- Email: [email protected]
S1949 Differences of Genetic Features in Two Types of Laterally Spreading Tumors of the Colorectum
colorectal cancer occurrence and progression. Methods: Genotypes were determined in DNA from peripheral blood lymphocytes of 100 colorectal cancer patients and 100 age, sex-, ageand ethnicity-matched cancer-free controls by restriction fragment length polymorphism RFLP. Results: We found an association between colorectal cancer occurrence and the Lys/ Lys variant of the Lys751Gln polymorphism (OR 1.76; 95% CI 1.08-1.86) of the XPD gene and the Ser/Cys variant of the Ser326Cys polymorphism (OR 2.19; 95% CI 1.22-3.94) of the hOGG1 gene. Gene-gene interaction between the Lys751Lys-XPD variant Ser326CyshOGG1 variant increased the risk of colorectal cancer (OR 2.23; 95% CI 1.07-4.67). We did not observe any correlation between either polymorphism and colorectal cancer progression assessed by node metastasis, tumour size and Duke's stage. Conclusion: XPD and hOGG1 may play a role in the colorectal carcinogenesis and the Lys751Gln-XPD and the Ser326CyshOGG1 polymorphisms may be considered as an independent, early diagnostic markers in this disease.
Relevance of GSTM1, GSTT1, and GSTP1 Gene Polymorphisms On Gastric Cancer Susceptibility Maria Asuncion Garcia-Gonzalez, Enrique Quintero, Rafael Benito, Mark Strunk, David Nicolás-Pérez, Adolfo Parra-Blanco, Santos Santolaria, Federico Sopena, Elena Piazuelo, Pilar Jimenez, Maria Badia, Jesús Espinel, Rafael Campo, Marisa Manzano, Fernando Geijo, Maria Pellise, Ferrán González-Huix, Miguel Nieto, Jorge C. Espinós, LLúcia Titó, Luis Bujanda, Manuel Zaballa, María Angeles Pérez-Aisa, Isabel María Méndez-Sánchez, Angel Lanas Background & aim: Glutathione S-transferases (GSTs) are cytosolic phase II enzymes that play a key role in the defense of the body against cytotoxic/genotoxic compounds. The genes encoding the human GST isoenzymes, GSTM(mu)1, GSTT(theta)1, and GSTP(pi)1 are known to be polymorphic. Two independent deletion polymorphisms in the GSTM1 and GSTT1 genes, which result in a lack of the corresponding active protein, have been associated with an increased risk for developing neoplastic diseases. In addition, two SNP's in the GSTP1 gene (Ile105Val, and Val114Ala) have been related to reduced enzyme activity. Since the GST status of an individual may be a key determinant in the susceptibility to carcinogenesis we aimed to investigate the relevance of GST gene polymorphisms on gastric cancer (GC) risk. Methods: DNA from 515 unrelated Spanish Caucasians patients with GC and 515 sexand aged- (± 5 years) matched cancer-free healthy controls was typed for the GSTM1 and GSTT1 deletion by multiplex PCR, and the GSTP1 Val105Ile (rs1695) and GSTP1 Val114Ala (rs1138272) polymorphisms by RFLP based methods. Helicobacter pylori infection and CagA/ VacA antibody status were determined by western blot in patients and controls. Results: Helicobacter pylori infection with CagA strains (OR:2.33; 95% CI:1.78-3.06), smoking habit (OR:2.26; 95% CI:1.39-3.08) and positive family history of GC (OR:3.1; 95% CI:1.83-5.14) were identified as independent risk factors for GC. The frequencies of homozygous null genotypes of GSTM1 and GSTT1 genes in GC patients did not differ significantly from those observed in controls (52% vs 49%, OR:1.57; 95% CI:0.89-1.49 for GSTM1, and 22% vs 21%, OR:1.07; 95% CI:0.78-1.46 for GSTT1). Moreover, simultaneous carriage of both the GSTM1 and the GSTT1 homozygous null genotypes was almost identical in both groups (10.8% in GC vs 10.7% in HC; OR:1.14, 95% CI:0.73-1.78). No differences in carriage, genotype, and allele frequencies of the GSTP1 Val105Ile, and GSTP1 Val114Ala polymorphisms were found between GC patients and controls. Finally, no significant associations between GSTM1, GSTT1, and GSTP1 polymorphisms and GC risk were found when GC patients were categorized according to smoking habit, H. pylori infection, CagA/VacA antibody status, gender, age, anatomic location of the tumor, histological subtype of the tumor, previous history of peptic ulcer disease, and family history of gastric cancer. Conclusion: Our data show that, in our population, the GSTM1, GSTT1 and GSTP1 gene polymorphisms are not relevant in determining the individual susceptibility to GC risk.
S1949 Differences of Genetic Features in Two Types of Laterally Spreading Tumors of the Colorectum Takafumi Sugimoto, Miki Ohta, Atsuo Yamada, Motohisa Tada, Mitsuhiro Fujishiro, Tsuneo Ikenoue, Keiji Ogura, Yutaka Yamaji, Takao Kawabe, Masao Omata [OBJECTIVE] Recent advances in colonoscopic techniques have led to the increased detection of superficial-type colorectal tumors, “laterally spreading tumors (LSTs)” They are endoscopically classified to 2 types; granular type (LST-G) and non-granular type (LST-NG). However, little is known about the molecular characteristics of LSTs. The aim of the present study is to elucidate genetic features of two types of LSTs. [MATERIALS AND METHODS] Genetic alterations of KRAS, BRAF, and PIK3CA genes and abnormal expression of TP53, betacatenin, and MYC were analyzed using direct DNA sequencing and immunohistochemistry in 35 LST of granular-type (LST-G) and 19 LST of non-granular-type (LST-NG). Additionally, the loss of heterozygositiy (LOH) of adenomatous polyposis coli (APC) gene was examined in all LSTs. [RESULTS] In univariate analysis, significant difference on ratio of alternation was seen in KRAS mutation between LST-NG (21.1%) and LST-G (54.3%) (p=0.0156) and in nuclear accumulation of beta-catenin between LST-NG (68.4%) and LST-G (37.1%) (p= 0.0267). MYC was also highly expressed in 42.1% of LST-NG, which was significantly higher than 17.1% in LST-G (p=0.0456) in immunohistochemical analysis. Multivariate analysis also demonstrated that macroscopic subtype of LST was significantly associated with KRAS mutation (LST-NG: Odds ratio, 0.23; 95% CI, 0.06-0.90) and nuclear accumulation of beta-catenin (LST-NG: Odds ratio, 4.05; 95% CI, 1.11-14.8). The LOH in APC gene locus was detected in 47.4% of LST-NG, which was significantly higher than 20.0% of LST-G (p=0.0302). [CONCLUTION] Two different subtypes of LSTs were found to have different molecular characteristics, which suggests two or more different molecular mechanisms cause similar colorectal tumors.
S1947 S1950
HOGG1 Polymorphism in Post Helicobacter. Pylori Eradication Atrophic Gastritis Patients Leimin Sun, Jianfeng Cheng
Folate Intake and Colorectal Cancer Risks By CIMP and BRAF-Mutation Status Among Older Women David Limsui, Robert A. Vierkant, Lori S. Tillmans, Alice H. Wang, Daniel J. Weisenberger, Peter W. Laird, Charles F. Lynch, Kristin E. Anderson, Amy J. French, Robert W. Haile, Lisa J. Harnack, John D. Potter, Susan Slager, Thomas C. Smyrk, Stephen N. Thibodeau, James R. Cerhan, Paul J. Limburg
Objective: Helicobacter pylori infection and host genetic factors are supposed to be associated with atrophic gastritis and gastric cancer. Human oxoguanine glycosylase 1(hOGG1) is responsible for repairing 8-OHdG lesions and is one of the most important antioxidative enzyme. Among several hOGG1 gene polymorphisms, the Ser→Cys polymorphism at position 326 is related to decreased repair function. This prospective study investigates the association between Ser326Cys hOGG1 polymorphism and after H. pylori eradication atrophic gatritis and gastric cancer. Methods: 455 subjects (40 patients with gastric cancer, 160 atrophic gastritis and 255 controls) were prospectively collected. H. pylori-positive atrophic gastritis patients underwent endoscopy with multiple biopsy sampling. One year after H. pylori eradication, patients who were still diagnosed as atrophic gastritis on second endoscopy were enrolled. All gastric cancer patients were demonstrated by endoscopy. PCR-RFLP analysis was performed to distinguish the genotyping of hOGG1 Ser326Cys polymorphism. Logistic regression models were fitted to find the risk factors for gastric cancer and atrophic gastritis. Results: Patients with gastric cancer were significantly older than the control group (61.4±11.9yrs vs 43.6±10.2 yrs, P<0.0001) and atrophic gastritis group (61.4±11.9yrs vs 51.4±10.5 yrs, P<0.0001). Gastric cancer group had significantly higher rate of male than atrophic gastritis and control groups (72.5% vs 48.7% in atrophic gastritis and 60.0% in control, p<0.0095). Neither the hOGG1 Ser/Cys nor the Cys/Cys genotype was associated with gastric cancer, compared with the Ser/Ser genotype (P=0.37 and P=0.36). Cys/Cys was significantly associated with atrophic gastritis (OR: 2.38, 95%CI: 1.34-4.23) while Ser/Cys was marginally associated with atrophic gastritis (OR: 1.74, 95% CI: 1.02-2.98). After controlling for age, gender, smoking and alcohol, Cys/Cys was still significantly associated with atrophic gastritis (OR: 2.71, 95% CI: 1.44-5.10). Conclusion: Our study supported that hOGG1 polymorphisms (genotype Cys/Cys) is associated with H. pylori-negative atrophic gastritis. This association still exists after controlling for age, gender, smoking and alcohol. No significant association was detected between hOGG1 polymorphisms and gastric cancer. Key words: hOGG1 polymorphism, H. pylori, atrophic gastritis.
Background: Folate intake has been inconsistently associated with colorectal cancer (CRC) risk, with data from recent observational studies and randomized controlled trials demonstrating inconclusive results. Since folate is essential to both one-carbon metabolism and DNA synthesis pathways, it seems biologically plausible that folate intake may be differentially associated with molecularly defined CRC subtypes. Aim: To examine associations between folate intake and incident CRC, overall and among cases defined by CpG-island methylator phenotype (CIMP) and BRAF (a murine viral oncogene homolog)-mutation status, in a prospective cohort study. Methods: The Iowa Women's Health Study recruited 41,836 Iowa women, aged 55-69 years at study enrollment in 1986. Folate intake, including dietary and supplement sources, was assessed by self-report at baseline. After exclusions, the analytic cohort consisted of 35,216 women and there were 1298 incident CRC cases ascertained by annual linkage with the Iowa Cancer Registry. Archival CRC tissue for 514 (40%) of the eligible cases has been retrieved thus far (baseline age, body mass index, physical activity level, and total energy intake were similar to non-retrieved cases; p > 0.05 for each comparison). CIMP(-) and CIMP(+) cases were defined by promoter hypermethylation of 0-2 or ≥3 genes, respectively, using an established 5-gene panel. BRAF(wt) and BRAF(mut) were defined by fluorescent allele specific polymerase chain reaction to detect the V600E point mutation. Folate intake was analyzed by quartiles. Multivariate Cox regression models were fit to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs). Results: Folate intake was not associated with incident CRC, overall or by CIMP or BRAF subtypes (Table). Conclusions: In this prospective cohort study of older women, folate intake did not appear to influence overall CRC risk or that of the CIMP- and BRAF-defined subsets.
S1948 Polymorphism of the XPD and HOGG1 Genes in Colorectal Cancer in a Polish Subpopulation Maria A. Wisniewska-Jarosinska, Tomasz Sliwinski, Renata Krupa, Krystyna StecMichalska, Jan Chojnacki, Janusz Blasiak Introduction: Polymorphisms of DNA repair genes may influence individual DNA repair capacity, which is crucial for preventing genomic instability, which, in turn, may be associated with the risk of cancer transformation. Colorectal cancer represents a complex disease, with susceptibility that may be influenced by mutations in DNA repair genes. Purpose: In the present study we investigated the association of polymorphism in the nucleotide excision repair gene XPD (Lys751Gln) and the base excision repair gene hOGG1 (Ser326Cys) with
A-299
AGA Abstracts
AGA Abstracts
S1946
Relevance of GSTM1, GSTT1, and GSTP1 Gene Polymorphisms On Gastric Cancer Susceptibility Maria Asuncion Garcia-Gonzalez, Enrique Quintero, Rafael Benito, Mark Strunk, David Nicolás-Pérez, Adolfo Parra-Blanco, Santos Santolaria, Federico Sopena, Elena Piazuelo, Pilar Jimenez, Maria Badia, Jesús Espinel, Rafael Campo, Marisa Manzano, Fernando Geijo, Maria Pellise, Ferrán González-Huix, Miguel Nieto, Jorge C. Espinós, LLúcia Titó, Luis Bujanda, Manuel Zaballa, María Angeles Pérez-Aisa, Isabel María Méndez-Sánchez, Angel Lanas Background & aim: Glutathione S-transferases (GSTs) are cytosolic phase II enzymes that play a key role in the defense of the body against cytotoxic/genotoxic compounds. The genes encoding the human GST isoenzymes, GSTM(mu)1, GSTT(theta)1, and GSTP(pi)1 are known to be polymorphic. Two independent deletion polymorphisms in the GSTM1 and GSTT1 genes, which result in a lack of the corresponding active protein, have been associated with an increased risk for developing neoplastic diseases. In addition, two SNP's in the GSTP1 gene (Ile105Val, and Val114Ala) have been related to reduced enzyme activity. Since the GST status of an individual may be a key determinant in the susceptibility to carcinogenesis we aimed to investigate the relevance of GST gene polymorphisms on gastric cancer (GC) risk. Methods: DNA from 515 unrelated Spanish Caucasians patients with GC and 515 sexand aged- (± 5 years) matched cancer-free healthy controls was typed for the GSTM1 and GSTT1 deletion by multiplex PCR, and the GSTP1 Val105Ile (rs1695) and GSTP1 Val114Ala (rs1138272) polymorphisms by RFLP based methods. Helicobacter pylori infection and CagA/ VacA antibody status were determined by western blot in patients and controls. Results: Helicobacter pylori infection with CagA strains (OR:2.33; 95% CI:1.78-3.06), smoking habit (OR:2.26; 95% CI:1.39-3.08) and positive family history of GC (OR:3.1; 95% CI:1.83-5.14) were identified as independent risk factors for GC. The frequencies of homozygous null genotypes of GSTM1 and GSTT1 genes in GC patients did not differ significantly from those observed in controls (52% vs 49%, OR:1.57; 95% CI:0.89-1.49 for GSTM1, and 22% vs 21%, OR:1.07; 95% CI:0.78-1.46 for GSTT1). Moreover, simultaneous carriage of both the GSTM1 and the GSTT1 homozygous null genotypes was almost identical in both groups (10.8% in GC vs 10.7% in HC; OR:1.14, 95% CI:0.73-1.78). No differences in carriage, genotype, and allele frequencies of the GSTP1 Val105Ile, and GSTP1 Val114Ala polymorphisms were found between GC patients and controls. Finally, no significant associations between GSTM1, GSTT1, and GSTP1 polymorphisms and GC risk were found when GC patients were categorized according to smoking habit, H. pylori infection, CagA/VacA antibody status, gender, age, anatomic location of the tumor, histological subtype of the tumor, previous history of peptic ulcer disease, and family history of gastric cancer. Conclusion: Our data show that, in our population, the GSTM1, GSTT1 and GSTP1 gene polymorphisms are not relevant in determining the individual susceptibility to GC risk.
S1949 Differences of Genetic Features in Two Types of Laterally Spreading Tumors of the Colorectum Takafumi Sugimoto, Miki Ohta, Atsuo Yamada, Motohisa Tada, Mitsuhiro Fujishiro, Tsuneo Ikenoue, Keiji Ogura, Yutaka Yamaji, Takao Kawabe, Masao Omata [OBJECTIVE] Recent advances in colonoscopic techniques have led to the increased detection of superficial-type colorectal tumors, “laterally spreading tumors (LSTs)” They are endoscopically classified to 2 types; granular type (LST-G) and non-granular type (LST-NG). However, little is known about the molecular characteristics of LSTs. The aim of the present study is to elucidate genetic features of two types of LSTs. [MATERIALS AND METHODS] Genetic alterations of KRAS, BRAF, and PIK3CA genes and abnormal expression of TP53, betacatenin, and MYC were analyzed using direct DNA sequencing and immunohistochemistry in 35 LST of granular-type (LST-G) and 19 LST of non-granular-type (LST-NG). Additionally, the loss of heterozygositiy (LOH) of adenomatous polyposis coli (APC) gene was examined in all LSTs. [RESULTS] In univariate analysis, significant difference on ratio of alternation was seen in KRAS mutation between LST-NG (21.1%) and LST-G (54.3%) (p=0.0156) and in nuclear accumulation of beta-catenin between LST-NG (68.4%) and LST-G (37.1%) (p= 0.0267). MYC was also highly expressed in 42.1% of LST-NG, which was significantly higher than 17.1% in LST-G (p=0.0456) in immunohistochemical analysis. Multivariate analysis also demonstrated that macroscopic subtype of LST was significantly associated with KRAS mutation (LST-NG: Odds ratio, 0.23; 95% CI, 0.06-0.90) and nuclear accumulation of beta-catenin (LST-NG: Odds ratio, 4.05; 95% CI, 1.11-14.8). The LOH in APC gene locus was detected in 47.4% of LST-NG, which was significantly higher than 20.0% of LST-G (p=0.0302). [CONCLUTION] Two different subtypes of LSTs were found to have different molecular characteristics, which suggests two or more different molecular mechanisms cause similar colorectal tumors.
S1947 S1950
HOGG1 Polymorphism in Post Helicobacter. Pylori Eradication Atrophic Gastritis Patients Leimin Sun, Jianfeng Cheng
Folate Intake and Colorectal Cancer Risks By CIMP and BRAF-Mutation Status Among Older Women David Limsui, Robert A. Vierkant, Lori S. Tillmans, Alice H. Wang, Daniel J. Weisenberger, Peter W. Laird, Charles F. Lynch, Kristin E. Anderson, Amy J. French, Robert W. Haile, Lisa J. Harnack, John D. Potter, Susan Slager, Thomas C. Smyrk, Stephen N. Thibodeau, James R. Cerhan, Paul J. Limburg
Objective: Helicobacter pylori infection and host genetic factors are supposed to be associated with atrophic gastritis and gastric cancer. Human oxoguanine glycosylase 1(hOGG1) is responsible for repairing 8-OHdG lesions and is one of the most important antioxidative enzyme. Among several hOGG1 gene polymorphisms, the Ser→Cys polymorphism at position 326 is related to decreased repair function. This prospective study investigates the association between Ser326Cys hOGG1 polymorphism and after H. pylori eradication atrophic gatritis and gastric cancer. Methods: 455 subjects (40 patients with gastric cancer, 160 atrophic gastritis and 255 controls) were prospectively collected. H. pylori-positive atrophic gastritis patients underwent endoscopy with multiple biopsy sampling. One year after H. pylori eradication, patients who were still diagnosed as atrophic gastritis on second endoscopy were enrolled. All gastric cancer patients were demonstrated by endoscopy. PCR-RFLP analysis was performed to distinguish the genotyping of hOGG1 Ser326Cys polymorphism. Logistic regression models were fitted to find the risk factors for gastric cancer and atrophic gastritis. Results: Patients with gastric cancer were significantly older than the control group (61.4±11.9yrs vs 43.6±10.2 yrs, P<0.0001) and atrophic gastritis group (61.4±11.9yrs vs 51.4±10.5 yrs, P<0.0001). Gastric cancer group had significantly higher rate of male than atrophic gastritis and control groups (72.5% vs 48.7% in atrophic gastritis and 60.0% in control, p<0.0095). Neither the hOGG1 Ser/Cys nor the Cys/Cys genotype was associated with gastric cancer, compared with the Ser/Ser genotype (P=0.37 and P=0.36). Cys/Cys was significantly associated with atrophic gastritis (OR: 2.38, 95%CI: 1.34-4.23) while Ser/Cys was marginally associated with atrophic gastritis (OR: 1.74, 95% CI: 1.02-2.98). After controlling for age, gender, smoking and alcohol, Cys/Cys was still significantly associated with atrophic gastritis (OR: 2.71, 95% CI: 1.44-5.10). Conclusion: Our study supported that hOGG1 polymorphisms (genotype Cys/Cys) is associated with H. pylori-negative atrophic gastritis. This association still exists after controlling for age, gender, smoking and alcohol. No significant association was detected between hOGG1 polymorphisms and gastric cancer. Key words: hOGG1 polymorphism, H. pylori, atrophic gastritis.
Background: Folate intake has been inconsistently associated with colorectal cancer (CRC) risk, with data from recent observational studies and randomized controlled trials demonstrating inconclusive results. Since folate is essential to both one-carbon metabolism and DNA synthesis pathways, it seems biologically plausible that folate intake may be differentially associated with molecularly defined CRC subtypes. Aim: To examine associations between folate intake and incident CRC, overall and among cases defined by CpG-island methylator phenotype (CIMP) and BRAF (a murine viral oncogene homolog)-mutation status, in a prospective cohort study. Methods: The Iowa Women's Health Study recruited 41,836 Iowa women, aged 55-69 years at study enrollment in 1986. Folate intake, including dietary and supplement sources, was assessed by self-report at baseline. After exclusions, the analytic cohort consisted of 35,216 women and there were 1298 incident CRC cases ascertained by annual linkage with the Iowa Cancer Registry. Archival CRC tissue for 514 (40%) of the eligible cases has been retrieved thus far (baseline age, body mass index, physical activity level, and total energy intake were similar to non-retrieved cases; p > 0.05 for each comparison). CIMP(-) and CIMP(+) cases were defined by promoter hypermethylation of 0-2 or ≥3 genes, respectively, using an established 5-gene panel. BRAF(wt) and BRAF(mut) were defined by fluorescent allele specific polymerase chain reaction to detect the V600E point mutation. Folate intake was analyzed by quartiles. Multivariate Cox regression models were fit to estimate adjusted relative risks (RRs) and 95% confidence intervals (CIs). Results: Folate intake was not associated with incident CRC, overall or by CIMP or BRAF subtypes (Table). Conclusions: In this prospective cohort study of older women, folate intake did not appear to influence overall CRC risk or that of the CIMP- and BRAF-defined subsets.
S1948 Polymorphism of the XPD and HOGG1 Genes in Colorectal Cancer in a Polish Subpopulation Maria A. Wisniewska-Jarosinska, Tomasz Sliwinski, Renata Krupa, Krystyna StecMichalska, Jan Chojnacki, Janusz Blasiak Introduction: Polymorphisms of DNA repair genes may influence individual DNA repair capacity, which is crucial for preventing genomic instability, which, in turn, may be associated with the risk of cancer transformation. Colorectal cancer represents a complex disease, with susceptibility that may be influenced by mutations in DNA repair genes. Purpose: In the present study we investigated the association of polymorphism in the nucleotide excision repair gene XPD (Lys751Gln) and the base excision repair gene hOGG1 (Ser326Cys) with
A-299
AGA Abstracts
AGA Abstracts
S1946