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769 Effect of Polymorphisms in the 3' Untranslated Region (3'-UTR) of Vascular Endothelial Growth Factor (VEGF)Gene On Gastric Carcinogenesis in Japanese Population
AGA Abstracts
cell migration (3-fold of EV, p<0.05). Tumor xenografts from Sprouty transfectants were significantly larger than EV tumors (1.4 gm vs. 0.3 gm, p<0.05). Sprouty tumors showed 40% increases in proliferation and 200% increases in blood vessels compared to EV tumors. Several Sprouty cecal tumor xenografts, but not EV tumors metastasized to lung or liver. Conclusions: Sprouty expression is increased in human colon cancers and parallels c-Met expression. This is the first report to demonstrate that Sprouty functions as an oncogene in this malignancy. Moreover, Sprouty controls expression of c-Met, which likely mediates Sprouty's oncogenic signals.
for population stratification. We also tested whether AIMs are associated with CRC in AAs to discover population-specific risk alleles. Methods: We genotyped nine 8q24 SNPs and 100 AIMs in CRC cases and controls. We included 512 EAs (309 cases; 203 controls) and 500 AAs (276 cases; 224 controls). Ancestry estimates were obtained using STRUCTURE 2.1. We tested for allelic association and calculated odds ratios and confidence intervals using logistic regression adjusting for ancestry, age and gender. Empiric p-values were obtained by adaptive permutation. Results: rs7008482 in 8q24 region 4 was significantly associated with colorectal cancer in EAs (Table 1). rs16900305, also in region 4, was associated with colorectal cancer in AAs. Both SNPs are in a DNA repair gene NSMCE2. rs6983267 and rs10505477 in region 3 (previously implicated in CRC risk) were associated with disease in EAs but not in AAs. Testing for associations with AIMs identified significant p-values for derived alleles of rs10059859 and rs16891982 in separate regions of 5q in AAs. Conclusion: 8q24 region 4 contains novel CRC-associated alleles in EAs and AAs. NSMCE2 is a novel candidate gene in this region. Novel disease associations with derived alleles of loci on 5q suggest population-specific risk factors. Future CRC admixture mapping studies are warranted. Table 1: SNP Associations with CRC on 8q24 and 5q in European and African Americans
766 The Overexpression of the Thyroid Hormone Receptor Trα1 in the Mouse Intestinal Epithelium Leads to Tumor Development Elsa Kress, Michela Plateroti Introduction. Thyroid hormones, T3 and T4, are known regulators of the mouse intestinal development at weaning, via a positive control of the epithelial cell proliferation (Plateroti et al., 2001, 2006). Thyroid hormones act through nuclear receptors, the TRs, which are T3-dependent transcription factors (Laudet et al., 1992). We have previously shown that TRα1 is the T3 receptor involved in the control of epithelial cell proliferation. It enhances directly the transcription of several components of the Wnt/β-catenin pathway (Plateroti et al., 2006; Kress et al., 2008). This allows increased expression of β-catenin/Tcf4 target genes cyclins D1 and D2 as well as c-Myc. It is worth noting that the Wnt/β-catenin pathway is a major actor of the normal and pathological proliferation of the intestinal epithelial cells (Sancho et al., 2004). For this reason we addressed the question of the tumor inducer potentiality of the TRα1 receptor. Methods. We generated transgenic mice that express mouse TRα1 cDNA under the control of the murine Villin promoter in intestinal epithelial cells. This leads to the up-regulation of the TRα1 expression all along the crypt-villus axis, starting early during embryo development. Results. The Vill-TRα1 mice display hyperplasic and ectopic crypts and have altered crypt-villus architecture. This overexpression in itself doesn't lead to cancer development. However, it accelerates adenoma formation in threemonths old double transgenic mice Apc1638N/Vill-TRa1, compared to the simple Apc1638N mutants. These defects are reminiscent of the juvenile polyposis in humans. Conclusions and perspectives. We conclude that alteration of the TRα1 levels disturbs the homeostasis of the intestinal epithelium but is not sufficient per se to trigger carcinogenesis. However, when added to mutation in Apc, it accelerates the rate of non-neoplastic and neoplastic lesions in the intestine. We describe here for the first time a clear-cut tumor-inducer function of the TRa1 receptor. We are currently analyzing colon lesions from patients to define whether TRa1 is overexpressed and this overexpression characterizes specific tumoral stages.
Chr, chromosome; P*, corrected for West African ancestry, age and gender; Pemp, empirical p-value based on adaptive permutations of trait values in the sample; NA, non-applicable 769 Effect of Polymorphisms in the 3' Untranslated Region (3'-UTR) of Vascular Endothelial Growth Factor (VEGF)Gene On Gastric Carcinogenesis in Japanese Population Tomomitsu Tahara, Tomoyuki Shibata, Ichiro Hirata, Tomiyasu Arisawa
767
Background: A complex interaction of host genetic and environmental factors may be relevant in the development of Helicobacter pylori (H. pylori)-related gastric carcinogenesis. We investigated the effect of VEGF gene polymorphisms on the risk of gastric cancer (GC), peptic ulcer diseases, and intestinal metaplasia (IM) in a Japanese population. Methods: The G1612A and C936T polymorphisms in the 3' untranslated region (3'-UTR) of VEGF gene were genotyped in a total of 844 subjects including 385 GC, 143 ulcer including 98 gastric ulcer (GU), 45 duodenal ulcer (DU), and 316 non-ulcer subjects. Presence of IM in the gastric antrum was determined in 337 cancer free subjects. Results: The 1612A carrier held a significantly higher risk of GC when compared to both non-cancer and non-ulcer (Over all non-cancer vs. GC; adjusted OR=1.61, 95%CI=1.17-2.21, p=0.0038, Non-ulcer vs. GC; adjusted OR=1.54, 95%CI=1.07-2.22, p=0.0197). The 1612 A carrier was more closely associated with an increased risk of non cardiac cancer (adjusted OR=1.64, 95%CI=0.172.21, p=0.0038), lower third cancer (adjusted OR=1.97, 95%CI=1.30-3.00, p=0.002) and Lauren's diffuse type cancer (adjusted OR=1.75, 95%CI=1.24-2.46, p=0.001), while the same genotype was not associated with the progression of GC such as tumor depth, lymph node, and distant metastasis. The C936T genotype was not associated with a risk of GC and its progression. Both the G1612A and C936T genotypes were not associated with the risk of peptic ulcer diseases. Among 337 cancer free subjects, the 1612 GA genotype held a significantly higher incidence of IM in H. pylori positive subjects more than 65 years of age (OR=4.05, 95%CI=1.08-15.15, p=0.038). The degree of IM was also higher among the 1612 GA in the same generation (GG vs. GA; 0.98±0.87 vs. 1.55±0.96, p=0.026). Conclusion: The G1612A, but not the C936T polymorphisms in the 3'-UTR of VEGF gene is associated with the susceptibility to GC in the Japanese population. Furthermore, the same genotype is associated with the risk of developing intestinal metaplasia in H. pylori infected older subjects.
Genotype-Phenotype Correlation of Genetic Susceptibility Variants Identified Through Genome-Wide Association Studies for Colorectal Cancer Anna Abulí, Xavier Bessa, Clara Ruiz-Ponte, Ceres Fernandez-Rozadilla, Angel Carracedo, Lucas Ilzarbe, Xavier Llor, Rodrigo Jover, Jenifer Muñoz, Antoni Castells, Sergi CastellviBel, Montserrat Andreu Inherited susceptibility for colorectal cancer (CRC) is relevant in about 30% of cases, being due to hereditary mutations in less than 5%. Much of the remaining genetic risk may be attributable to a large number of common, low-penetrance variants. Recently, 10 of these genetic components associated with CRC risk have been identified by genome-wide association studies (GWAS) and subsequent meta-analysis. However, it is unknown whether patients with such variants have specific personal or familial characteristics. Objective. To establish a genotype-phenotype correlation between genetic variants previously identified by WGAS that influence CRC risk and personal and familial characteristics (demographic, clinical and tumor-related) in CRC patients from the EPICOLON cohort. Patients and methods. We genotyped the 8q23.3, 11q23, 10p14, 8q24, 18q21 (SMAD7), 15q13.3, 14q22.2, 16q22.1, 19q13.1 and 20p12.3 variants in 1096 DNA samples from CRC patients. Clinical characteristics for all patients were available including demographic, clinical, tumorrelated data and an extensive family history. The SSPS package was used for statistical calculations. Results. We observed significant association between the 8q23.3 and 11q23 variants and age of onset of CRC (<60 years, P=0.029 and <50, P=0.012 respectively). The 10p14 variant was significantly related to loss of MSH2 expression (P=0.005) and personal history of endometrial cancer (P=0.027). The 8q24 variant showed also some evidence of association with degree of tumor differentiation (P=0.031) and family history of colorectal cancer (P=0.026). Finally, the effect of the SMAD7 variant was significantly stronger in cases with loss of MLH1 protein expression (P=0.037). Conclusions. The effect of the 8q23.3 and 11q23 variants on CRC risk could predispose to an earlier onset of the disease, whereas an interaction of the 10p14 and SMAD7 variants with the expression of the DNA mismatch repair genes could also exist. Besides, our data may also suggest an involvement of the 10p14 variant to predispose as well to endometrial cancer, whereas the 8q24 variant may be more commonly associated with familial CRC.
770 Effect of Single Doses of Capromorelin and Ghrelin On Esophageal Reflux Parameters and Esophageal Function: A Randomized, Double-Blind, PlaceboControlled Study Amit Agrawal, Jeremy D. Gale, Neeraj Sharma, Wojciech Blonski, Kate Hargreaves, Richard Allan, Janice Freeman, Donald O. Castell AIM:Ghrelin has been shown to increase gastric emptying in both animals and humans, suggesting that ligands for ghrelin receptors (GHS-Rs) might offer a novel approach to gastroprokinetic therapy. Capromorelin has been shown to be an agonist at human GHSRs and has also been shown to increase gastric emptying in pre-clinical species. The aim of this study was to investigate the effect of single doses of capromorelin and ghrelin on reflux parameters and esophageal function during a 2 hour post-prandial period. METHODS: A randomized, double-blind, placebo-controlled, four-way crossover study (balanced incomplete block design) was performed to investigate the effect of two single oral doses (0.5mg and 20mg) of capromorelin, two single intravenous doses of human recombinant ghrelin (0.5 pmol/kg/min and 5 pmol/kg/min infused over 4hr) and placebo on reflux parameters using impedance;pHmetry and esophageal function using impedance:manometry in healthy volunteers, following a refluxigenic meal. Placebo and the high doses of capromorelin and ghrelin were to be received by 16 subjects. The lower doses of capromorelin and ghrelin were to be received by 8 subjects. RESULTS: The highest doses of both capromorelin and
768 Novel SNP Associations with Colorectal Cancer On 8q24 and 5q in African and European Americans Sonia Kupfer, Jada Benn Torres, Stanley Hooker, Jeffrey R. Anderson, Nathan A. Ellis, Rick Kittles Background: Determining colorectal cancer (CRC) genetic risk factors in African Americans (AAs) is important because this population has the highest overall CRC incidence and mortality rates. Regions on chromosome 8q24 are associated with CRC and prostate cancer. European genomewide studies have found single nucleotide polymorphism (SNP) associations with CRC and prostate cancer in region 3, while we reported a novel prostate cancer association in AAs in region 4. Aims: We tested for 8q24 SNP associations with CRC in European Americans (EAs) and AAs using ancestry informative markers (AIMs) to control
AGA Abstracts
A-120
cell migration (3-fold of EV, p<0.05). Tumor xenografts from Sprouty transfectants were significantly larger than EV tumors (1.4 gm vs. 0.3 gm, p<0.05). Sprouty tumors showed 40% increases in proliferation and 200% increases in blood vessels compared to EV tumors. Several Sprouty cecal tumor xenografts, but not EV tumors metastasized to lung or liver. Conclusions: Sprouty expression is increased in human colon cancers and parallels c-Met expression. This is the first report to demonstrate that Sprouty functions as an oncogene in this malignancy. Moreover, Sprouty controls expression of c-Met, which likely mediates Sprouty's oncogenic signals.
for population stratification. We also tested whether AIMs are associated with CRC in AAs to discover population-specific risk alleles. Methods: We genotyped nine 8q24 SNPs and 100 AIMs in CRC cases and controls. We included 512 EAs (309 cases; 203 controls) and 500 AAs (276 cases; 224 controls). Ancestry estimates were obtained using STRUCTURE 2.1. We tested for allelic association and calculated odds ratios and confidence intervals using logistic regression adjusting for ancestry, age and gender. Empiric p-values were obtained by adaptive permutation. Results: rs7008482 in 8q24 region 4 was significantly associated with colorectal cancer in EAs (Table 1). rs16900305, also in region 4, was associated with colorectal cancer in AAs. Both SNPs are in a DNA repair gene NSMCE2. rs6983267 and rs10505477 in region 3 (previously implicated in CRC risk) were associated with disease in EAs but not in AAs. Testing for associations with AIMs identified significant p-values for derived alleles of rs10059859 and rs16891982 in separate regions of 5q in AAs. Conclusion: 8q24 region 4 contains novel CRC-associated alleles in EAs and AAs. NSMCE2 is a novel candidate gene in this region. Novel disease associations with derived alleles of loci on 5q suggest population-specific risk factors. Future CRC admixture mapping studies are warranted. Table 1: SNP Associations with CRC on 8q24 and 5q in European and African Americans
766 The Overexpression of the Thyroid Hormone Receptor Trα1 in the Mouse Intestinal Epithelium Leads to Tumor Development Elsa Kress, Michela Plateroti Introduction. Thyroid hormones, T3 and T4, are known regulators of the mouse intestinal development at weaning, via a positive control of the epithelial cell proliferation (Plateroti et al., 2001, 2006). Thyroid hormones act through nuclear receptors, the TRs, which are T3-dependent transcription factors (Laudet et al., 1992). We have previously shown that TRα1 is the T3 receptor involved in the control of epithelial cell proliferation. It enhances directly the transcription of several components of the Wnt/β-catenin pathway (Plateroti et al., 2006; Kress et al., 2008). This allows increased expression of β-catenin/Tcf4 target genes cyclins D1 and D2 as well as c-Myc. It is worth noting that the Wnt/β-catenin pathway is a major actor of the normal and pathological proliferation of the intestinal epithelial cells (Sancho et al., 2004). For this reason we addressed the question of the tumor inducer potentiality of the TRα1 receptor. Methods. We generated transgenic mice that express mouse TRα1 cDNA under the control of the murine Villin promoter in intestinal epithelial cells. This leads to the up-regulation of the TRα1 expression all along the crypt-villus axis, starting early during embryo development. Results. The Vill-TRα1 mice display hyperplasic and ectopic crypts and have altered crypt-villus architecture. This overexpression in itself doesn't lead to cancer development. However, it accelerates adenoma formation in threemonths old double transgenic mice Apc1638N/Vill-TRa1, compared to the simple Apc1638N mutants. These defects are reminiscent of the juvenile polyposis in humans. Conclusions and perspectives. We conclude that alteration of the TRα1 levels disturbs the homeostasis of the intestinal epithelium but is not sufficient per se to trigger carcinogenesis. However, when added to mutation in Apc, it accelerates the rate of non-neoplastic and neoplastic lesions in the intestine. We describe here for the first time a clear-cut tumor-inducer function of the TRa1 receptor. We are currently analyzing colon lesions from patients to define whether TRa1 is overexpressed and this overexpression characterizes specific tumoral stages.
Chr, chromosome; P*, corrected for West African ancestry, age and gender; Pemp, empirical p-value based on adaptive permutations of trait values in the sample; NA, non-applicable 769 Effect of Polymorphisms in the 3' Untranslated Region (3'-UTR) of Vascular Endothelial Growth Factor (VEGF)Gene On Gastric Carcinogenesis in Japanese Population Tomomitsu Tahara, Tomoyuki Shibata, Ichiro Hirata, Tomiyasu Arisawa
767
Background: A complex interaction of host genetic and environmental factors may be relevant in the development of Helicobacter pylori (H. pylori)-related gastric carcinogenesis. We investigated the effect of VEGF gene polymorphisms on the risk of gastric cancer (GC), peptic ulcer diseases, and intestinal metaplasia (IM) in a Japanese population. Methods: The G1612A and C936T polymorphisms in the 3' untranslated region (3'-UTR) of VEGF gene were genotyped in a total of 844 subjects including 385 GC, 143 ulcer including 98 gastric ulcer (GU), 45 duodenal ulcer (DU), and 316 non-ulcer subjects. Presence of IM in the gastric antrum was determined in 337 cancer free subjects. Results: The 1612A carrier held a significantly higher risk of GC when compared to both non-cancer and non-ulcer (Over all non-cancer vs. GC; adjusted OR=1.61, 95%CI=1.17-2.21, p=0.0038, Non-ulcer vs. GC; adjusted OR=1.54, 95%CI=1.07-2.22, p=0.0197). The 1612 A carrier was more closely associated with an increased risk of non cardiac cancer (adjusted OR=1.64, 95%CI=0.172.21, p=0.0038), lower third cancer (adjusted OR=1.97, 95%CI=1.30-3.00, p=0.002) and Lauren's diffuse type cancer (adjusted OR=1.75, 95%CI=1.24-2.46, p=0.001), while the same genotype was not associated with the progression of GC such as tumor depth, lymph node, and distant metastasis. The C936T genotype was not associated with a risk of GC and its progression. Both the G1612A and C936T genotypes were not associated with the risk of peptic ulcer diseases. Among 337 cancer free subjects, the 1612 GA genotype held a significantly higher incidence of IM in H. pylori positive subjects more than 65 years of age (OR=4.05, 95%CI=1.08-15.15, p=0.038). The degree of IM was also higher among the 1612 GA in the same generation (GG vs. GA; 0.98±0.87 vs. 1.55±0.96, p=0.026). Conclusion: The G1612A, but not the C936T polymorphisms in the 3'-UTR of VEGF gene is associated with the susceptibility to GC in the Japanese population. Furthermore, the same genotype is associated with the risk of developing intestinal metaplasia in H. pylori infected older subjects.
Genotype-Phenotype Correlation of Genetic Susceptibility Variants Identified Through Genome-Wide Association Studies for Colorectal Cancer Anna Abulí, Xavier Bessa, Clara Ruiz-Ponte, Ceres Fernandez-Rozadilla, Angel Carracedo, Lucas Ilzarbe, Xavier Llor, Rodrigo Jover, Jenifer Muñoz, Antoni Castells, Sergi CastellviBel, Montserrat Andreu Inherited susceptibility for colorectal cancer (CRC) is relevant in about 30% of cases, being due to hereditary mutations in less than 5%. Much of the remaining genetic risk may be attributable to a large number of common, low-penetrance variants. Recently, 10 of these genetic components associated with CRC risk have been identified by genome-wide association studies (GWAS) and subsequent meta-analysis. However, it is unknown whether patients with such variants have specific personal or familial characteristics. Objective. To establish a genotype-phenotype correlation between genetic variants previously identified by WGAS that influence CRC risk and personal and familial characteristics (demographic, clinical and tumor-related) in CRC patients from the EPICOLON cohort. Patients and methods. We genotyped the 8q23.3, 11q23, 10p14, 8q24, 18q21 (SMAD7), 15q13.3, 14q22.2, 16q22.1, 19q13.1 and 20p12.3 variants in 1096 DNA samples from CRC patients. Clinical characteristics for all patients were available including demographic, clinical, tumorrelated data and an extensive family history. The SSPS package was used for statistical calculations. Results. We observed significant association between the 8q23.3 and 11q23 variants and age of onset of CRC (<60 years, P=0.029 and <50, P=0.012 respectively). The 10p14 variant was significantly related to loss of MSH2 expression (P=0.005) and personal history of endometrial cancer (P=0.027). The 8q24 variant showed also some evidence of association with degree of tumor differentiation (P=0.031) and family history of colorectal cancer (P=0.026). Finally, the effect of the SMAD7 variant was significantly stronger in cases with loss of MLH1 protein expression (P=0.037). Conclusions. The effect of the 8q23.3 and 11q23 variants on CRC risk could predispose to an earlier onset of the disease, whereas an interaction of the 10p14 and SMAD7 variants with the expression of the DNA mismatch repair genes could also exist. Besides, our data may also suggest an involvement of the 10p14 variant to predispose as well to endometrial cancer, whereas the 8q24 variant may be more commonly associated with familial CRC.
770 Effect of Single Doses of Capromorelin and Ghrelin On Esophageal Reflux Parameters and Esophageal Function: A Randomized, Double-Blind, PlaceboControlled Study Amit Agrawal, Jeremy D. Gale, Neeraj Sharma, Wojciech Blonski, Kate Hargreaves, Richard Allan, Janice Freeman, Donald O. Castell AIM:Ghrelin has been shown to increase gastric emptying in both animals and humans, suggesting that ligands for ghrelin receptors (GHS-Rs) might offer a novel approach to gastroprokinetic therapy. Capromorelin has been shown to be an agonist at human GHSRs and has also been shown to increase gastric emptying in pre-clinical species. The aim of this study was to investigate the effect of single doses of capromorelin and ghrelin on reflux parameters and esophageal function during a 2 hour post-prandial period. METHODS: A randomized, double-blind, placebo-controlled, four-way crossover study (balanced incomplete block design) was performed to investigate the effect of two single oral doses (0.5mg and 20mg) of capromorelin, two single intravenous doses of human recombinant ghrelin (0.5 pmol/kg/min and 5 pmol/kg/min infused over 4hr) and placebo on reflux parameters using impedance;pHmetry and esophageal function using impedance:manometry in healthy volunteers, following a refluxigenic meal. Placebo and the high doses of capromorelin and ghrelin were to be received by 16 subjects. The lower doses of capromorelin and ghrelin were to be received by 8 subjects. RESULTS: The highest doses of both capromorelin and
768 Novel SNP Associations with Colorectal Cancer On 8q24 and 5q in African and European Americans Sonia Kupfer, Jada Benn Torres, Stanley Hooker, Jeffrey R. Anderson, Nathan A. Ellis, Rick Kittles Background: Determining colorectal cancer (CRC) genetic risk factors in African Americans (AAs) is important because this population has the highest overall CRC incidence and mortality rates. Regions on chromosome 8q24 are associated with CRC and prostate cancer. European genomewide studies have found single nucleotide polymorphism (SNP) associations with CRC and prostate cancer in region 3, while we reported a novel prostate cancer association in AAs in region 4. Aims: We tested for 8q24 SNP associations with CRC in European Americans (EAs) and AAs using ancestry informative markers (AIMs) to control
AGA Abstracts
A-120