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Cigarette Smoking and Colorectal Adenoma Risk Among Older Women
gene (phosphomannomutase-1). Relative expression ratios were determined by the 2-ΔΔCt method. Results showed that mean tumour expression of Olfm4, Ascl2, Lgr5, Bmi-1, and DCAMKL-1 were increased by 35, 28, 12, 2.6 and 1.4-fold respectively when compared to expression in the corresponding normal mucosa. Tumour over-expression by ≥ 2-fold was found in 17/22 pairs (77%) for Lgr5, 15/22 (68%) for Olfm4, 9/22 (41%) for Bmi-1, 12/ 22 (55%) for Ascl2, and 4/22 (18%) for DCAMKL1. Hence a panel comprised of Lgr5, OLFM4 and Ascl2 would be appropriate for use in detection of tumour-specific stem cells in blood of CRC patients. Sa1911 Cigarette Smoking and Colorectal Adenoma Risk Among Older Women Niloy Jewel Samadder, Robert Vierkant, Alice Wang, Aaron Folsom, Beth A. Virnig, James R. Cerhan, Paul J. Limburg Background: Cigarette smoking (CS) is an established risk factor for colorectal cancer (CRC). However, the association between CS and premalignant colorectal adenomas (CRAs) is less clearly defined, particularly among women. The goal of this population-based cohort study was to assess CS and CRA risk among women enrolled in the Iowa Women's Health Study (IWHS). Methods: The IWHS is a prospective cohort study of cancer and related endpoints among randomly selected Iowa women, ages 55-69 years of age and holding a valid drivers license at enrollment (1986). CS was assessed by self-report at baseline. CRAs were identified from Medicare data for 1993-2004 (hospitalization, outpatient and carrier files), using ICD9 codes 211.3 and 211.4. Exclusion criteria were defined as: never enrolled in both parts A and B of Medicare for at least one month on or after January 1, 1993; no response to 1992 IWHS follow-up questionnaire; prior malignancy (except non-melanoma skin cancer) or CRA; < 1 year of follow-up; or incomplete CS data. CS was analyzed as baseline smoking status (former, current), pack-years smoked (1-19, 20-39, ≥ 40) and average number of cigarettes per day (1-19, 20-39, ≥ 40); never smokers were defined as the reference group. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: Complete CS and CRA data were available for 26,131 subjects. During 227,055 person-years of follow-up, 5,485 women were identified with at least one newly diagnosed CRA from Medicare data. Compared to never smokers, current (RR=1.22; 95% CI, 1.12-1.33) and former (RR=1.14; 95% CI, 1.06-1.22) smokers had significantly higher CRA risks (p trend < 0.001). CRA risks also increased progressively by pack-years smoked (p trend < 0.001) and number of cigarettes per day (p trend < 0.001) (see Table). Conclusion: In this large prospective cohort study, CS was strongly associated with CRA risk among older women. These data support CS as a potentially modifiable risk factor for premalignant colorectal neoplasia.
Sa1910 Aberrant Expression of MUC17 Correlates With Survival in Advanced Stage Colorectal Adenocarcinomas Ke Li, Aaron Lee, Brandon S. Kandarian, Vahig Manugian, Michael R. Peterson, Surinder K. Batra, Samuel B. Ho Background: MUC17, an intestinal membrane-bound mucin, has been shown to enhance mucosal restitution by stimulation of cell migration and inhibition of apoptosis (Ho et al BBA 2010;1800:629-638). MUC17 is highly expressed on the surface epithelium of normal colonic mucosa, however expression becomes altered in colorectal neoplasia. The purpose of this study was to investigate the patterns of expression and prognostic significance of MUC17 expression in colorectal adenocarcinomas. Design: Immunohistochemical analysis of human colorectal adenocarcinoma surgical resection specimens (n=86) was performed using anti-MUC17 apomucin tandem repeat antibody. A semi-quantitative score system was used to measure MUC17 expression. MUC17 expression levels were correlated with clinicopathological features and patient survival. Survival curves were compared by the logrank (Mantel-Cox) method. Result: Overall MUC17 expression was decreased in colorectal adenocarcinoma and preserved in normal colonic mucosa. Expression of MUC17 did not significantly differ between specimens of different stage or grade. The colorectal adenocarcinomas were categorized into groups of relative high MUC17 expression (51of 86 patients; 59%) or low expression (36 of 86 patients; 41%). Patients with advanced stage cancers (stages III and IV) with high MUC17 expression had a longer overall survival (log-rank; p = 0.0051) than patients who had low expression. The median survivals were 12.87 months for patients with low MUC17 expression and 24.55 months for those with high MUC17 expression. Patients with early stage cancers (stages I and II) did not demonstrate such a difference. Conclusion: These results indicate that a high expression of MUC17 is associated with a longer overall survival in patients with stage III and IV colorectal adenocarcinomas. Further studies of the possible role of other membrane-bound mucins in cancer behavior and prognosis are needed. Sa1910a Colonic Stem Cell Biomarkers for the Detection of Circulating Cancer Stem Cells Phulwinder K. Grover, Jennifer E. Hardingham, Irene Kanter, Timothy J. Price, Peter J. Hewett, Ian C. Roberts-Thomson, Adrian G. Cummins
*Relative risk and 95% confidence interval adjusted for age; **Relative risk and 95% confidence interval adjusted for age, body mass index, waist-to-hip ratio, physical activity, exogenous estrogen use, and daily intakes of total energy, total fat, calcium, folate, red meat, methionine, sucrose, vitamin E and alcohol.
Colorectal cancer (CRC) is the second most common cancer in Australia. Patients diagnosed with early stage CRC undergo curative surgical tumour resection, yet up to 25% relapse with recurrent or metastatic disease within 5 years of surgery. It is now accepted that occult circulating tumour cells (CTC) with proliferative and metastatic potential are responsible for relapse in these patients. Our previous study (Int J Cancer 89:8-13, 2000) using immunomagnetic bead capture and epithelial expression markers showed that patients who were positive for CTC had a shorter disease-free survival (P=0.0001). However, at least some patients with CTC do not develop metastases. One possibility is that the metastatic potential of an individual CTC is extremely low or that metastases only arise from a distinct subgroup of cancer cells, perhaps cancer stem cells. The purpose of this study was to identify biomarkers of cancer stem cells that could then be applied to the detection of cancer stem cells in peripheral blood. We used five biomarkers which have been described for the identification of two types of intestinal stem cells, the stem cell in the '+4 position' from the crypt base and the 'stem cell zone' also known as crypt basal columnar cells. The markers included doublecortin and CaM Kinase-Like-1 (DCAMKL-1) and polycomb ring finger oncogene (Bmi-1) that have been associated with the '+4 position' stem cells and the leucine-rich repeat-containing G-protein-coupled receptor (Lgr5), olfactomedin-4 (Olfm4) and achaete scute-like-2 (Ascl2) that have been associated with basal columnar stem cells. Tissue samples of tumour and corresponding normal mucosa were obtained from 22 patients undergoing surgical resection for primary colon cancer. The samples were snap frozen in liquid nitrogen and RNA was extracted using the RNeasy kit (Qiagen). RNA was then quantified (QIAxcel, Qiagen) and analysed by qRT-PCR (Taqman assay) for each marker gene and a reference
Sa1912 Colorectal Cancer in Hispanics: A Population-Based Study of Trends in Incidence and Survival Nadim Jafri, Milena Gould, Hashem El-Serag, Jessica A. Davila BACKGROUND: Hispanics are the largest and fastest growing ethnic group in the United States. The incidence and survival of colorectal cancer (CRC) among Hispanics in the United States have not been examined. METHODS: Using data from the Surveillance, Epidemiology, and End Results (SEER) program, the age-adjusted and age-specific incidence rates were calculated in Hispanics diagnosed with CRC in three consecutive 5-year periods (19931997, 1998-2002, and 2003-2007). Annual percent change (APC), utilizing weighted least squares method were calculated. Temporal trends were examined using Poisson multivariate regression controlling for changes in age and gender among CRC cases and the underlying population at risk. The observed and relative survival rates were also calculated. RESULTS: We identified 110,659 Hispanics diagnosed with CRC during 1993-2007. The overall ageadjusted incidence rate declined from 40.3 in 1993-1997 to 37.1 per 100,000 in 20032007. The APC during 1993-2007 was -0.8/year. However, a 21% increase in CRC incidence was observed in ages 20-39 from 2.6 (95% CI: 2.4-2.7) in 1993-1997 to 3.3 per 100,000 (95% CI: 3.1-3.5) in 2003-2007 and a 13% increase was observed in ages 40-49 from 15.9
S-345
AGA Abstracts
AGA Abstracts
ovarian cancer. Primary Dicer transcripts can be processed at three alternative polyadenylation sites, generating two pools of mRNAs that carry either a long or a short 3'UTR, both encoding the same Dicer protein. The different 3'UTRs in Dicer1 mRNAs interact with distinct transacting factor, thus offering a mechanism to decrease the capacity and complexity for regulation of Dicer expression at posttranscriptional levels. The importance of regulation by 3'UTRs is recently highlighted by the findings that 3' untranslated regions (UTRs) are altered in length in cancer cell lines, however, little is known about the 3'UTRs are altered in clinical human CRC. We aim to investigate the expression of total Dicer mRNAs and the expression of Dicer mRNA with a long 3'UTR (long 3'UTR Dicer mRNA). Methods: Tissues were obtained from 52 patients with CRC. Matched tumor and normal mucosal specimens were obtained from endoscopic biopsy. Standard histological techniques were used to classify malignancy at 0 to IV stage according to TNM classification, yielding stage 0 (n = 2), I (n = 13), II (n = 16), III or IV(n = 21).Total RNA was extracted, subjected to DNase treatment and reverse transcribed using Superscript III reverse transcriptase with oligo (dT). Real-time PCR of a long 3'UTR Dicer mRNA, coding Dicer mRNA and beta-2-microglobulin was carried out using TaqMan probe. Statistical significance was determined by the Wilcoxon signed-rank test. Results: The median expression level of coding Dicer mRNA in tumor was 8.8 (range; 1.8-220), which was significantly lower than those in normal mucosa [18.0 (2.9-380): P < 0.005]. There was no significant difference in expression levels of long 3'UTR Dicer mRNA between tumor [4.6 (0.6-45)], and normal mucosa [4.1 (0-23): P = 0.44]. The median expression ratio of a long 3'UTR Dicer mRNA to coding Dicer mRNA in tumor specimens was significantly higher than that in normal mucosa (P < 0.001).there was no significant correlation between pathological findings such as TNM classification and tumor location and expression levels of coding Dicer mRNA, or expression level of a long 3'UTR Dicer mRNA or the ratio of a long 3'UTR Dicer mRNA expression to coding Dicer mRNA expression. Conclusion: These results suggested that the dysregulation of Dicer expression may be involved in colon carcinogenesis through not only transcriptional levels but also posttranscriptional levels in CRC, and that early event in colon carcinogenesis.
Sa1910 Aberrant Expression of MUC17 Correlates With Survival in Advanced Stage Colorectal Adenocarcinomas Ke Li, Aaron Lee, Brandon S. Kandarian, Vahig Manugian, Michael R. Peterson, Surinder K. Batra, Samuel B. Ho Background: MUC17, an intestinal membrane-bound mucin, has been shown to enhance mucosal restitution by stimulation of cell migration and inhibition of apoptosis (Ho et al BBA 2010;1800:629-638). MUC17 is highly expressed on the surface epithelium of normal colonic mucosa, however expression becomes altered in colorectal neoplasia. The purpose of this study was to investigate the patterns of expression and prognostic significance of MUC17 expression in colorectal adenocarcinomas. Design: Immunohistochemical analysis of human colorectal adenocarcinoma surgical resection specimens (n=86) was performed using anti-MUC17 apomucin tandem repeat antibody. A semi-quantitative score system was used to measure MUC17 expression. MUC17 expression levels were correlated with clinicopathological features and patient survival. Survival curves were compared by the logrank (Mantel-Cox) method. Result: Overall MUC17 expression was decreased in colorectal adenocarcinoma and preserved in normal colonic mucosa. Expression of MUC17 did not significantly differ between specimens of different stage or grade. The colorectal adenocarcinomas were categorized into groups of relative high MUC17 expression (51of 86 patients; 59%) or low expression (36 of 86 patients; 41%). Patients with advanced stage cancers (stages III and IV) with high MUC17 expression had a longer overall survival (log-rank; p = 0.0051) than patients who had low expression. The median survivals were 12.87 months for patients with low MUC17 expression and 24.55 months for those with high MUC17 expression. Patients with early stage cancers (stages I and II) did not demonstrate such a difference. Conclusion: These results indicate that a high expression of MUC17 is associated with a longer overall survival in patients with stage III and IV colorectal adenocarcinomas. Further studies of the possible role of other membrane-bound mucins in cancer behavior and prognosis are needed. Sa1910a Colonic Stem Cell Biomarkers for the Detection of Circulating Cancer Stem Cells Phulwinder K. Grover, Jennifer E. Hardingham, Irene Kanter, Timothy J. Price, Peter J. Hewett, Ian C. Roberts-Thomson, Adrian G. Cummins
*Relative risk and 95% confidence interval adjusted for age; **Relative risk and 95% confidence interval adjusted for age, body mass index, waist-to-hip ratio, physical activity, exogenous estrogen use, and daily intakes of total energy, total fat, calcium, folate, red meat, methionine, sucrose, vitamin E and alcohol.
Colorectal cancer (CRC) is the second most common cancer in Australia. Patients diagnosed with early stage CRC undergo curative surgical tumour resection, yet up to 25% relapse with recurrent or metastatic disease within 5 years of surgery. It is now accepted that occult circulating tumour cells (CTC) with proliferative and metastatic potential are responsible for relapse in these patients. Our previous study (Int J Cancer 89:8-13, 2000) using immunomagnetic bead capture and epithelial expression markers showed that patients who were positive for CTC had a shorter disease-free survival (P=0.0001). However, at least some patients with CTC do not develop metastases. One possibility is that the metastatic potential of an individual CTC is extremely low or that metastases only arise from a distinct subgroup of cancer cells, perhaps cancer stem cells. The purpose of this study was to identify biomarkers of cancer stem cells that could then be applied to the detection of cancer stem cells in peripheral blood. We used five biomarkers which have been described for the identification of two types of intestinal stem cells, the stem cell in the '+4 position' from the crypt base and the 'stem cell zone' also known as crypt basal columnar cells. The markers included doublecortin and CaM Kinase-Like-1 (DCAMKL-1) and polycomb ring finger oncogene (Bmi-1) that have been associated with the '+4 position' stem cells and the leucine-rich repeat-containing G-protein-coupled receptor (Lgr5), olfactomedin-4 (Olfm4) and achaete scute-like-2 (Ascl2) that have been associated with basal columnar stem cells. Tissue samples of tumour and corresponding normal mucosa were obtained from 22 patients undergoing surgical resection for primary colon cancer. The samples were snap frozen in liquid nitrogen and RNA was extracted using the RNeasy kit (Qiagen). RNA was then quantified (QIAxcel, Qiagen) and analysed by qRT-PCR (Taqman assay) for each marker gene and a reference
Sa1912 Colorectal Cancer in Hispanics: A Population-Based Study of Trends in Incidence and Survival Nadim Jafri, Milena Gould, Hashem El-Serag, Jessica A. Davila BACKGROUND: Hispanics are the largest and fastest growing ethnic group in the United States. The incidence and survival of colorectal cancer (CRC) among Hispanics in the United States have not been examined. METHODS: Using data from the Surveillance, Epidemiology, and End Results (SEER) program, the age-adjusted and age-specific incidence rates were calculated in Hispanics diagnosed with CRC in three consecutive 5-year periods (19931997, 1998-2002, and 2003-2007). Annual percent change (APC), utilizing weighted least squares method were calculated. Temporal trends were examined using Poisson multivariate regression controlling for changes in age and gender among CRC cases and the underlying population at risk. The observed and relative survival rates were also calculated. RESULTS: We identified 110,659 Hispanics diagnosed with CRC during 1993-2007. The overall ageadjusted incidence rate declined from 40.3 in 1993-1997 to 37.1 per 100,000 in 20032007. The APC during 1993-2007 was -0.8/year. However, a 21% increase in CRC incidence was observed in ages 20-39 from 2.6 (95% CI: 2.4-2.7) in 1993-1997 to 3.3 per 100,000 (95% CI: 3.1-3.5) in 2003-2007 and a 13% increase was observed in ages 40-49 from 15.9
S-345
AGA Abstracts
AGA Abstracts
ovarian cancer. Primary Dicer transcripts can be processed at three alternative polyadenylation sites, generating two pools of mRNAs that carry either a long or a short 3'UTR, both encoding the same Dicer protein. The different 3'UTRs in Dicer1 mRNAs interact with distinct transacting factor, thus offering a mechanism to decrease the capacity and complexity for regulation of Dicer expression at posttranscriptional levels. The importance of regulation by 3'UTRs is recently highlighted by the findings that 3' untranslated regions (UTRs) are altered in length in cancer cell lines, however, little is known about the 3'UTRs are altered in clinical human CRC. We aim to investigate the expression of total Dicer mRNAs and the expression of Dicer mRNA with a long 3'UTR (long 3'UTR Dicer mRNA). Methods: Tissues were obtained from 52 patients with CRC. Matched tumor and normal mucosal specimens were obtained from endoscopic biopsy. Standard histological techniques were used to classify malignancy at 0 to IV stage according to TNM classification, yielding stage 0 (n = 2), I (n = 13), II (n = 16), III or IV(n = 21).Total RNA was extracted, subjected to DNase treatment and reverse transcribed using Superscript III reverse transcriptase with oligo (dT). Real-time PCR of a long 3'UTR Dicer mRNA, coding Dicer mRNA and beta-2-microglobulin was carried out using TaqMan probe. Statistical significance was determined by the Wilcoxon signed-rank test. Results: The median expression level of coding Dicer mRNA in tumor was 8.8 (range; 1.8-220), which was significantly lower than those in normal mucosa [18.0 (2.9-380): P < 0.005]. There was no significant difference in expression levels of long 3'UTR Dicer mRNA between tumor [4.6 (0.6-45)], and normal mucosa [4.1 (0-23): P = 0.44]. The median expression ratio of a long 3'UTR Dicer mRNA to coding Dicer mRNA in tumor specimens was significantly higher than that in normal mucosa (P < 0.001).there was no significant correlation between pathological findings such as TNM classification and tumor location and expression levels of coding Dicer mRNA, or expression level of a long 3'UTR Dicer mRNA or the ratio of a long 3'UTR Dicer mRNA expression to coding Dicer mRNA expression. Conclusion: These results suggested that the dysregulation of Dicer expression may be involved in colon carcinogenesis through not only transcriptional levels but also posttranscriptional levels in CRC, and that early event in colon carcinogenesis.