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Type 2 Diabetes Mellitus and Colorectal Neoplasia Risk in Puerto Rican Hispanics: A Case-Control Study
AGA Abstracts
Su1082
has not been well studied in Hispanics, an ethnic minority at high risk for type 2 DM. Objective To evaluate the association between type 2 DM and colorectal neoplasia (CRN) in Puerto Rican Hispanic adults enrolled in the studies Epidemiology of Loss of Imprinting in Colorectal Cancer, Familial Colorectal Cancer Registry and the Type 2 diabetes mellitus and colorectal neoplasia risk in Hispanics: A case-control study at the VA Caribbean Healthcare System. Methods The case-control study included patients with incident CRN and controls with negative colonoscopy and without previous history of CRC or adenomas evaluated from January 1, 2005 to December 31, 2009. Diagnosis of type 2 DM was established by previous medical diagnosis and/or anti-diabetic medications use. Unconditional logistic regression was employed to estimate the odds ratio (OR) between type 2 DM and CRN using STATA 10.0. Results A total of 422 participants (mean age 60.8 ± 12.1 yrs., 61.1% males), prevalence of type 2 DM was 26.3%. 276 patients with CRN and 146 controls were evaluated. In the cases, the prevalence of colorectal adenomas was 25.4% (70/276) and the prevalence of colorectal cancer was 74.6% (206/276). Colorectal neoplasia were mostly adenocarcinomas (60.4%), located in the distal colon (37.3%), and with TNM stage III (21.4%). Cases were mostly men (p=0.01), had lower education (p<0.001) and reported lower use of aspirin (p=0.02) compared to the controls. Cases and controls did not differ by median age (p=0.52), first degree of family history of CRC (p=0.27), first degree of family history of DM (p=0.33) or obesity (p=0.73). There were no statistical significant associations between DM and CRN (OR=1.41; 95% CI: 0.74-2.68), DM and CRC (OR=1.70; 95% CI: 0.74-3.87) or DM and colorectal adenomas (OR=1.04; 95% CI: 0.45-2.42) after adjusting for gender, age, education, aspirin use, obesity and study center. Conclusion We did not observe a statistical significant association between type 2 DM and CRN. Nonetheless, a tendency towards an increase risk of colorectal neoplasia was observed among type 2 DM patients on adjusted analysis. Possible explanation for our lack of association may be related to high prevalence of type 2 DM in cases and controls and/or the high prevalence of obesity in the study sample.
Prevalence of Adenomas and Colon Cancer in People of Asian Origin in the United States Appears to Be at Least Similar to Those of Non Asians Undergoing Screening Rupesh Prasad, Hershel Raff, Michael M. Einstein, Nalini M. Guda, Marc F. Catalano, Joseph E. Geenen Introduction: Colorectal cancer is the second leading cause of cancer deaths in the United States. Cancer screening rates appear to vary based on race and ethnicity. Data on incidence of colorectal neoplasia in Asian Americans are not clear. AIM: To assess the prevalence of adenomas and colon cancer in Asian Americans undergoing screening at a large urban referral practice and compare them to non Asian Americans undergoing screening colonoscopy. Material and Methods: A retrospective analysis of Asian subjects undergoing a screening colonoscopy between January 2005 and June 2010 at a large urban referral practice was done. Ethnic origin was ascertained by use of NIH ethnicity codes. Data were abstracted using standardized abstraction sheets and included: age, reason for exam, location of the lesion, pathology of the lesion. The control group was comprised of 200 consecutive nonAsian subjects undergoing screening colonoscopy from January 2010. Those with prior history colon cancer or those undergoing colonoscopy for symptom evaluation were excluded. Results: A total of 144 subjects met the inclusion criteria in the Asian group. The frequency data were analyzed using Chi-square test while continuous data were analyzed by analysis of variance. The median age of the Asian group (63) at screening was higher than controls (53). The severity and grade of polypoid lesion was higher as the age increased in Asian subjects only. Further the incidence of all lesions was higher in the Asians as compared to the non-Asians (p=< 0.001). There was a trend for advanced adenoma to be more frequent in Asians (percent vs. percent), although the difference did not reach statistical significant (p=0.092) There was no significant difference in the location of lesions in the two groups (p= 0.732 in low-risk adenomas, p= 0.348 in advanced adenomas). We analyzed a subset of the population below 60 years of age (88 Asians; 200 non-Asians). The median age in the groups was the same (53 years). The incidence of all lesions was noted to be higher in the Asian group (p= 0.031), with subset analysis revealing higher incidence of low-risk lesions (p=0.025) but no statistical difference in advanced adenomas (p= 0.741). Conclusion: There are limited data about colon cancer screening in Asian-Americans. Our study highlights that Asian-Americans had screening done at a later age as compared to the general population. The incidence of low-risk lesions was higher in the study group even when the median age was same in both groups. The incidence of advanced lesions in the Asian population is at least similar to that in the non-Asian population. Asian Americans should adhere to the current guidelines and undergo screening at the age of 50. Limitations: Small sample size, lack of data on duration of residence, dietary habits.
Su1085 Boswellia Extracts Induce DNA Methylation Changes in Colon Cancer Cells Yan Shen, Alexander Link, Masanobu Takahashi, Francesc Balaguer, Keun Hur, C. Richard Boland, Ajay Goel background: Accumulating evidence indicates that the chemopreventive effects of several dietary polyphenols are in part mediated by their ability to demethylate and subsequently reactivate methylation-silenced tumor suppressor genes in human cancers. Boswellia extracts (BE), which are derived from the plant species Boswellia serrata (commonly known as Frankincense) possess potent anti-inflammatory and anti-oxidant activities. Consequently, BE have been successfully used to treat a wide variety of inflammatory diseases including arthritis, chronic colitis, Crohn's disease and cancer. However, precise molecular mechanisms underlying BE-mediated chemopreventive effects remain elusive. Aim: We hypothesized that BE may modulate DNA promoter methylation in colorectal cancer (CRC) cells and eventually reactivate methylation-silenced tumor suppressor genes. Material and Methods: We treated RKO and SW48 CRC cell lines with the most active principle present in BE, acetyl-keto-beta-boswellic acid (AKBA), at a dose range of 0-40uM. A series of assays was performed to study the effects of BE on cell viability (MTT assay), proliferation (BrdU assay), and clonogenic survival (colony formation). Genome-wide DNA promoter methylation analyses were performed using Illumina's Infinium HumanMethylation27 BeadChip microarrays, which includes analyses of 27,000 CpG loci that span across 14,000 genes. In addition, gene expression analysis was performed using Illumina's HumanHT-12 microarrays. A βvalue of 0.1 (indicating 10% methylation change) and an increase in 2-fold gene expression was considered significant. Methylation and gene expression results were subsequently validated by methylation specific PCR and quantitative real time PCRs, respectively. 5-aza2'-deoxycytidine (DAC) treated cells were used as positive controls for demethylation. Results: BE inhibited cell proliferation, decreased cell viability, and decreased clonogenic survival in RKO and SW48 cells. Methylation microarray results showed that in contrast to global hypomethylation induced by DAC, BE treatment resulted in a more selective demethylation and simultaneous restoration of gene expression. To confirm our microarray results, we successfully validated BE-induced demethylation in a subset of tumor suppressor genes (BNC1, CREB5, DIRAS3, SAMD14, and SMPD3), as well as the corresponding increase in gene expression for SAMD14 and SMPD3 genes. Conclusions: Our data provide novel evidence for BE-induced DNA demethylation and reactivation of gene expression in a subset of tumor suppressor genes in CRC cells. BE-induced reactivation of a subset of tumor suppressor genes may in part contribute to its growth inhibitory effects in CRC cells. These data provide further mechanistic insights into the chemopreventive effects of boswellia extracts.
Su1083 Induction of Methanogenesis in High Colon Cancer Risk African Americans Kayellen Umeakunne, Junhai Ou, James DeLany, H. Rex Gaskins, Keith Newton, Stephen J. O'Keefe African Americans living in the US typically consume a westernized, high red meat, high fat, low fiber, low complex carbohydrate diet creating a microbiome consistent with risk for colon cancer. One of the activities of the microbiota is the production of gas from metabolites. The type of gas present in expired breath depends on the type of bacteria present in the lower gut. Our human investigations suggest that higher meat intakes and lower rates of bacterial methanogensis in high colon cancer risk African Americans compared to low risk, high resistant starch and low meat consuming native Africans support a plausible interaction between diet, colonic microbiota and their resultant metabolites. METHODS: End-expiratory breath samples were collected from 4 healthy African Americans (AA) (2 males, 2 females) at 4 hours post lunch meal during Home Visits and on Day 14 of a 2 week controlled Dietary Intervention. Prior to the Dietary Intervention, 6 Day food records were collected and documented by home visit to determine the distribution of macronutrients and fiber in the usual diet. During the intervention AA subjects received an African diet consisting of high complex carbohydrate, high fiber, high resistant starch and low meat. Breath samples were analyzed for hydrogen and methane gas using a QuinTron Gas Analyzer (QuinTron, Milwaukee, WI). RESULTS: Methane production was significantly higher following the African diet in African Americans compared to the Home diet. The increase in methane production was accompanied by a decrease in hydrogen production demonstrating a resultant inverse relationship between the two gases in response to type of diet. CONCLUSION: These results provide indirect evidence that a change in diet in high colon cancer risk African Americans to a high fiber/high resistant starch/low meat diet can alter hydrogenotrophic bacteria towards more benign methanogenesis within 2 weeks, potentially reducing risk. Table 1: Hydrogen and Methane Gas Production in Response to Diet in AA
Su1086 Apigenin Inhibits mTORC2 Through Down-Regulation of RICTOR Expression in Colorectal Cancer Cells Zheng Guo, Yuning Zhou, B. M. Evers, Qingding Wang Knockdown of rictor, a component of Mammalian Target of Rapamycin Complex 2 (mTORC2), blocks Akt phosphorylation and inhibits Akt activation and thus, results in inhibition of colorectal cancer growth. However, little is known about the signaling pathways that regulate rictor expression. Apigenin, a common dietary flavonoid, has proven to be one of the most promising compounds in the inhibition of colorectal cancer cell growth. The purpose of this study was to investigate the effects of apigenin on mTORC2 signaling. METHODS. HT29 and HCT116 colon cancer cells were treated with various dosages of apigenin. Cell growth was determined using a sulforhodamine B assay kit from Sigma. Rictor, p-Akt, Akt, mTOR and beta-actin expression was analyzed by Western blot. Rictor mRNA expression was determined by real time RT-PCR. To investigate whether apigenin transcriptionally regulates rictor expression, we cloned the 5'-upstream region (1038 bp) of the human rictor gene utilizing the human Genome Walker Kit and inserted it upstream of the luciferase reporter gene. HCT116 cells were transiently transfected with this rictor promoter construct and the promoter activity was determined by luciferase activity assay. RESULTS. Treatment with apigenin inhibited HT29 and HCT116 cell growth. Moreover, treatment
* p<0.05 Su1084 Type 2 Diabetes Mellitus and Colorectal Neoplasia Risk in Puerto Rican Hispanics: A Case-Control Study Yaritza Diaz-Algorri, Dilka I. Gonzalez-Ortiz, Jessica Hernandez, Carmen Pedrosa, Doris H. Toro, Marcia R. Cruz-Correa Background Epidemiological studies have provided inconclusive evidence regarding the potential link between type 2 diabetes mellitus (DM) and colorectal cancer (CRC).The association between type 2 DM and colorectal neoplasia (colorectal cancer and/or adenomas)
AGA Abstracts
S-400
Su1082
has not been well studied in Hispanics, an ethnic minority at high risk for type 2 DM. Objective To evaluate the association between type 2 DM and colorectal neoplasia (CRN) in Puerto Rican Hispanic adults enrolled in the studies Epidemiology of Loss of Imprinting in Colorectal Cancer, Familial Colorectal Cancer Registry and the Type 2 diabetes mellitus and colorectal neoplasia risk in Hispanics: A case-control study at the VA Caribbean Healthcare System. Methods The case-control study included patients with incident CRN and controls with negative colonoscopy and without previous history of CRC or adenomas evaluated from January 1, 2005 to December 31, 2009. Diagnosis of type 2 DM was established by previous medical diagnosis and/or anti-diabetic medications use. Unconditional logistic regression was employed to estimate the odds ratio (OR) between type 2 DM and CRN using STATA 10.0. Results A total of 422 participants (mean age 60.8 ± 12.1 yrs., 61.1% males), prevalence of type 2 DM was 26.3%. 276 patients with CRN and 146 controls were evaluated. In the cases, the prevalence of colorectal adenomas was 25.4% (70/276) and the prevalence of colorectal cancer was 74.6% (206/276). Colorectal neoplasia were mostly adenocarcinomas (60.4%), located in the distal colon (37.3%), and with TNM stage III (21.4%). Cases were mostly men (p=0.01), had lower education (p<0.001) and reported lower use of aspirin (p=0.02) compared to the controls. Cases and controls did not differ by median age (p=0.52), first degree of family history of CRC (p=0.27), first degree of family history of DM (p=0.33) or obesity (p=0.73). There were no statistical significant associations between DM and CRN (OR=1.41; 95% CI: 0.74-2.68), DM and CRC (OR=1.70; 95% CI: 0.74-3.87) or DM and colorectal adenomas (OR=1.04; 95% CI: 0.45-2.42) after adjusting for gender, age, education, aspirin use, obesity and study center. Conclusion We did not observe a statistical significant association between type 2 DM and CRN. Nonetheless, a tendency towards an increase risk of colorectal neoplasia was observed among type 2 DM patients on adjusted analysis. Possible explanation for our lack of association may be related to high prevalence of type 2 DM in cases and controls and/or the high prevalence of obesity in the study sample.
Prevalence of Adenomas and Colon Cancer in People of Asian Origin in the United States Appears to Be at Least Similar to Those of Non Asians Undergoing Screening Rupesh Prasad, Hershel Raff, Michael M. Einstein, Nalini M. Guda, Marc F. Catalano, Joseph E. Geenen Introduction: Colorectal cancer is the second leading cause of cancer deaths in the United States. Cancer screening rates appear to vary based on race and ethnicity. Data on incidence of colorectal neoplasia in Asian Americans are not clear. AIM: To assess the prevalence of adenomas and colon cancer in Asian Americans undergoing screening at a large urban referral practice and compare them to non Asian Americans undergoing screening colonoscopy. Material and Methods: A retrospective analysis of Asian subjects undergoing a screening colonoscopy between January 2005 and June 2010 at a large urban referral practice was done. Ethnic origin was ascertained by use of NIH ethnicity codes. Data were abstracted using standardized abstraction sheets and included: age, reason for exam, location of the lesion, pathology of the lesion. The control group was comprised of 200 consecutive nonAsian subjects undergoing screening colonoscopy from January 2010. Those with prior history colon cancer or those undergoing colonoscopy for symptom evaluation were excluded. Results: A total of 144 subjects met the inclusion criteria in the Asian group. The frequency data were analyzed using Chi-square test while continuous data were analyzed by analysis of variance. The median age of the Asian group (63) at screening was higher than controls (53). The severity and grade of polypoid lesion was higher as the age increased in Asian subjects only. Further the incidence of all lesions was higher in the Asians as compared to the non-Asians (p=< 0.001). There was a trend for advanced adenoma to be more frequent in Asians (percent vs. percent), although the difference did not reach statistical significant (p=0.092) There was no significant difference in the location of lesions in the two groups (p= 0.732 in low-risk adenomas, p= 0.348 in advanced adenomas). We analyzed a subset of the population below 60 years of age (88 Asians; 200 non-Asians). The median age in the groups was the same (53 years). The incidence of all lesions was noted to be higher in the Asian group (p= 0.031), with subset analysis revealing higher incidence of low-risk lesions (p=0.025) but no statistical difference in advanced adenomas (p= 0.741). Conclusion: There are limited data about colon cancer screening in Asian-Americans. Our study highlights that Asian-Americans had screening done at a later age as compared to the general population. The incidence of low-risk lesions was higher in the study group even when the median age was same in both groups. The incidence of advanced lesions in the Asian population is at least similar to that in the non-Asian population. Asian Americans should adhere to the current guidelines and undergo screening at the age of 50. Limitations: Small sample size, lack of data on duration of residence, dietary habits.
Su1085 Boswellia Extracts Induce DNA Methylation Changes in Colon Cancer Cells Yan Shen, Alexander Link, Masanobu Takahashi, Francesc Balaguer, Keun Hur, C. Richard Boland, Ajay Goel background: Accumulating evidence indicates that the chemopreventive effects of several dietary polyphenols are in part mediated by their ability to demethylate and subsequently reactivate methylation-silenced tumor suppressor genes in human cancers. Boswellia extracts (BE), which are derived from the plant species Boswellia serrata (commonly known as Frankincense) possess potent anti-inflammatory and anti-oxidant activities. Consequently, BE have been successfully used to treat a wide variety of inflammatory diseases including arthritis, chronic colitis, Crohn's disease and cancer. However, precise molecular mechanisms underlying BE-mediated chemopreventive effects remain elusive. Aim: We hypothesized that BE may modulate DNA promoter methylation in colorectal cancer (CRC) cells and eventually reactivate methylation-silenced tumor suppressor genes. Material and Methods: We treated RKO and SW48 CRC cell lines with the most active principle present in BE, acetyl-keto-beta-boswellic acid (AKBA), at a dose range of 0-40uM. A series of assays was performed to study the effects of BE on cell viability (MTT assay), proliferation (BrdU assay), and clonogenic survival (colony formation). Genome-wide DNA promoter methylation analyses were performed using Illumina's Infinium HumanMethylation27 BeadChip microarrays, which includes analyses of 27,000 CpG loci that span across 14,000 genes. In addition, gene expression analysis was performed using Illumina's HumanHT-12 microarrays. A βvalue of 0.1 (indicating 10% methylation change) and an increase in 2-fold gene expression was considered significant. Methylation and gene expression results were subsequently validated by methylation specific PCR and quantitative real time PCRs, respectively. 5-aza2'-deoxycytidine (DAC) treated cells were used as positive controls for demethylation. Results: BE inhibited cell proliferation, decreased cell viability, and decreased clonogenic survival in RKO and SW48 cells. Methylation microarray results showed that in contrast to global hypomethylation induced by DAC, BE treatment resulted in a more selective demethylation and simultaneous restoration of gene expression. To confirm our microarray results, we successfully validated BE-induced demethylation in a subset of tumor suppressor genes (BNC1, CREB5, DIRAS3, SAMD14, and SMPD3), as well as the corresponding increase in gene expression for SAMD14 and SMPD3 genes. Conclusions: Our data provide novel evidence for BE-induced DNA demethylation and reactivation of gene expression in a subset of tumor suppressor genes in CRC cells. BE-induced reactivation of a subset of tumor suppressor genes may in part contribute to its growth inhibitory effects in CRC cells. These data provide further mechanistic insights into the chemopreventive effects of boswellia extracts.
Su1083 Induction of Methanogenesis in High Colon Cancer Risk African Americans Kayellen Umeakunne, Junhai Ou, James DeLany, H. Rex Gaskins, Keith Newton, Stephen J. O'Keefe African Americans living in the US typically consume a westernized, high red meat, high fat, low fiber, low complex carbohydrate diet creating a microbiome consistent with risk for colon cancer. One of the activities of the microbiota is the production of gas from metabolites. The type of gas present in expired breath depends on the type of bacteria present in the lower gut. Our human investigations suggest that higher meat intakes and lower rates of bacterial methanogensis in high colon cancer risk African Americans compared to low risk, high resistant starch and low meat consuming native Africans support a plausible interaction between diet, colonic microbiota and their resultant metabolites. METHODS: End-expiratory breath samples were collected from 4 healthy African Americans (AA) (2 males, 2 females) at 4 hours post lunch meal during Home Visits and on Day 14 of a 2 week controlled Dietary Intervention. Prior to the Dietary Intervention, 6 Day food records were collected and documented by home visit to determine the distribution of macronutrients and fiber in the usual diet. During the intervention AA subjects received an African diet consisting of high complex carbohydrate, high fiber, high resistant starch and low meat. Breath samples were analyzed for hydrogen and methane gas using a QuinTron Gas Analyzer (QuinTron, Milwaukee, WI). RESULTS: Methane production was significantly higher following the African diet in African Americans compared to the Home diet. The increase in methane production was accompanied by a decrease in hydrogen production demonstrating a resultant inverse relationship between the two gases in response to type of diet. CONCLUSION: These results provide indirect evidence that a change in diet in high colon cancer risk African Americans to a high fiber/high resistant starch/low meat diet can alter hydrogenotrophic bacteria towards more benign methanogenesis within 2 weeks, potentially reducing risk. Table 1: Hydrogen and Methane Gas Production in Response to Diet in AA
Su1086 Apigenin Inhibits mTORC2 Through Down-Regulation of RICTOR Expression in Colorectal Cancer Cells Zheng Guo, Yuning Zhou, B. M. Evers, Qingding Wang Knockdown of rictor, a component of Mammalian Target of Rapamycin Complex 2 (mTORC2), blocks Akt phosphorylation and inhibits Akt activation and thus, results in inhibition of colorectal cancer growth. However, little is known about the signaling pathways that regulate rictor expression. Apigenin, a common dietary flavonoid, has proven to be one of the most promising compounds in the inhibition of colorectal cancer cell growth. The purpose of this study was to investigate the effects of apigenin on mTORC2 signaling. METHODS. HT29 and HCT116 colon cancer cells were treated with various dosages of apigenin. Cell growth was determined using a sulforhodamine B assay kit from Sigma. Rictor, p-Akt, Akt, mTOR and beta-actin expression was analyzed by Western blot. Rictor mRNA expression was determined by real time RT-PCR. To investigate whether apigenin transcriptionally regulates rictor expression, we cloned the 5'-upstream region (1038 bp) of the human rictor gene utilizing the human Genome Walker Kit and inserted it upstream of the luciferase reporter gene. HCT116 cells were transiently transfected with this rictor promoter construct and the promoter activity was determined by luciferase activity assay. RESULTS. Treatment with apigenin inhibited HT29 and HCT116 cell growth. Moreover, treatment
* p<0.05 Su1084 Type 2 Diabetes Mellitus and Colorectal Neoplasia Risk in Puerto Rican Hispanics: A Case-Control Study Yaritza Diaz-Algorri, Dilka I. Gonzalez-Ortiz, Jessica Hernandez, Carmen Pedrosa, Doris H. Toro, Marcia R. Cruz-Correa Background Epidemiological studies have provided inconclusive evidence regarding the potential link between type 2 diabetes mellitus (DM) and colorectal cancer (CRC).The association between type 2 DM and colorectal neoplasia (colorectal cancer and/or adenomas)
AGA Abstracts
S-400