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Papers - KANAI Yae

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Primary low-grade lymphoma of mucosa-associated lymphoid tissue of the urinary bladder: a case report with special reference to the use of ancillary diagnostic studies.

Ando K, Matsuno Y, Kanai Y, Sakamoto M, Fujimoto H, Narabayashi M, Tobisu K.

Jpn J Clin Oncol (Japanese Journal of Clinical Oncology) 29 ( 12 ) 636 - 639 1999

Accepted, ISSN 03682811

We report a case of primary low-grade B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) type of the urinary bladder. The patient, a 77-year-old woman, presented with a sense of urinary retention. An intravenous pyelogram and cystoscopy revealed a wide-based submucosal mass measuring 3 cm in the left wall of the urinary bladder. Histological findings of the tissue obtained by transurethral resection (TUR) showed a dense, monomorphic atypical lymphoid (centrocyte-like) infiltrate with reactive lymph follicles in the subepithelial tissue. Monocytoid and plasmacytoid features were readily evident in a population of these cells. Lymphoepithelial lesions involving the urothelium were also noticed in some areas. These features were strongly suggestive of primary low-grade lymphoma of the MALT type. The diagnosis was confirmed by immunohistochemical and flow cytometric studies, both of which showed a clear immunoglobulin restriction to lambda light chain and also by polymerase chain reaction-based assay using a formalin-fixed paraffin-embedded TUR tissue sample, which showed a clonal Ig heavy-chain gene rearrangement. Clinical staging procedures revealed that the tumor was localized in the urinary bladder. The patient has not received chemotherapy and is alive and well with no evidence of recurrence, 3 years after TUR. This case demonstrates that these ancillary tests are worth performing for confirmation of B-cell clonality in TUR tissue samples showing dense B-lymphocytic infiltration. © 1999 Foundation for Promotion of Cancer Research.

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Reduction of integrin β4 and enhanced migration on laminin in association with intraepithelial spreading of urinary bladder carcinomas.

Harabayashi T, Kanai Y, Yamada T, Sakamoto M, Ochiai A, Kakizoe T, Koyanagi T, Hirohashi S.

J Urol (Journal of Urology) 161 ( 4 ) 1364 - 1371 1999

Accepted, ISSN 00225347

Purpose: The aim of the present study was to investigate the biological and molecular basis of intraepithelial spreading (IES) of carcinomas in situ (CIS) of the urinary bladder, which were considered to be precursors of nodular invasive carcinomas. Materials and Methods: The propensity for IES of human transitional carcinoma cells was examined by inoculation into murine renal pelvis and urinary bladder, and the biological character of the cells with a high propensity for IES was explored in vitro. Results: Three of 6 cell lines exhibited a high propensity for IES. When cultured on laminin, these IES cells scattered, whereas 3 non-IES cells and 2 immortalized transitional epithelial cells did not. IES cells showed strong adhesiveness, haptotaxis and enhanced migration on laminin compared with both non-IES and immortalized transitional epithelial cells. In IES cells, expression of the integrin β4 subunit was markedly reduced and the integrin α6β1 complex was predominant compared with the integrin α6β4 complex. Transfection of IES cells with integrin β4 subunit cDNA inhibited their ability to migrate on laminin and their propensity for IES. In addition, expression of the integrin β4 subunit was reduced in surgically resected specimens of CIS of the urinary bladder. Conclusion: The results indicate that a reduction in integrin β4 plays a role in IES of CIS of the urinary bladder through enhanced migration on laminin.

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Disruption of E-cadherin-mediated cell adhesion systems in gastric cancers in young patients.

Saito A, Kanai Y, Maesawa C, Ochiai A, Torii A, Hirohashi S.

Jpn J Cancer Res (Japanese Journal of Cancer Research) 90 ( 9 ) 993 - 999 1999

Accepted, ISSN 09105050

The aim of this study was to elucidate the pathogenetic backgrounds of early-onset gastric cancers. Mutations of the E-cadherin and β-catenin genes were analyzed by subjecting microdissected cancer cells and corresponding non-cancerous epithelial cells obtained from 9 gastric cancer patients under 35 years old to polymerase chain reaction-single strand conformation polymorphism analysis. Somatic, but no germline, E-cadherin gene mutations were detected in 6 (67%) of the patients. The cancer cells of 2 patients were exon 9-deleted E-cadherin molecule-immunoreactive. Neither somatic nor germline mutations in exon 3 of the β-catenin gene were observed in any patient. One patient lacked β-catenin immunoreactivity and the cancer cells of 6 others showed cytoplasmic β-catenin immunoreactivity. The E-cadherin-mediated cell adhesion system in the cancer cells of all the patients examined appeared to be disrupted, indicating that somatically acquired dysfunction of this system plays an important role in early-onset diffuse-type gastric cancers. Helicobacter pylori infection was observed in 6 (67%) of our 9 patients, an incidence higher than the average in young Japanese individuals. Thus, early-onset gastric cancers may be attributabIe to environmental factors such as Helicobacter pylori infection.

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Reduced mRNA expression of the DNA demethylase, MBD2, in human colorectal and stomach cancers.

Kanai Y, Ushijima S, Nakanishi Y, Hirohashi S.

Biochem Biophys Res Commun (Biochemical and Biophysical Research Communications) 264 ( 3 ) 962 - 966 1999

Accepted, ISSN 0006291X

A study was performed to evaluate the significance of aberrations of the newly identified DNA demethylase, MBD2, in human carcinogenesis. Levels of expression of DNA demethylase mRNA were examined by reverse transcription followed by real-time quantitative detection of the PCR products in 32 samples of colorectal cancer tissue, 24 stomach cancers, and the corresponding noncancerous mucosae. DNA demethylase mRNA levels normalized with glyceraldehyde-phosphate dehydrogenase (GAPDH) mRNA were reduced in 31 (97%) of the 32 colorectal cancers and in 22 (92%) of the 24 stomach cancers when compared with the levels in the corresponding noncancerous mucosae. The average levels of DNA demethylase mRNA expression normalized with GAPDH mRNA in each of the colorectal (0.81 ± 0.55) and stomach (2.88 ± 0.23) cancers were significantly lower than in the noncancerous mucosae (1.90 ± 0.16 and 5.11 ± 0.34, respectively, p < 0.0001). There was no significant association between the DNA demethylase mRNA level and malignant potential in both colorectal and stomach cancers. These data suggest that reduced expression of DNA demethylase may play a role at a certain step of multistage carcinogenesis. Reduction of DNA demethylase mRNA expression may be, if anything, one of the early events of carcinogenesis, but may not participate in the malignant progression of tumors.

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Cloning and characterization of the human β<inf>4</inf>-integrin gene promoter and enhancers

Takaoka A., Yamada T., Gotoh M., Kanai Y., Imai K., Hirohashi S.

Journal of Biological Chemistry (Journal of Biological Chemistry) 273 ( 50 ) 33848 - 33855 1998.12

ISSN 00219258

The cell-surface adhesion molecule α6β4-integrin is a receptor for laminins and a component of hemidesmosomes. β4-Integrin expression is restricted to proliferating basal keratinocytes in the epidermis and is suppressed when differentiation commences. Altered β4-integrin expression levels correlate significantly with the aggressive behavior of cancers. In order to clarify the mechanisms that regulate transcription of the β4- integrin gene, we cloned its 5'-flanking region. This 5'-flanking region was found to have a high G + C content and not to contain either TATA or CAAT boxes. Nested delimitation and reporter analyses mapped a basal promoter to nucleotides -106 to +105, surrounding the most proximal transcription initiation site. Gel retardation and mutational analyses revealed that cooperation between AP1 and Ets, interacting with other factors, mediated the promoter activity. In addition to the promoter element, enhancer activity was found in the first intron (+1905/+3933) and in a sequence upstream of the promoter region (-414/-107). These findings should facilitate our understanding of the regulation of β4-integrin gene expression in processes such as cell growth and differentiation, apoptosis, and cancer development and metastasis.

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Reduced p27(Kip1) expression in hepatocellular carcinomas

Hui A., Sun L., Kanai Y., Sakamoto M., Hirohashi S.

Cancer Letters (Cancer Letters) 132 ( 1-2 ) 67 - 73 1998.10

ISSN 03043835

This study was designed to determine whether changes in p27(Kip1) expression are involved in human hepatocarcinogenesis. We examined the p27(Kip1) mRNA expression in hepatocellular carcinomas and surrounding non-cancerous liver tissue samples from 21 patients using a reverse-transcriptase polymerase chain reaction assay. The mean p27(Kip1) mRNA expression levels (ratio of p27(Kip1)/β-actin mRNA) were significantly lower in hepatocellular carcinomas than in non-cancerous liver tissues (0.49±0.24 versus 0.57±0.22, P<0.05). p27(Kip1) mRNA expression was reduced in 11 (52%) of the 21 hepatocellular carcinomas when compared with the surrounding non-cancerous liver tissues. These findings suggest that reduced p27(Kip1) expression may be at least partly responsible for human hepatocarcinogenesis. Copyright (C) 1998 Elsevier Science Ireland Ltd.

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Japanese late-onset breast cancer families: Their clinicopathological characteristics and absence of BRCA1 and BRCA2 germline mutations

Okumura T., Fukutomi T., Tsuda H., Kanai Y., Ushijima T., Akashi-Tanaka S., Nanasawa T.

Breast Cancer (Breast Cancer) 5 ( 3 ) 251 - 254 1998.07

ISSN 13406868

Background: The causes and pathologic and prognostic phenotypes of late-onset familial breast cancers are still unknown. The purpose of this study was to document the clinicopathological features of late-onset familial breast cancers using genetic testing of BRCA1 and BRCA2. Methods: We analyzed 11 breast cancers from 10 patients from 8 Japanese late-onset Breast cancer families. Results: The average age of the patients was 55 years (range 43 to 89). Bilateral occurrence was noted in 2 patients (8%). All the tumors were invasive ductal carcinomas, except for 1 case of invasive lobular carcinoma. Tumor size ranged from 0.8 cm to 7.8 cm (median 2.3 cm) and lymph node metastasis occurred in 6 of the 11 patients (55%). Six (55%) of the 11 tumors were histologically grade 2 and 5 (45%) were histologically grade 3. Estrogen receptor (ER) positivity was 80% (8/10). Overexpression of c-erbB-2 and p53 protein was detected in 18% (2/11) and 9% (1/11) of the tumors, respectively. Five patients from 4 families received genetic testing but all were negative for BRCA 1 and BRCA2 germline mutations. All the patients were alive after a median follow-up period of 32 months, except for 1 patient. Conclusions: In this study, no germline mutations of BRCA1 or BRCA2 were detected. However, there was a tendency towards ER-positive tumors, but the positivity of p53 protein was considered to be lower then that of sporadic tumors.

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Small polypoid lesions of the gallbladder. Differential diagnosis and surgical indications by helical computed tomography

Furukawa H., Kosuge T., Shimada K., Yamamoto J., Kanai Y., Mukai K., Iwata R., Ushio K.

Archives of Surgery (Archives of Surgery) 133 ( 7 ) 735 - 739 1998.07

ISSN 00040010

Objectives: To demonstrate the helical computed tomographic (CT) features of small polypoid lesions of the gallbladder and to establish a clinical strategy based on CT findings for the treatment of such lesions. Design: Validation cohort study. Setting: Tertiary care public hospital. Patients: Thirty-one patients with polypoid lesions of the gallbladder (≤3 cm) underwent CT followed by resection. Main Outcome Measure: The detectability of the lesions on both unenhanced and enhanced CT and the configuration of the lesions on enhanced CT were prospectively evaluated in comparison with the histopathological findings. Results: Unenhanced CT detected 14 (45%) of the 31 lesions, whereas enhanced CT detected all of the lesions. The detection rates of the neoplastic lesions (adenoma, adenocarcinoma, and metastatic tumor) and cholesterol polyps were 81% (13/16) and 7% (1/15), respectively (P<.001). Among the 20 lesions demonstrated as pedunculated, 6 (30%) were neoplastic, whereas 10 (91%) of the 11 lesions demonstrated as sessile were neoplastic (P<.001). When a lesion was demonstrated on unenhanced CT or its shape was sessile on enhanced CT, the case was diagnosed as a neoplastic lesion. The sensitivity, specificity, positive predictive value, negative predictive value, and overall accuracy of the CT diagnosis of the neoplastic lesions were 88% (14/16), 87% (13/15), 88% (14/16), 87% (13/15), and 87% (27/31), respectively. Conclusion: Computed tomography can differentiate neoplastic and nonneoplastic small polypoid lesions of the gallbladder and reliably identify the presence of neoplastic lesions that should be resected.

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Apocrine Carcinoma of the Breast: Clinicopathological Analysis and Histological Subclassification of 12 Cases.

Matsuo K, Fukutomi T, Tsuda H, Kanai Y, Tanaka SA, Nanasawa T.

Breast Cancer (Breast Cancer) 5 ( 3 ) 279 - 284 1998

Accepted, ISSN 13406868

Background: Apocrine carcinoma is rare and most of its clinicopathological features are still unknown. The purpose of this study was to identify the clinicopathological characteristics of apocrine carcinoma. Methods: We clinicopathologically analyzed apocrine breast carcinomas resected from 12 Japanese women and subclassified them histopathologically. Results: The average age of the patients at diagnosis was 60.1 years (range: 38-78). Tumor diameters ranged from 0.5 to 4.5 cm (median 2.4). Mammography revealed tumor shadows without microcalcifications in all patients. Two (17%) of the 12 patients were lymph node metastasis-positive, and lymphatic permeation by tumor cells was observed in 3 (25%). Apocrine carcinoma in this study could be classified into three subtypes according to predominant histopathological growth pattern: type I, intraductal spreading type (4 patients); type II, adenosis-associated type (3 patients); and type III, infiltrating type (5 patients). Types I and II showed no lymph node metastasis and had an excellent prognosis, whereas the infiltrating type was associated with lymph node metastasis and death from cancer. Estrogen receptors and progesterone receptors were positive in 17% (1/6) and 60% (3/5), respectively, of the tumors tested. Conclusions: In the present study, apocrine carcinoma of the breast was characterized by higher patient age and tumor shadows without microcalcifications on mammography. However, the tumors were heterogenous with regard to pattern of local spread.

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Local recurrence after conservative surgery without postoperative radiation for pure tubular carcinoma of the breast: a case report with reference to multifocality of tubular carcinoma.

Okano K, Fukutomi T, Tsuda H, Akashi-Tanaka S, Nanasawa T, Kanai Y.

Breast Cancer (Breast Cancer) 5 ( 2 ) 201 - 204 1998

Accepted, ISSN 13406868

A 49-year-old premenopausal woman with stage I breast carcinoma underwent left quadrantectomy with axillary dissection in 1992. The tumor was 0.7×0.5 cm. Histopathologically, this was a pure tubular carcinoma without lymph node metastasis or lymphatic or vascular invasion. Although the surgical margin was pathologically negative, atypical ductal hyperplasia was present close to the cut margin's edge. Neither adjuvant chemotherapy nor radiotherapy had been given after the operation. Approximately 5 years after the first surgery, she had a local recurrence in the vicinity of the operative wound. There was no clinical evidence of distant metastasis. A salvage mastectomy was performed. Histopathological examination revealed that the second tumor was an invasive ductal carcinoma, histological grade 2, with extensive intraductal component. It was difficult to determine whether this was a true in-breast recurrence or a second primary cancer. Overexpression of p53 and c-erbB-2 was observed in the second tumor. Estrogen receptor and progesterone receptor were both negative. No postoperative chemotherapy was given. Multifocality and atypical ductal hyperplasia were observed in 7 (87.5%) and 6 [75%) of 8 patients, respectively, with tubular carcinoma between 1991 and 1997 at the National Cancer Center Hospital. Coexisting disease associated with tubular carcinoma suggests that radiotherapy may be an important component of breast conservation treatment to prevent local recurrence in this type of tumor.

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Microinvasive breast carcinoma with extensive involvement of level III axillary lymph nodes: a case report.

Fujii K, Fukutomi T, Tsuda H, Akashi-Tanaka S, Nanasawa T, Kanai Y, Muramatsu Y.

Jpn J Clin Oncol (Japanese Journal of Clinical Oncology) 28 ( 1 ) 47 - 49 1998

Accepted, ISSN 03682811

A 44-year-old woman presented with a right huge axillary mass. Both mammography and ultrasonography revealed a primary cancer of 2.8 cm maximum diameter in the right breast and metastases in the axillary lymph nodes, both being confirmed by aspiration cytology as ductal carcinoma. Right standard radical mastectomy with level III axillary lymph node dissection was carried out. Pathologically, the tumor was diagnosed as ductal carcinoma in situ with microinvasion (DCISM), histologic grade 3. The area of stromal invasion measured 1 mm at its widest point. Sixteen of the 17 resected axillary lymph nodes contained metastases, including six level III lymph nodes. Immunohistochemical studies of the tumor revealed overexpression of p53 protein, but not that of c-erbB-2 protein. The frequency of lymph node metastases from DCISM is reported to be very low. Therefore, the present case with extensive involvement of level III lymph nodes was unusual.

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Breast cancer in Cowden's disease: a case report with review of the literature.

Tsubosa Y, Fukutomi T, Tsuda H, Kanai Y, Akashi-Tanaka S, Nanasawa T, Linuma G, Ushio K.

Jpn J Clin Oncol (Japanese Journal of Clinical Oncology) 28 ( 1 ) 42 - 46 1998

Accepted, ISSN 03682811

We report a case of invasive breast cancer in a 62-year-old female patient with Cowden's disease. A left modified radical mastectomy was performed and histopathology of the tumor showed invasive ductal carcinoma, histological grade 3, without lymph node metastasis. The patient had a past history of endometrial cancer at 55 but did not have a family history of malignant disease. Goiter was palpable but aspiration cytology revealed no malignancy. There were several papillomas on the oral mucosa and multiple papillomatous lesions on the right femur. Barium X-ray and endoscopic examination revealed multiple, small, hyperplastic polypoid lesions on the esophagus, stomach and rectum. Histopathology of the biopsy specimens from the esophagus and stomach showed acanthotic squamous epithelium and foveolar hyperplastic polyps. The patient was followed up closely to monitor the thyroid lesions and polyposis of the digestive tract. A total of 12 breast cancer patients who also had Cowden's disease have been reported in Japan and these cases are reviewed in this report.

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Expression of CD44 variants and its association with survival in pancreatic cancer.

Gotoda T, Matsumura Y, Kondo H, Saitoh D, Shimada Y, Kosuge T, Kanai Y, Kakizoe T.

Jpn J Cancer Res (Japanese Journal of Cancer Research) 89 ( 10 ) 1033 - 1040 1998

Accepted, ISSN 09105050

Since the CD44 variant 6(v6) molecule has been noted as a marker for tumor metastasis and prognosis in several tumors, we examined whether or not v6 is a useful marker for evaluating the prognosis of pancreatic cancer patients. In addition, we attempted to assess the clinicopathological implications for pancreatic cancer of the variant 2 (v2) isoform using a recently developed monoclonal antibody against a v2 epitope. The expression of CD44 variants was evaluated immunohistochemically in paraffin-embedded pancreatic cancer tissues from 42 patients who were confirmed surgically and histologically to have received curative resection. An indirect immunoperoxidase method was used with monoclonal antibodies against epitopes of the standard (CD44s) portion, v6 and v2. Protein expression data were evaluated statistically for any correlations with the length of survival or with histological parameters. The expression of CD44v6 and v2 was observed only in tumor cells, if at all. On the other hand, expression of total CD44 (including CD44v, as well as CD44s) was observed in both tumors and adjacent normal sites. Tumor tissue from 21 (50%) and 16 (38%) patients showed positive immunoreactivity with mAb 2F10 (anti-CD44v6) and mAb M23.6.1 (anti-CD44v2), respectively. The expression of CD44v6 and v2 was correlated with decreased overall survival (P = 0.0160 and P = 0.0125, respectively). A significant correlation was obtained between CD44v2 peptide expression and vessel invasion (P = 0.026). These results suggest that CD44v2 and CD44v6 may be useful markers for poor prognosis in curatively resected primary pancreatic cancer.

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Nonfunctioning islet cell tumors of the pancreas: clinical, imaging and pathological aspects in 16 patients.

Furukawa H, Mukai K, Kosuge T, Kanai Y, Shimada K, Yamamoto J, Mizuguchi Y, Ushio K.

Jpn J Clin Oncol (Japanese Journal of Clinical Oncology) 28 ( 4 ) 255 - 261 1998

Accepted, ISSN 03682811

Background: Nonfunctioning islet cell tumors (NFICTs) usually reach a large size prior to detection, at which stage patients have some symptoms or signs. Recently, NFICTs have been discovered in asymptomatic patients with increasing frequency owing to advances in diagnostic imaging techniques. This study investigated clinical, imaging and pathological features in recent cases of NFICT. Methods: The medical records, radiographs and pathological specimens of 16 patients with NFICT who were evaluated between April 1991 and March 1996 were reviewed. Results: Tumor sizes ranged from 0.8 to 17 cm (average, 5.2 cm). Five patients (31%) had some symptoms or signs at the time of diagnosis; however, the other 11 (69%) had no symptoms. Of 10 patients with a tumor of size 5 cm or less, nine were asymptomatic and all tumors were histologically benign. In contrast, in six patients with a tumor larger than 5 cm, four had some symptoms and five tumors were malignant. The detection rates of pancreatic tumor mass on ultrasonography and computed tomography were 94% (15/16) each. All 14 patients in whom the tumor was completely resected survived without recurrence; however, the remaining two patients with liver metastases died following recurrence. Conclusions: US and CT are useful in detecting NFICTs even if the tumor is small and the patient is asymptomatic. The detection of NFICTs of small size and their complete removal are essential for a successful cure.

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Small polypoid lesions of the gallbladder: differential diagnosis and surgical indications by helical computed tomography.

Furukawa H, Kosuge T, Shimada K, Yamamoto J, Kanai Y, Mukai K, Iwata R, Ushio K.

Arch Surg 133 735 - 739 1998

Accepted

Helical computed tomography in the diagnosis of portal vein invasion by pancreatic head carcinoma: usefulness for selecting surgical procedures and predicting the outcome.

Furukawa H, Kosuge T, Mukai K, Iwata R, Kanai Y, Shimada K, Yamamoto J, Ushio K.

Arch Surg (Archives of Surgery) 133 ( 1 ) 61 - 65 1998

Accepted, ISSN 00040010

Objective: To evaluate the use of helical computed tomography (CT) in diagnosing portal vein (PV) invasion by pancreatic head carcinoma and its usefulness in predicting outcome. Design: Validation cohort study. Setting: Tertiary care public hospital. Patients: Twenty-seven patients with carcinoma involving the pancreatic head were preoperatively studied with helical CT. All patients underwent resection. Main Outcome Measure: By quantifying the contact between the tumor and PV on helical CT, the relationship between them was classified into 1 of 4 types: type 1, visible fat layer between PV and the tumor; type 2, with the total PV circumference defined as 360°, contact between the tumor and PV was considered to be 90°or less; type 3, contact ranged between 91°and 180°; and type 4, contact greater than 180°. Helical CT results were compared with intraoperative observation, histological findings of the resected specimen, and postoperative course. Results: When helical CT showed type 3 or 4, the case was diagnosed as positive for PV invasion. Sensitivity, specificity, and overall accuracy were 83%, 100%, and 89% when compared with the intraoperative assessment, and 92%, 79%, and 85% with the histological assessment, respectively. One- and 2-year survival rates were 86% and 69% for type 1,100% and 75% for type 2, and 33% and 12% for type 3, respectively. The survival rates of patients with types 1 and 2 were significantly higher than that of those with type 3 (P<.05). All 3 patients with type 4 died within 9 months. Conclusions: Helical CT facilitates detection of PV invasion by pancreatic head carcinoma. The extent of PV involvement reflected the outcome after pancreatectomy.

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Epidermoid cyst in an intrapancreatic accessory spleen: CT and pathologic findings.

Furukawa H, Kosuge T, Kanai Y, Mukai K.

AJR Am J Roentgenol (American Journal of Roentgenology) 171 ( 1 ) 271 1998

Accepted, ISSN 0361803X

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Cloning and characterization of the human β4-integrin gene promoter and enhancers.

Takaoka AS, Yamada T, Gotoh M, Kanai Y, Imai K, Hirohashi S.

J Biol Chem 273 33848 - 33855 1998

Accepted

Reduced p27Kip1 expression in hepatocellular carcinomas.

Hui AM, Sun L, Kanai Y, Sakamoto M, aHirohashi S.

Cancer Lett 132: 67 - 73 1998

Accepted

DNA hypermethylation at the D17S5 locus is associated with gastric carcinogenesis.

Kanai Y, Ushijima S, Ochiai A, Eguchi K, Hui A, Hirohashi S.

Cancer Lett (Cancer Letters) 122 ( 1-2 ) 135 - 141 1998

Accepted, ISSN 03043835

The aim of this study was to elucidate the significance of aberrant DNA methylation in gastric carcinogenesis. The DNA methylation status at the D17S5 locus, at which a candidate tumor suppressor gene, HIC-1, was identified, of gastric cancers and non-cancerous gastric mucosae from 42 gastric cancer patients was examined by Southern blotting using a methylation-sensitive restriction enzyme. DNA hypermethylation was observed in 15, 13, 25 and 45% of the tissues showing no remarkable histological findings, chronic gastritis without intestinal metaplasia, intestinal metaplasia and gastric cancer, respectively. The incidence of DNA hypermethylation was significantly higher in gastric cancers than in non-cancerous gastric mucosae (P < 0.05). DNA hypermethylation was often accompanied by allelic loss at the same locus in gastric cancers. DNA hypermethylation at the D17S5 locus, which was even detected in precancerous conditions, including intestinal metaplasia, may play a role in gastric carcinogenesis.

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