative effects on androgen-independent prostate cancer cell lines [9]. Furthermore, the promoter-region of TMEFF2 gene was frequently found to be hypermethylated in many cancers, suggesting a possible role of TMEFF2 as a tumor suppressor [2,9,10,11,12,13,14,15,16,17]. Additionally, the tumor suppressor activity of TMEFF2 was shown to depend on its cytoplasmic tail interacting with sarcosine dehydrogenase [18].…”

Inactivation of p16, RUNX3, and HPP1 occurs early in Barrett's-associated neoplastic progression and predicts progression risk

“…Certain methylation events can occur with aging or inflammation (which itself underlies BE), conditions associated with increased neoplastic risk (Issa et al, 1994(Issa et al, , 1996(Issa et al, , 2001). Hypermethylation of several genes, including p16, APC, HPP1, and TIMP3 has been observed in primary BE and EAC tissues (Wong et al, 1997(Wong et al, , 2001Eads et al, 2000Eads et al, , 2001Corn et al, 2001;Bian et al, 2002;Geddert et al, 2004;Sarbia et al, 2004).…”

Epigenetic Silencing of the MLH1 Promoter in Relation to the Development of Gastric Cancer and its use as a Biomarker for Patients with Microsatellite Instability: a Systematic Analysis

“…1 shows that careful scanning using the inclusion criteria yielded 62 studies published from 1999 to 2016 [15-21, 29-83], including 4654 patients with GC and 3669 non-malignant controls. Twenty-nine studies involving 2583 GC patients and 2396 adjacent tissue samples evaluated the association between MLH1 promoter methylation and GC [18-20, 30-33, 36, 40, 41, 49, 50, 55, 56, 59, 61-63, 65, 67, 68, 70, 73, 74, 76, 78, 80-82]. Seven studies with 409 GC patients and 266 intestinal metaplasia cases assessed the correlation between MLH1 promoter methylation and GC [17, 20, 21, 29, 32, 34, 38].…”

“…Cancer-related genes, such as tumor suppressor genes (TSGs), or DNA repair genes are commonly methylated in the promoter regions of CpG islands, which leads to the dysfunction or loss of gene expression, cancer initiation and progression [84, 85]. The absence or downregulation of MLH1 gene expression via promoter methylation was reported in GC [15, 32-34, 36, 37, 39, 42, 44-46, 50, 56, 59, 60, 62, 64, 72, 76, 77]. MLH1 promoter methylation is detected in some cancers, such as bladder cancer [86], colorectal cancer [87] and GC [18].…”