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Frequent Promoter Methylation of CDH1 in Non-Neoplastic Mucosa of Sporadic Diffuse Gastric Cancer

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ANTICANCER RESEARCH 33: 3765-3774 (2013) Frequent Promoter Methylation of CDH1 in Non-neoplastic Mucosa of Sporadic Diffuse Gastric Cancer KYUNG HWA LEE1*, DAVID HWANG2*, KI YOUNG KANG2, SOONG LEE3, DONG YI KIM4, YOUNG EUN JOO5 and JAE HYUK LEE1 Departments of 1Pathology, 4Surgery, and 5Internal Medicine, Chonnam National University Medical School, Gwangju, Republic of Korea; Departments of 2Anatomy and 3Internal Medicine, College of Medicine, Seonam University, Namwon, Republic of Korea Abstract. Background/Aim: To identify promoter observed in recent decades (1, 2). Diffuse gastric cancer methylation as a major silencing mechanism in potential (DGC) accounts for approximately 30% of all gastric precursor lesions of sporadic diffuse gastric cancer (DGC), carcinomas, and the prognosis is poor particularly for young we investigated promoter methylation of CDH1 (E-Cadherin patients (3, 4). It has long been known that DGCs show gene) in a series of DGCs and matched normal mucosa. diminished homophilic cell-to-cell cohesion (5). Inactivating Materials and Methods: The extent of CDH1 gene promoter germline CDH1 (E-Cadherin gene) mutation has been methylation was explored using methylation-specific described in the families with hereditary DGC, an polymerase chain reaction (MSP) and pyrosequencing (PS) autosomal-dominant disease characterized by clustering of in 72 DGCs with a matched pair of normal mucosa. Results: early-onset DGC (6, 7). The diminished or lack of E- MSP and PS revealed CDH1 promoter methylation in 73.6% Cadherin immunoreactivity observed in hereditary DGC cells (53/72) and 77.8% (56/72) of DGC samples, respectively. PS harboring CDH1 mutations is consistent with bi-allelic detected CDH1 methylation in 70.8% (51/72) and 72.2% CDH1 inactivation by a second-hit mechanism that leads to (52/72) of matched normal mucosa from adjacent and remote E-Cadherin loss and determines diffuse cancer development foci, respectively. In comparison, CDH1 promoter (8, 9). Epigenetic silencing of CDH1 through promoter methylation was detected in 12/24 normal gastric mucosa methylation plays an important role as a second-hit samples without DGC, and this difference was statistically mechanism in patients with hereditary DGC and patients significant (p=0.016). Conclusion: The current study showed with germline CDH1 mutations. Moreover, CDH1 promoter that the majority of DGC cases demonstrated concurrent methylation is also frequently found in sporadic DGC, and CDH1 promoter methylation in tumor tissues and in non- is responsible for inactivation of the second allele following neoplastic mucosa. somatic mutations of the first allele (10, 11). In this study, we hypothesized that CDH1 promoter Gastric carcinoma is one of the most common malignancies methylation would be detected more frequently in the non- and remains the second leading cause of cancer death neoplastic gastric mucosa from patients with DGCs than in worldwide although a universally declining trend has been the normal gastric mucosa from patients without DGCs. By performing a comparison of qualitative methylation determined by methylation-specific polymerase chain This article is freely accessible online. reaction (MSP) with quantitative methylation determined by pyrosequencing (PS), CpG methylation in the CDH1 *These Authors contributed equally to this work. promoter was investigated in 72 cases of DGCs with matched pairs of tumor-adjacent and tumor-remote gastric Correspondence to: Jae Hyuk Lee, MD, Ph.D., Department of mucosa and in 24 control samples of normal gastric mucosa Pathology, Chonnam National University Medical School, #8, Hak- along with E-Cadherin protein expression determined by dong, Dong-gu, Gwangju, 501-757, Republic of Korea. Tel: +82 immuno-histochemistry. Additionally, in order to determine 613797073, Fax: +82 613797099, e-mail: [email protected] which method has greater potential for clinical application, Key Words: Methylation, human CDH1 protein; stomach neoplasm, the correlation between methylation status and diffuse gastric cancer, methylation-specific polymerase chain clinicopathological variables, as well as survival rates was reaction, pyrosequencing. also investigated. 0250-7005/2013 $2.00+.40 3765 ANTICANCER RESEARCH 33: 3765-3774 (2013) Materials and Methods Table I. Clinicopathological features of selected patients. Patients and specimens. DGC specimens were obtained from 72 Characteristics Total n Proportion (%) patients who underwent surgical resection at the Chonnam National University Hospital between 2004 and 2008. The cases were identified Age, years <55 33 45.8 retrospectively based on clinicopathological data. Patients with a ≥55 39 54.2 history of familial gastric cancer were excluded. Samples of gastric Gender M 37 51.4 F 35 48.6 carcinoma; non-neoplastic mucosa adjacent to the tumor, but at least Location Upper third 9 12.5 1.5 cm away from the tumor; and non-neoplastic mucosa remote from Middle third 13 18.1 the tumor, at least 5 cm away from the tumor, respectively were Lower third 49 68.1 obtained. To exclude the possibility of a field defect, a control group of Whole 1 1.4 normal gastric mucosas from 24 patients with benign gastric pathology Tumor size, cm <2.5 35 48.6 was included. The diagnoses of patients in the control group were as ≥2.5 37 51.4 follows: 11 cases of gastric peptic ulcer, five cases of ectopic pancreas, Lauren classification Diffuse 66 91.7 four cases of leiomyoma, two cases of schwannoma, and two cases of Mixed 6 8.3 hyperplastic polyps. None of the control patients had a clinical history Differentiation Poor 52 72.2 of gastric dysplasia or carcinoma. The tumors were divided into two Signet 20 27.8 histological subgroups: poorly-differentiated adenocarcinomas and Depth of invasion T1 45 62.5 signet ring carcinomas. Of the 72 gastric tumors, 40 tumors were of T2 20 27.8 the pure diffuse type and 32 tumors were of the mixed type, according T3 7 9.7 to the Lauren classification. The extent of the tumor was determined Lymph node metastasis Absent 49 68.1 using the American Joint Committee on Cancer (AJCC) staging Present 23 31.9 criteria (12). Patients were followed-up for an average duration of 92.4 Distant metastasis Absent 69 95.8 months (range 3 to 108 months) to determine the clinical outcomes. Present 3 4.2 This study was approved by the Institutional Review Board of TNM stage I 52 72.2 Chonnam National University Hospital (#2013-78). II 11 15.3 III 6 8.3 IV 3 4.2 Microdissection and DNA extraction. Tissues were carefully microdissected on H&E-stained slides, as described previously (13). Genomic DNA was extracted from the microdissected tissue according to the manufacturer’s instruction (Boehringer Mannheim, Germany). In brief, the microdissected tissue was treated with Pyrosequencing. PS of the PCR products from the bisulfite-treated 50 μL of buffer containing 0.5% Tween 20 (Boehringer Mannheim, DNA was used to determine the percentage of methylation of the Germany), 20 μg of proteinase K (Boehringer Mannheim), eight CpG sites within the CDH1 gene promoter. DNA (30-50 ng) 50 mmol/L Trizma base at pH 8.9, and 2 mmol/L EDTA, followed was amplified by PCR in a 50-μl reaction mixture containing forward by incubation at 56˚C for 12-18 h. Proteinase K was inactivated by primer (5’-TTTGATTTTAGGTTTTAGTGAGT-3’) and biotinylated incubating the samples at 100˚C for 10 min. reverse primer (5’-biotin-ACCACAACCAATC AACAAC-3’). PS was performed according to the manufacturer’s instructions using the Bisulfite treatment of DNA and MSP. The methylation status of sequencing primer (5’ TGTGTGTT TGAGGATTTG-3’) on a PSQ 96 CDH1 exon 1 was determined by MSP after bisulfite treatment of MA System (Biotage AB, Uppsala, Sweden). Amplification was the DNA, as described previously but with some modifications (14). performed under the following conditions: 95˚C for 15 min, 35 cycles Methprimer (http://www.urogene.org/methprimer/index1.html) was of 95˚C for 30 s, 54˚C for 40 s, 72˚C for 1 min, and finally 72˚C for used to design MSP primer sets for methylated DNA (forward, 5’- 10 min. The methylation status determined by the PS assay was TTAGGTTAGAGGGTTATCGCG-3’, and reverse, 5’- TAACTAA analyzed as both a continuous variable (methylation level) and a AAATTCACCTACCGAC-3’, yielding a 116-bp product) and categorical variable (methylation negative: methylation level <10%; unmethylated DNA (forward 5’-TAATTTTAGGTTAGAGGG methylation positive: methylation level ≥10%). An empirical cut-off TTATTGT-3’, and reverse 5’ CACAACCAATCAACACA-3’, of ≥10% was selected, according to the limit of the unmethylated yielding a 98-bp product) in CDH1 exon 1 (Figure 1). Briefly, for control. The technical controls for PS revealed median methylation MSP analysis, 2 μg of genomic DNA were denatured by NaOH and of 4% (unmethylated control) and 90% (methylated control) in the modified by bisulfite. The modified DNA was purified using a DNA eight sequential CpG sites, defining the detection limits of the assay cleanup kit (Promega, Madison, WI, USA), treated with NaOH to (Figure 2A and B). disulfonate, precipitated with ethanol and resuspended in water. PCR amplification was carried out in a GeneAmp PCR System 9700 Immunohistochemical staining and assessment. Immunohisto- thermocycler (Perkin Elmer, Santa Clara, California, USA). PCR chemical staining for E-Cadherin protein was performed on 4-μm products were visualized on 2% agarose gels stained with ethidium thick paraffin-embedded tissue sections. Immunohistochemistry was bromide. Genomic DNA after bisulfite modification and after performed using automated standard procedures (Flex Plus detection treatment with Sss1 methylase (New England Biolabs, Ipswich, MA, system; DAKO, Carpinteria, CA, USA) and monoclonal antibody USA) was used as a positive control for methylated DNA. A sample to E-Cadherin (Clone M3612; DAKO Carpinteria, CA, USA) at was deemed positive for methylation if a band was seen in the DNA dilution 1:100. The specific standardized protocol provided by the that were amplified using the methylated reaction primers (Figure 2).
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