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(American Journal of Pathology. 2000;157:717-722.)
© 2000 American Society for Investigative Pathology

Short Communications

Frequent Hypermethylation of the hMLH1 Gene Promoter in Differentiated-Type Tumors of the Stomach with the Gastric Foveolar Phenotype

Yasushi Endoh*, Gen Tamura*, Yoichi Ajioka{dagger}, Hidenobu Watanabe{dagger} and Teiichi Motoyama*

From the Department of Pathology,* Yamagata UniversitySchool of Medicine, Yamagata; and the Department ofPathology,{dagger} Niigata University School ofMedicine, Niigata, Japan


   Abstract
Top
 Abstract
Materials and Methods
 Results
 Discussion
 References
 
Hypermethylation of the hMLH1 mismatch repair gene promoter has been revealed to lead to microsatellite instability (MSI). Previously, we demonstrated a high prevalence of MSI in differentiated-type gastric tumors showing distinct features of gastric foveolar epithelium (foveolar type). To clarify the significance of hMLH1 promoter hypermethylation in the development of this tumor type, we studied promoter methylation status and expression of hMLH1 in foveolar-type tumors and their surrounding non-neoplastic mucosae, as well as in tumors with other cellular phenotypes. The results were compared to MSI status. After phenotypical analyses using mucin histochemistry and immunohistochemistry, 41 differentiated-type tumors with distinct cellular phenotypes were classified into three categories: foveolar type, intestinal type (tumors with the distinct cellular phenotype of the intestine), and combined type (tumors with both foveolar and intestinal phenotypes). Methylation-specific polymerase chain reaction (MSP) was performed to determine the methylation status of hMLH1 promoter. hMLH1 protein expression was immunohistochemically examined. MSI was detected in 57% of the foveolar type, 8% of the intestinal type, and 67% of the combined-type tumors. Hypermethylation of hMLH1 promoter was found in 74% of the foveolar type, 33% of the intestinal type, and 83% of the combined-type tumors. Of 18 MSI-positive tumors, all but one were hypermethylated. Methylation status of hMLH1 promoter correlated well with protein expression in foveolar-type tumors. Moreover, hypermethylation was also detected frequently (71%) in the non-neoplastic surrounding mucosa of the hypermethylated tumors. Hypermethylation of hMLH1 promoter is an initial, vital event in the development of foveolar-type tumors of the stomach.

Gastric carcinomas are histopathologically divided into two types, differentiated and undifferentiated type1 or intestinal and diffuse type,2 based on their tendency to form glands. Differentiated-type tumors have long been believed to develop from intestinal metaplasia and have a predominantly intestinal cellular phenotype.1-3 However, differentiated-type tumors with the phenotype of gastric foveolar epithelium (foveolar-type tumor), which are considered to derive from gastric proper epithelium, have been revealed with the development of phenotypical analyses using mucin histochemical and immunohistochemical procedures.4-13 The frequency of this type tumor was reported to be 18 to 41% in the intramucosal differentiated-type tumors of the stomach.6,8,9,11 In one of our recent studies,13 we made it clear that genetic backgrounds of differentiated-type tumors were quite different among cellular phenotypes. We demonstrated frequent microsatellite instability (MSI) and infrequent p53 mutations in foveolar-type tumors and, conversely, infrequent MSI and considerable p53 mutations in tumors with a distinct intestinal cellular phenotype (the intestinal-type tumor). MSI is believed to be caused by a deficient DNA mismatch repair. Recent studies revealed that epigenetic methylation-associated inactivation of the hMLH1 mismatch repair gene is a potent trigger of MSI, especially of high-rate MSI, in gastrointestinal carcinomas.14-17 Foveolar-type tumors contain several histopathological problems as follows: 1) They are prone to lose their glandular structure and progress to undifferentiated-type tumors,5,11 and thus should be regarded as precursors of the undifferentiated-type tumors;11 and 2) histopathological diagnosis is difficult; ie, it is often difficult to distinguish such lesions from regenerative or inflammatory changes in the foveolar epithelium, rather than the neoplastic lesion.5,11

To clarify the significance of hMLH1 promoter hypermethylation in the development of foveolar-type tumors, we studied promoter methylation status and expression of hMLH1, and the results were compared to MSI status. In addition, we pursued the possibility that these molecular biological and immunohistochemical methods would be helpful in the diagnosis of this perplexing but obvious tumor.


   Materials and Methods
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 Abstract
 Materials and Methods
Results
 Discussion
 References
 
Phenotypical Analysis and Classification

Representative sections from paraffin blocks were examined for phenotypical analysis. As markers for gastric foveolar phenotype, galactose oxidase-Schiff (GOS) mucin stain,8,18 and immunostain of human gastric mucin (45 M1, Novocastra, Newcastle, UK)19 were used. To detect intestinal phenotypical expressions, immunostains of MUC2 (Ccp58, Novocastra), a marker for intestinal goblet-cell mucin,20 and CD10 (56C6, Novocastra), which detect the brush border of absorptive cells, a marker for small intestine (complete-type intestinal metaplasia),10 were performed. Using these procedures, 41 lesions from 39 patients, which showed marked phenotypical expressions, were selected. To investigate the relationship between the genetic analyses and the phenotypic expressions of tumors, tumors without overt phenotypical expressions were excluded from this study. Tumors were classified as follows: (i) 23 foveolar-type tumors that had frequent gastric foveolar-type mucin (>50% of neoplastic cells are positive for the GOS stain or human gastric mucin), but infrequent intestinal markers (<5% of MUC2- and CD10-positive cells) (Figure 1, A and B) ; (ii) 12 intestinal-type tumors that had predominantly either MUC2- or CD10-positive cells or both (>30% of neoplastic cells); and (iii) 6 combined-type tumors that showed both foveolar and intestinal phenotypes (>30% of neoplastic cells express both foveolar and intestinal type markers). We followed the Padova international classification21 that was recently proposed to estimate the intramucosal lesion of the stomach, about which there is a difference of opinion between Western and Japanese pathologists.22 Clinicopathological findings are summarized in Table 1 .


Figure 1
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  		Figure 1. A: Typical foveolar-type tumor (case 11). Glands were lined by cells with clear to slightly basophilic cytoplasm and oval-to-round, basally oriented nuclei, mimicking well the foveolar epithelium (H&E; original magnification, x200). B: Diffuse apical staining for GOS, case 11. (GOS; original magnification, x200). C: Case 7, foveolar-type tumor with MSI and hypermethylated hMLH1 (H&E; original magnification, x100). D: Case 7, hMLH1 protein expression is markedly diminished in the tumor compared to the adjacent normal mucosa (streptavidin-biotin peroxidase stain with methyl green counterstain; original magnification, x100).

 

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  		Table 1. Characteristics of Gastric Epithelial Lesions and the Results of Genetic Analyses

 
DNA Extraction

DNA was extracted from tumors and normal mucosa surrounding tumors as described by Goelz et al23 from ten 10-µm-thick formalin-fixed, paraffin-embedded serial sections.

Methylation-Specific Polymerase Chain Reaction (MSP)

DNA methylation patterns in the hMLH1 promoter were determined by MSP, as described previously.14,15,17 MSP distinguishes unmethylated from methylated alleles of a given gene based on sequence changes that are produced following bisulfite treatment of DNA, which converts unmethylated cytosines to uracils, while leaving methylated cytosines unaffected. Subsequent polymerase chain reaction (PCR) using primers specific to sequences that correspond to either methylated or unmethylated DNA was performed. Primer sequences of each methylated and unmethylated sequence of the hMLH1 promoter were also described in the protocols.14 Briefly, 2 µg of genomic DNA were denatured by treatment with NaOH and modified by sodium bisulfite. DNA samples were then purified using a Wizard DNA purification resin (Promega, Madison, WI), treated with NaOH, precipitated with ethanol, and resuspended in 30 µl of water. Modified DNA was amplified in a total volume of 20 µl 1x GeneAmp PCR Gold Buffer (PE Applied Biosystems, Foster City, CA) containing 1.0 mmol/L MgCl2, l µmol/L of each primer, 0.2 mmol/L dNTPs, and 1 unit of Taq polymerase (AmpliTaq Gold DNA Polymerase, PE Applied Biosystems). After activation of the Taq polymerase at 95° for 10 minutes, the PCR was performed in a thermal cycler (GeneAmp 2400, PE Applied Biosystems) for 35 cycles consisting of denaturation at 95° for 15 seconds, annealing at 60° for 15 seconds, and extension at 72° for 30 seconds, followed by a final 7-minute extension at 72° for all primer sets. The PCR products were then loaded onto nondenaturing 6% polyacrylamide gels, stained with ethidium bromide, and visualized under UV illumination.

MSI

We screened MSI using the mononucleotide repeats BAT26 and BAT25 according to the published protocols.13,24 They are sensitive and recommended to detect MSI-positive, especially high-rate MSI tumors.25-28 The bands of different molecular weights in tumor DNA, not observed in normal DNA, were designated as MSI-positive.

Immunohistochemistry

Immunohistochemistry was performed on formalin-fixed, paraffin-embedded sections using the standard labeled streptavidin-biotin system (Nichirei, Tokyo, Japan). Mouse monoclonal antibody to the hMLH1 gene product, G168–728 (PharMingen, San Diego, CA), was used at 1:50 dilution after antigen retrieval by microwave. Expression was evaluated by comparison to normal tissue in the same section using three categories: markedly decreased (decreasing in more than half of the tumor tissue), lightly decreased (decreasing in less than half of the tumor tissue), and not decreased.

Sequencing Analysis

The methylated and unmethylated DNA-derived PCR products from several tumors were directly sequenced using a terminator cycle sequencing kit (dRhodamine Terminator Cycle Sequencing FS Ready Reaction Kits; PE Applied Biosystems) and a DNA sequencer (310 Genetic Analyzer; PE Applied Biosystems).

Statistical Analysis

Statistical comparisons were performed using Fisher’s exact test with a criterion of P < 0.05.


   Results
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 Abstract
 Materials and Methods
 Results
Discussion
 References
 
The results are summarized in Table 1 and Figure 2 . MSI was detected in 57% (13/23) of the foveolar type, 8% (1/12) of the intestinal type, and 67% (4/6) of the combined-type tumors. In foveolar-type tumors, the frequency of MSI was significantly higher in early lesions, mucosa (m) and submucosa (sm) (71%; 12/17) than advanced lesions, subserosa (ss) and exposed beyond the subserosa (se) (17%; 1/6). The hMLH1 promoter hypermethylation was detected more extensively than MSI among all phenotypes (Figures 2 and 3A) . The frequencies were 74% (17/23) of the foveolar type, 33% (4/12) of the intestinal type, and 83% (5/6) of the combined-type tumors. The frequency of both MSI and hypermethylation of hMLH1 was significantly higher in the foveolar type than in the intestinal-type tumors (P = 0.006 for MSI, and P = 0.02 for hypermethylation). Taking the foveolar- and the combined-type tumors together, the differences were more obvious (P = 0.003 for MSI, P = 0.01 for hypermethylation). In total, the hMLH1 promoter hypermethylation occurred in 94% (17/18) of the MSI+ cases.


Figure 2
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  		Figure 2. Comparison of frequency of MSI and promoter hypermethylation of hMLH1 among three phenotypical types.

 
Direct sequencing of the methylated DNA PCR product confirmed the retention of cytosines at all CpGs within the PCR product, whereas cytosines were all converted to thymines in the unmethylated DNA PCR product (Figure 3B) .


Figure 3
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  		Figure 3. A: MSP in foveolar-type tumors. In cases 16 and 18, a hypermethylated hMLH1 band is observed. B: Sequencing histograms of the PCR products of methylated and unmethylated hMLH1. Cytosines at all CpGs within the methylated DNA PCR product are retained, whereas all cytosines were converted to thymines in the unmethylated DNA PCR product. The number indicates the case number; U, unmethylated hMLH1; M, hypermethylated hMLH1.

 
All foveolar-type tumors, in which frequent hMLH1 hypermethylation was detected, were immunohistochemically tested for hMLH1 protein expression (Figure 1, C and D) . In early lesions, the cases with both MSI and the hypermethylation of hMLH1 showed decreased expression of hMLH1 in tumor nuclei without exception, but this was not the case in advanced lesions.

The surrounding mucosa within 2 cm of 17 foveolar-type hypermethylated tumors was also tested for hMLH1 promoter hypermethylation. Methylated hMLH1 alleles were detected in 71% (12/17) of the non-neoplastic mucosa surrounding the tumors (Table 1) ; however, no decreases in hMLH1 protein expression and MSI were observed.


   Discussion
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 Abstract
 Materials and Methods
 Results
 Discussion
References
 
We have demonstrated considerably high prevalences of MSI and hMLH1 promoter hypermethylation in both the foveolar- and combined-type tumors, but not in the intestinal-type tumors. These results indicate that MSI and hMLH1 promoter hypermethylation affect the tumors showing gastric foveolar phenotypical expression, irrespective of intestinal phenotypical expression. Actually, we could not make morphological distinctions between the combined- and foveolar-type tumors, and the intestinal phenotypical expressions in the combined-type tumors were all revealed after mucin histochemical and immunohistochemical examinations.

Previous studies have reported infrequent MSI in early, but frequent MSI in advanced, differentiated-type carcinomas of the stomach (early, 9–19% versus advanced, 27–38%).24,29,30 These results suggest that the MSI phenotype does not play an important role in the early phase of differentiated-type tumors of the stomach. The MSI phenotype would be accumulated secondarily during tumor progression. The high incidence of MSI in early foveolar-type tumors (71%) contrasts sharply with these results. In the foveolar-type tumor, the MSI phenotype would be deeply involved from the early stage of tumorigenesis. In early foveolar-type tumors, hypermethylation associated with hMLH1 protein reduction caused MSI without exception. Hypermethylation alone, not associated with hMLH1 protein reduction, did not cause MSI at all. These results are consistent with those of previous studies.14,15,17 They demonstrated that enough (biallelic or complete) hypermethylation of hMLH1 promoter caused protein reduction and sequentially induced MSI.14,31 However, this sequence did not apply to half of the advanced foveolar-type tumors (case numbers 20–22). We may have to discriminate between the advanced and early foveolar-type tumors from the standpoint of genetic alterations; however, further studies will be necessary to answer this question.

In the colon and rectum, considerable hypermethylation of hMLH1 promoter in non-neoplastic mucosa adjacent to the tumors, especially in MSI-negative tumors, was reported.32 No such methylation in adjacent mucosa was reported in carcinomas of the stomach.33 Frequent hMLH1 hypermethylation in non-neoplastic mucosa adjacent to foveolar-type tumors strongly suggests that hypermethylation of hMLH1 is an initial vital event in the early tumorigenesis of foveolar-type tumors.

The difficulty in histopathological diagnosis of foveolar-type tumors, especially of early lesions, has been pointed out.5,11 This type of tumor often shows a low-grade cytologic atypia even in cases with overt invasion, but intramucosal tumorous elements are usually well preserved. Indeed, 75% (9/12) of intramucosal foveolar-type tumors were classified as non-invasive neoplasia, low-grade. Therefore, a histopathological diagnosis is difficult, especially based on superficial biopsy samples alone. Detection of hMLH1 promoter hypermethylation and reduced hMLH1 protein expression may be useful as potential diagnostic markers because more than half of the early foveolar-type lesions showed these features, even though the expression was well preserved in surrounding non-neoplastic mucosa. Moreover, the assessment of the status of hMLH1 promoter hypermethylation in non-neoplastic gastric mucosa may be useful in early detection of foveolar-type tumors.


   Footnotes
 
Address reprint requests to Yasushi Endoh, M.D., Yamagata University School of Medicine, 2–2-2 Iida-nishi, Yamagata 990-9585, Japan. E-mail: yendo{at}med.id.yamagata-u.ac.jp

Supported in part by grants-in-aid for cancer research (nos.10–3 and 11–34) from the Ministry of Health and Welfare of Japan, and by a Japanese grant-in-aid (no. 11770084) from the Ministry of Education, Science, Sports and Culture of Japan.

Accepted for publication June 14, 2000.


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 Abstract
 Materials and Methods
 Results
 Discussion
 References
 

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