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T2069 Role of Ciap2 in Gastric Cancer
AGA Abstracts
EphA4 expression by siRNA in EphA4-overexpressing gastric cancer cell lines resulted in a significant decrease in cell growth. Our results suggest that overexpression of EphA4 plays an important role in gastric cancer. EphA4 could be an attractive target for molecular therapy by a therapeutic antibody and/or by small molecules targeting its kinase activities.
were detected during the observation period. The incidence for cardia type I-III adenocarcinoma tended to decrease from 1982 to 2006 from 5.07 to 4.16/100 000. The incidence rates for noncardia gastric adenocarcinoma strongly (P < 0.001) decreased from 1982 to 2006 from 6.61 to 2.83/100 000 (Figure). Conclusions: As in other Western countries, the incidence of noncardia gastric cancer strongly decreased within the last 25 years in Central Switzerland. In contrast to other Western countries, cardia type I-III adenocarcinoma did not increase in the last 25 years.
T2066 Endoscopic Mucosal Resection for Undifferentiated Intramucosal Gastric Cancer: Different Indications Between Signet Ring Cell Carcinoma and Poorly Differentiated Adenocarcinoma Hoi Jin Kim, Jae J Kim, Eun Ran Kim, Dong Hyun Sinn, Young-Ho Kim, Jun Haeng Lee, Dong Kyung Chang, Poong-lyul Rhee, Jong Chul Rhee Background) Small undifferentiated gastric cancer limited to the mucosal layer has been proposed as an extended indication for endoscopic mucosal resection (EMR). However, there is limited data about the difference of lymph node metastasis (LNM) in different histological subtypes between intramucosal signet ring cell carcinoma (SRC) and poorly differentiated adenocarcinoma (PDC). The aim of this study was to identify risk factors of the LNM and to suggest appropriate indications for EMR for undifferentiated intramucosal cancers. Method) We reviewed medical records of 2128 patients with intramucosal gastric cancers treated with gastrectomy and regional lymph node dissection at the Samsung Medical Center from 1994 to 2005. Clinicopathological factors related to LNM for intramucosal SRC and PDC were evaluated in comparison to differentiated intramucosal gastric cancers (DAC). Results) Out of 2128 intramucosal gastric cancers, 9 of 1243 (0.7%) cases of DAC, 20 of 594 (3.4%) cases of SRC and 18 of 291 (6.2%) cases of PDC had LNM. LNM increased significantly in SRC (OR=4.18 95% CI: 1.64-10.6) and PDC (OR=12.4 95% CI: 4.83-32.1) compared to DAC as determined by multivariate analysis. Tumor size (OR =3.36, 95% CI: 1.07-10.5) and lymphovascular invasion (OR=13.6 95% CI: 4.65-40.1) were other significant risk factors associated with LNM. None of 175 SRCs less than 20 mm in size (95% CI: 02.09) and none of 21 PDCs less than 10 mm in size (95% CI: 0-16.11) without lymphovascular invasion had LNM. Conclusion) Histological subtype, tumor size and lymphovascular invasion are risk factors of LNM in undifferentiated intramucosal gastric cancers. Intramucosal SRC has an intermediate LNM risk between the differentiated type and PDC. SRCs less than 20 mm and PDCs less than 10 mm in size without lymphovascular invasion are possible candidates for EMR.
T2069
T2067
Role of Ciap2 in Gastric Cancer Zesong Li, Liang Qiao, Yun Dai, Bing Zou, Juan Ma, HuiYao Lan, Benjamin C.Y. Wong BACKGROUND AND OBJECTIVES cIAP2 is a member of the IAP family and is overexpressed in most cancer tissues. Expression of cIAP2 can be induced by gastric carcinogen H. pylori. Therefore enhanced expression of cIAP2 may be related to gastric carcinogenesis. We aimed to investigate the feasibility of targeting cIAP2 in gastric cancer therapy. METHODS AND MATERIALS 12 pairs of human gastric cancer tissues and matched non-cancerous tissues were used to extract total RNA by Trizol method. Whole tissue lysates were prepared by using RIPA lysis buffer. Expressions of cIAP2 were detected by RT-PCR and Western blot analysis. Gastric cancer BGC-7901 cells were transfected with specific siRNA against cIAP2 for 48 h, and the effect of siRNA-cIAP2 on cell proliferation was detected by standard WST-1 assay. Apoptosis was detected by TUNEL staining and quantitated by flow cytometry. RESULTS Over 70% of gastric cancer tissues expressed higher levels of cIAP2 compared to non-cancerous gastric tissues at both mRNA and protein levels. Over-expression of cIAP2 was also confirmed by immunohistochemical staining which cIAP2 is strongly expressed in most gastric cancer tissues, whereas in normal gastric tissues, cIAP2 is expressed in gastric epithelium with weak to medium intensity. Knocking down of cIAP2 in BGC-7901 cells by siRNA-cIAP2 resulted in a 30% decrease in cell proliferation and a 20% increase in apoptosis as revealed by flow cytometry. CONCLUSION cIAP2 may be a potential target for gastric cancer therapy. Further studies are under way to investigate the efficacy of cIAP downregulation in gastric cancer In Vivo.
Prospective Analysis of Metachronous Early Gastric Cancer in High Risk Patients After H. pylori Eradication Akiko Shiotani, Noriya Uedo, Tomoari Kamada, Hiroyasu Iishi, Masaharu Tatsuta, Minoru Fujita, Ken-ichi Tarumi, Noriaki Manabe, Hiroaki Kusunoki, Ken Haruma Background: It has been reported that H. pylori eradication reduced the risk for development of gastric cnacer in the subgroup without precancerous lesions. We previously reported that residual inflammation and no improvement of atrophy after eradication were more frequently detected in the cancer group than in the controls (Int J Cancer 2007;15:1182). Aim: We evaluated the development of new malignant lesions in the patients with prior medical endoscopic treatment after eradication to determine a prediction marker of second cancerogenesis. Methods: Histology was evaluated using two specimens from each sample site, the antrum greater curve and corpus greater and lesser curves. Serum pepsinogen (PG) I and II were measured using enzyme-linked immunosorbent assay (ELISA) kits. Results: Eightysix patients were enrolled and 76 patients had been successfully treated for H. pylori and followed up more than 2 years (average observation period 27 months, range 24-60 months). Metachronous gastric cancers developed in eight (10.5%) patients. All cases were men, and an average size of tumors was 6.5mm (3~12mm, superficial depressed type (IIc) 6 lesions and superficial elevated type (IIa) 2 lesions). Serum PG I and I/II ratio before eradication were significantly lower (PG I 18 vs 44, p=0.008; I/II ratio 0.9 vs 1.4, p=0.03) in the group that developed cancer compared to the group that did not. Atrophy at corpus lesser curve was severe in the all cancer cases; the frequency of sever atrophy was higher in the group that developed cancer compared to the group that did not (100% vs 51%, p=0.04). Conclusions: Prevention of cancer will likely require H. pylori eradication prior to the development of atrophy. The cancer risk post eradication relates to the extent and severity of atrophy. Studies are needed to identify the parameters dictating surveillance intervals and duration after H. pylori eradication in those with H. pylori -induced gastric atrophy.
T2070 The Promoter Polymorphism of Nuclear Factor-Erythroid 2-Related Factor 2 (NRF2) Gene Affects the Aberrant Promoter Methylation of Tumor-Related Genes in Gastric Epithelium Tomiyasu Arisawa, Tomomitsu Tahara, Tomoyuki Shibata, Masakatsu Nakamura, MItsuo Nagasaka, Yoshio Kamiya, Hiroshi Fujita, Daisuke Yoshioka, Masaaki Okubo, Yuko Arima, Hiroaki Shimazaki, Ichiro Hirata, Hiroshi Nakano
T2068
[Background and Aim] Aberrant promoter methylation is an important mechanism for gene silencing. Generated reactive oxygens may contribute to this CpG island methylation. Nrf2 is known to regulate the expression of detoxifying and antioxidant genes. We investigated the relationship between promoter polymorphisms of Nrf2 gene (G-686A, G-684A and C650A) and the CpG island methylation in non-cancerous gastric mucosa. [Methods] The study was performed in 85 subjects [46 without gastric malignancies (non-GC group) and 39 with gastric cancer (GC group)]. The promoter methylation status of the p14(ARF), p16(INK4a) and p21(Waf1) genes was determined by Methylation-Specific-Polymerase Chain Reaction (MSP). The Nrf2 gene genotypes were determined by the PCR-SSCP method. [Results] In all 85 subjects, CpG island methylation was found in 25.9% for p14, 15.3% for p16 and none for p21. The frequency of methylated genes was significantly higher in GC group than non-GC group (OR, 2.67; 95%CI, 1.10-6.49; p=0.029). In particular, the frequency of p16 gene methylation was largely higher in GC group (p=0.0023). The Nrf2 -686/-684 G/G haplotype was positively associated and A/G haplotype was inversely associated with the development of CpG island methylation, especially p14 gene methylation (OR, 3.28; 95%CI, 1.26-8.59; p=0.015, and OR, 0.38; 95%CI, 0.15-0.96; p=0.040, respectively). In Helicobacter pylori (H. pylori) infected subjects, the number of -686/-684 G/G allele was positively correlated and that of A/G allele was inversely correlated to the methylation status, especially p14 methylation, by the adjusted analysis (OR, 2.90; 95%CI, 1.14-7.36; p=0.026, and OR, 0.33; 95%CI, 0.13-0.88; p=0.027, respectively). There was no significant association between C-650A polymorphism and the DNA aberrant methylation. [Conclusions] Our
Incidence Rates of Esophageal and Gastric Carcinoma in Central Switzerland Within the Last 25 Years: There Is No Increase of the Incidence of Adenocarcinoma of the Gastroesophageal Junction Adrian Schmassmann, Marie-Gabrielle Oldendorf, Jan-Olaf Gebbers Background: A strong increase of adenocarcinoma incidence rates of the gastroesophageal junction has been reported in several other Western countries. The goal of this study was to examine subsite-specific and histology-specific esophageal and gastric carcinoma incidence patterns among the Central Swiss population within the last 25 years. Methods: Data on newly diagnosed esophageal and gastric carcinoma during 1982-2006 were obtained from the Cancer Registry of the Department of Pathology Lucerne, representing a catch population of about 700 000. Age, gender, tumor localization, histology, and incidence rates were assessed. Results: Between 1982-2006, there were (1) 344 patients with esophageal squamous cell carcinoma, (2) 669 patients with cardia type I-III adenocarcinoma, (3) 1061 patients with noncardia adenocarcinoma, and (4) 147 patients with gastric adenocarcinoma of unclear localization. The male-female sex ratio was 5.3 for esophageal squamous cell carcinoma, 3.1 for cardia type I-III, and 1.3 for noncardia gastric carcinoma, respectively. The mean age of diagnosis for all esophageal and gastric cancers was between 67-70 years. The average incidence for epithelial squamous cell carcinoma was 2.2/100 000; no significant changes
AGA Abstracts
A-612
EphA4 expression by siRNA in EphA4-overexpressing gastric cancer cell lines resulted in a significant decrease in cell growth. Our results suggest that overexpression of EphA4 plays an important role in gastric cancer. EphA4 could be an attractive target for molecular therapy by a therapeutic antibody and/or by small molecules targeting its kinase activities.
were detected during the observation period. The incidence for cardia type I-III adenocarcinoma tended to decrease from 1982 to 2006 from 5.07 to 4.16/100 000. The incidence rates for noncardia gastric adenocarcinoma strongly (P < 0.001) decreased from 1982 to 2006 from 6.61 to 2.83/100 000 (Figure). Conclusions: As in other Western countries, the incidence of noncardia gastric cancer strongly decreased within the last 25 years in Central Switzerland. In contrast to other Western countries, cardia type I-III adenocarcinoma did not increase in the last 25 years.
T2066 Endoscopic Mucosal Resection for Undifferentiated Intramucosal Gastric Cancer: Different Indications Between Signet Ring Cell Carcinoma and Poorly Differentiated Adenocarcinoma Hoi Jin Kim, Jae J Kim, Eun Ran Kim, Dong Hyun Sinn, Young-Ho Kim, Jun Haeng Lee, Dong Kyung Chang, Poong-lyul Rhee, Jong Chul Rhee Background) Small undifferentiated gastric cancer limited to the mucosal layer has been proposed as an extended indication for endoscopic mucosal resection (EMR). However, there is limited data about the difference of lymph node metastasis (LNM) in different histological subtypes between intramucosal signet ring cell carcinoma (SRC) and poorly differentiated adenocarcinoma (PDC). The aim of this study was to identify risk factors of the LNM and to suggest appropriate indications for EMR for undifferentiated intramucosal cancers. Method) We reviewed medical records of 2128 patients with intramucosal gastric cancers treated with gastrectomy and regional lymph node dissection at the Samsung Medical Center from 1994 to 2005. Clinicopathological factors related to LNM for intramucosal SRC and PDC were evaluated in comparison to differentiated intramucosal gastric cancers (DAC). Results) Out of 2128 intramucosal gastric cancers, 9 of 1243 (0.7%) cases of DAC, 20 of 594 (3.4%) cases of SRC and 18 of 291 (6.2%) cases of PDC had LNM. LNM increased significantly in SRC (OR=4.18 95% CI: 1.64-10.6) and PDC (OR=12.4 95% CI: 4.83-32.1) compared to DAC as determined by multivariate analysis. Tumor size (OR =3.36, 95% CI: 1.07-10.5) and lymphovascular invasion (OR=13.6 95% CI: 4.65-40.1) were other significant risk factors associated with LNM. None of 175 SRCs less than 20 mm in size (95% CI: 02.09) and none of 21 PDCs less than 10 mm in size (95% CI: 0-16.11) without lymphovascular invasion had LNM. Conclusion) Histological subtype, tumor size and lymphovascular invasion are risk factors of LNM in undifferentiated intramucosal gastric cancers. Intramucosal SRC has an intermediate LNM risk between the differentiated type and PDC. SRCs less than 20 mm and PDCs less than 10 mm in size without lymphovascular invasion are possible candidates for EMR.
T2069
T2067
Role of Ciap2 in Gastric Cancer Zesong Li, Liang Qiao, Yun Dai, Bing Zou, Juan Ma, HuiYao Lan, Benjamin C.Y. Wong BACKGROUND AND OBJECTIVES cIAP2 is a member of the IAP family and is overexpressed in most cancer tissues. Expression of cIAP2 can be induced by gastric carcinogen H. pylori. Therefore enhanced expression of cIAP2 may be related to gastric carcinogenesis. We aimed to investigate the feasibility of targeting cIAP2 in gastric cancer therapy. METHODS AND MATERIALS 12 pairs of human gastric cancer tissues and matched non-cancerous tissues were used to extract total RNA by Trizol method. Whole tissue lysates were prepared by using RIPA lysis buffer. Expressions of cIAP2 were detected by RT-PCR and Western blot analysis. Gastric cancer BGC-7901 cells were transfected with specific siRNA against cIAP2 for 48 h, and the effect of siRNA-cIAP2 on cell proliferation was detected by standard WST-1 assay. Apoptosis was detected by TUNEL staining and quantitated by flow cytometry. RESULTS Over 70% of gastric cancer tissues expressed higher levels of cIAP2 compared to non-cancerous gastric tissues at both mRNA and protein levels. Over-expression of cIAP2 was also confirmed by immunohistochemical staining which cIAP2 is strongly expressed in most gastric cancer tissues, whereas in normal gastric tissues, cIAP2 is expressed in gastric epithelium with weak to medium intensity. Knocking down of cIAP2 in BGC-7901 cells by siRNA-cIAP2 resulted in a 30% decrease in cell proliferation and a 20% increase in apoptosis as revealed by flow cytometry. CONCLUSION cIAP2 may be a potential target for gastric cancer therapy. Further studies are under way to investigate the efficacy of cIAP downregulation in gastric cancer In Vivo.
Prospective Analysis of Metachronous Early Gastric Cancer in High Risk Patients After H. pylori Eradication Akiko Shiotani, Noriya Uedo, Tomoari Kamada, Hiroyasu Iishi, Masaharu Tatsuta, Minoru Fujita, Ken-ichi Tarumi, Noriaki Manabe, Hiroaki Kusunoki, Ken Haruma Background: It has been reported that H. pylori eradication reduced the risk for development of gastric cnacer in the subgroup without precancerous lesions. We previously reported that residual inflammation and no improvement of atrophy after eradication were more frequently detected in the cancer group than in the controls (Int J Cancer 2007;15:1182). Aim: We evaluated the development of new malignant lesions in the patients with prior medical endoscopic treatment after eradication to determine a prediction marker of second cancerogenesis. Methods: Histology was evaluated using two specimens from each sample site, the antrum greater curve and corpus greater and lesser curves. Serum pepsinogen (PG) I and II were measured using enzyme-linked immunosorbent assay (ELISA) kits. Results: Eightysix patients were enrolled and 76 patients had been successfully treated for H. pylori and followed up more than 2 years (average observation period 27 months, range 24-60 months). Metachronous gastric cancers developed in eight (10.5%) patients. All cases were men, and an average size of tumors was 6.5mm (3~12mm, superficial depressed type (IIc) 6 lesions and superficial elevated type (IIa) 2 lesions). Serum PG I and I/II ratio before eradication were significantly lower (PG I 18 vs 44, p=0.008; I/II ratio 0.9 vs 1.4, p=0.03) in the group that developed cancer compared to the group that did not. Atrophy at corpus lesser curve was severe in the all cancer cases; the frequency of sever atrophy was higher in the group that developed cancer compared to the group that did not (100% vs 51%, p=0.04). Conclusions: Prevention of cancer will likely require H. pylori eradication prior to the development of atrophy. The cancer risk post eradication relates to the extent and severity of atrophy. Studies are needed to identify the parameters dictating surveillance intervals and duration after H. pylori eradication in those with H. pylori -induced gastric atrophy.
T2070 The Promoter Polymorphism of Nuclear Factor-Erythroid 2-Related Factor 2 (NRF2) Gene Affects the Aberrant Promoter Methylation of Tumor-Related Genes in Gastric Epithelium Tomiyasu Arisawa, Tomomitsu Tahara, Tomoyuki Shibata, Masakatsu Nakamura, MItsuo Nagasaka, Yoshio Kamiya, Hiroshi Fujita, Daisuke Yoshioka, Masaaki Okubo, Yuko Arima, Hiroaki Shimazaki, Ichiro Hirata, Hiroshi Nakano
T2068
[Background and Aim] Aberrant promoter methylation is an important mechanism for gene silencing. Generated reactive oxygens may contribute to this CpG island methylation. Nrf2 is known to regulate the expression of detoxifying and antioxidant genes. We investigated the relationship between promoter polymorphisms of Nrf2 gene (G-686A, G-684A and C650A) and the CpG island methylation in non-cancerous gastric mucosa. [Methods] The study was performed in 85 subjects [46 without gastric malignancies (non-GC group) and 39 with gastric cancer (GC group)]. The promoter methylation status of the p14(ARF), p16(INK4a) and p21(Waf1) genes was determined by Methylation-Specific-Polymerase Chain Reaction (MSP). The Nrf2 gene genotypes were determined by the PCR-SSCP method. [Results] In all 85 subjects, CpG island methylation was found in 25.9% for p14, 15.3% for p16 and none for p21. The frequency of methylated genes was significantly higher in GC group than non-GC group (OR, 2.67; 95%CI, 1.10-6.49; p=0.029). In particular, the frequency of p16 gene methylation was largely higher in GC group (p=0.0023). The Nrf2 -686/-684 G/G haplotype was positively associated and A/G haplotype was inversely associated with the development of CpG island methylation, especially p14 gene methylation (OR, 3.28; 95%CI, 1.26-8.59; p=0.015, and OR, 0.38; 95%CI, 0.15-0.96; p=0.040, respectively). In Helicobacter pylori (H. pylori) infected subjects, the number of -686/-684 G/G allele was positively correlated and that of A/G allele was inversely correlated to the methylation status, especially p14 methylation, by the adjusted analysis (OR, 2.90; 95%CI, 1.14-7.36; p=0.026, and OR, 0.33; 95%CI, 0.13-0.88; p=0.027, respectively). There was no significant association between C-650A polymorphism and the DNA aberrant methylation. [Conclusions] Our
Incidence Rates of Esophageal and Gastric Carcinoma in Central Switzerland Within the Last 25 Years: There Is No Increase of the Incidence of Adenocarcinoma of the Gastroesophageal Junction Adrian Schmassmann, Marie-Gabrielle Oldendorf, Jan-Olaf Gebbers Background: A strong increase of adenocarcinoma incidence rates of the gastroesophageal junction has been reported in several other Western countries. The goal of this study was to examine subsite-specific and histology-specific esophageal and gastric carcinoma incidence patterns among the Central Swiss population within the last 25 years. Methods: Data on newly diagnosed esophageal and gastric carcinoma during 1982-2006 were obtained from the Cancer Registry of the Department of Pathology Lucerne, representing a catch population of about 700 000. Age, gender, tumor localization, histology, and incidence rates were assessed. Results: Between 1982-2006, there were (1) 344 patients with esophageal squamous cell carcinoma, (2) 669 patients with cardia type I-III adenocarcinoma, (3) 1061 patients with noncardia adenocarcinoma, and (4) 147 patients with gastric adenocarcinoma of unclear localization. The male-female sex ratio was 5.3 for esophageal squamous cell carcinoma, 3.1 for cardia type I-III, and 1.3 for noncardia gastric carcinoma, respectively. The mean age of diagnosis for all esophageal and gastric cancers was between 67-70 years. The average incidence for epithelial squamous cell carcinoma was 2.2/100 000; no significant changes
AGA Abstracts
A-612