• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5011-5016
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• 2013

Background: Several epidemiological studies have shown associations between colorectal cancer (CRC) risk and type 2 diabetes and obesity. Any effects would be expected to be mediated through the insulin pathway. Therefore it is possible that variants of genes encoding components of the insulin pathway play roles in CRC susceptibility. In this study, we hypothesized that polymorphisms in the genes involving the insulin pathway are associated with risk of CRC. Materials and Methods: The associations of four single nucleotide polymorphisms (SNPs) in IGF-I (rs6214), IGFBP-3 (rs3110697), INSR (rs1052371), and IRS2 (rs2289046) genes with the risk of CRC were evaluated using a case-control design with 167 CRC cases and 277 controls by the PCR-RFLP method. Results: Overall, we observed no significant difference in genotype and allele frequencies between the cases and controls for the IGF-I, IGFBP-3, INSR, IRS2 gene variants and CRC before or after adjusting for confounders (age, BMI, sex, and smoking status). However, we observed that the IRS2 (rs2289046) GG genotype compared with AA+AG genotypes has a protective effect for CRC in normal weight subjects (p=0.035, OR=0.259, 95%CI= 0.074-0.907). Conclusions: These findings do not support plausible associations between polymorphic variations in IGF-I, IGFBP-3, INSR, IRS2 genes and risk of CRC. However, the evidence for a link between the IRS2 (rs2289046) variant and risk of CRC dependent on the BMI of the subjects, requires confirmation in subsequent studies with greater sample size.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.2
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• pp.1047-1055
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• 2014

Background: MicroRNAs (miRNAs) are an abundant class of endogenous small non-coding RNAs of 20-25 nucleotides in length that function as negative gene regulators. MiRNAs play roles in most biological processes, as well as diverse human diseases including cancer. Recently, many studies investigated the association between SNPs in miR-146a rs2910164, miR-196a2 rs11614913, miR-149 rs229283, miR-499 rs3746444 and colorectal cancer (CRC), which results have been inconclusive. Methodology/Principal Findings: PubMed, EMBASE, CNKI databases were searched with the last search updated on November 5, 2013. For miR-196a2 rs11614913, a significantly decreased risk of CRC development was observed under three genetic models (dominant model: OR = 0.848, 95%CI: 0.735-0.979, P = 0.025; recessive model: OR = 0.838, 95%CI: 0.721-0.974, P = 0.021; homozygous model: OR = 0.754, 95%CI: 0.627-0.907, P = 0.003). In the subgroup analyses, miR-$196a2^*T$ variant was associated with a significantly decreased susceptibility of CRC (allele model: OR = 0.839, 95%CI: 0.749-0.940, P = 0.000; dominant model: OR = 0.770, 95%CI: 0.653-0.980, P = 0.002; recessive model: OR = 0.802, 95%CI: 0.685-0.939, P = 0.006; homozygous model: OR = 0.695, 95%CI: 0.570-0.847, P = 0.000). As for miR-149 rs2292832, the two genetic models (recessive model: OR = 1.199, 95% CI 1.028-1.398, P = 0.021; heterozygous model: OR = 1.226, 95% CI 1.039-1.447, P = 0.013) demonstrated increased susceptibility to CRC. On subgroup analysis, significantly increased susceptibility of CRC was found in the genetic models (recessive model: OR = 1.180, 95% CI 1.008-1.382, P = 0.040; heterozygous model: OR = 1.202, 95% CI 1.013-1.425, P = 0.013) in the Asian group. Conclusions: These findings supported that the miR-196a2 rs11614913 and miR-149 rs2292832 polymorphisms may contribute to susceptibility to CRC.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.11
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• pp.6673-6680
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• 2013

Objective: Insulin resistance (IR) is an established risk factor for colorectal cancer (CRC). Given that CRC and IR physiologically overlap and the calpain-10 gene (CAPN10) is a candidate for IR, we explored the association between CAPN10 and CRC risk. Methods: Blood samples of 400 case-control pairs were genotyped, and the lifestyle and dietary habits of these pairs were recorded and collected. Unconditional logistic regression (LR) was used to assess the effects of CAPN10 SNP43 and SNP19, and environmental factors. Both generalized multifactor dimensionality reduction (GMDR) and the classification and regression tree (CART) were used to test gene-environment interactions for CRC risk. Results: The GA+AA genotype of SNP43 and the Del/Ins+Ins/Ins genotype of SNP19 were marginally related to CRC risk (GA+AA: OR = 1.35, 95% CI = 0.92-1.99; Del/Ins+Ins/Ins: OR = 1.31, 95% CI = 0.84-2.04). Notably, a high-order interaction was consistently identified by GMDR and CART analyses. In GMDR, the four-factor interaction model of SNP43, SNP19, red meat consumption, and smoked meat consumption was the best model, with a maximum cross-validation consistency of 10/10 and testing balance accuracy of 0.61 (P < 0.01). In LR, subjects with high red and smoked meat consumption and two risk genotypes had a 6.17-fold CRC risk (95% CI = 2.44-15.6) relative to that of subjects with low red and smoked meat consumption and null risk genotypes. In CART, individuals with high smoked and red meat consumption, SNP19 Del/Ins+Ins/Ins, and SNP43 GA+AA had higher CRC risk (OR = 4.56, 95%CI = 1.94-10.75) than those with low smoked and red meat consumption. Conclusions: Though the single loci of CAPN10 SNP43 and SNP19 are not enough to significantly increase the CRC susceptibility, the combination of SNP43, SNP19, red meat consumption, and smoked meat consumption is associated with elevated risk.

• Journal of Microbiology and Biotechnology
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• v.30 no.11
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• pp.1607-1613
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• 2020

Colorectal cancer (CRC) is regarded as one of the most common and deadly forms of cancer. Gut microbiota is vital to retain and promote several functions of intestinal. Although previous researches have shown that some gut microbiota have the abilities to inhibit tumorigenesis and prevent cancer from progressing, they have not yet clearly identified associative mechanisms. This review not only concentrates on the antitumor effects of metabolites produced by gut microbiota, for example, SCFA, ferrichrome, urolithins, equol and conjugated linoleic acids, but also the molecules which constituted the bacterial cell wall have the antitumor effect in the host, including lipopolysaccharide, lipoteichoic acid, β-glucans and peptidoglycan. The aim of our review is to develop a possible therapeutic method, which use the products of gut microbiota metabolism or gut microbiota constituents to help treat or prevent colorectal cancer.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.14
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• pp.5601-5605
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• 2014

Background: Agrocybe aegerita Lectin (AAL) has been identified to have high affinity for sulfated and ${\alpha}2$-3-linked sialic acid glycoconjugates, especially the sulfated and sialyl TF (Thomsen-Friedenreich) disaccharide. This study was conducted to investigate the clinicopathological and prognostic value of AAL in identifying aberrant glycosylation in colorectal cancer (CRC). Materials and Methods: Glycoconjugate expression in 59 CRC tissues were detected using AAL-histochemistry. Clinicopathological associates of expression were analyzed with chisquare test or Fisher's exact test. Relationships between expression and the various clinicopathological parameters was estimated using Kaplan-Meier analysis and Cox regression models. Results: AAL specific glycoconjugate expression was significantly higher in tumor than corresponding normal tissues (66.1% and 46.1%, respectively, p=0.037), correlating with depth of invasion (p=0.015) and TNM stage (p=0.024). Patients with lower expression levels had a significantly higher survival rate than those with higher expression (p=0.046 by log rank test and p=0.047 by Breslow test for overall survival; p=0.054 by log rank test and P=0.038 by Breslow test for progress free survival). A marginally significant association was found between AAL specific glycoconjugate expression and overall survival by univariate Cox regression analysis (p=0.059). Conclusions: Lower AAL specific glycoconjugate expression is a significant favorable prognostic factor for overall and progress free survival in CRC. This is the first report about the employment of AAL for histochemical analysis of cancer tissues. The binding characteristics of AAL means it has potential to become a powerful tool for the glycan investigation and clinical application.

• Korean Journal of Clinical Oncology
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• v.14 no.2
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• pp.76-82
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• 2018

Purpose: Lgr5 is a well-known stem cell marker in colorectal cancer (CRC). This retrospective study evaluated the expressions of Lgr5 in CRC specimens, and examined whether these expressions were associated with survival outcomes. Methods: We used immunohistochemistry to retrospectively examine expressions of Lgr5 in paraffin-embedded specimens from 337 patients with CRC between January 2009 and December 2013. All clinicopathologic data were collected by retrospective review based on medical records. The correlation between its expression and clinicopathological data as well as clinical outcomes of patients was analyzed. Results: Low expression and high expression of Lgr5 in 337 patients were 175 (51.9%) and 162 (48.1%), respectively. There was no statistically significant difference in the association of Lgr5 expression with clinicopathologic factors (age, tumor location, lymphatic invasion, vascular invasion, perineural invasion, TNM stage, and differentiation). In the survival analysis, the high expression group of Lgr5 showed a better prognosis than the low expression group in disease-free survival (P=0.044). However, overall survival was not significantly different between the two groups (P=0.087). In multivariate analysis, we found that high expression of Lgr5 was independent prognostic factor for tumor relapse (hazard ratio, 0.601; 95% confidence interval, 0.388-0.929; P=0.022). Conclusion: In present study, high expression of Lgr5 is an independent predictor of favorable prognosis in patients with CRC. So, further well designed, prospective, large scale studies are needed to examine the value of Lgr5 as a prognostic biomarker for CRC.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.11
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• pp.4637-4642
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• 2014

Background: Hypoxia-inducible factor $1{\alpha}$ (HIF-$1{\alpha}$) plays an important role in regulating cell survival and angiogenesis, which are critical for tumor growth and metastasis. Genetic variations of HIF1A have been shown to influence the susceptibility to many kinds of human tumors. Increased expression of HIF-$1{\alpha}$ has also been demonstrated to be involved in tumor progression. However, the prognostic value of single nucleotide polymorphisms (SNPs) inthe HIF1A gene remains to be determined in most cancer types, including colorectal cancer (CRC). In this study, we sought to investigate the predictive role of HIF1A SNPs in prognosis of CRC patients and efficacy of chemotherapy. Materials and Methods: We genotyped two functional SNPs in HIF1A gene using the Sequenom iPLEX genotyping system and then assessed their associations with clinicopathological parameters and clinical outcomes of 697 CRC patients receiving radical surgery using Cox logistic regression model and Kaplan Meier curves. Results: Generally, no significant association was found between these 2 SNPs and clinical outcomes of CRC. In stratified analysis of subgroup without adjuvant chemotherapy, patients carrying CT/TT genotypes of rs2057482 exhibited a borderline significant association with better overall survival when compared with those carrying CC genotype [Hazard ratio (HR), 0.47; 95% confidence interval (95% CI): 0.29-0.76; P < 0.01]. Moreover, significant protective effects on CRC outcomes conferred by adjuvant chemotherapy were exclusively observed in patients carrying CC genotype of rs2057482 and in those carrying AC/CC genotype of rs2301113. Conclusions: Genetic variations in HIF1A gene may modulate the efficacy of adjuvant chemotherapy after surgery in CRC patients.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.3
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• pp.973-978
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• 2016

Background: Between October 2012 and February 2015, 25 patients with metastatic colorectal cancer (mCRC) (mean age, $57.0{\pm}12.1years$) were granted access to aflibercept via the Aflibercept Named Patient Program at four centers. Materials and Methods: Here we reported the initial experience of aflibercept / FOLFIRI in combination. We evaluated treatment-related adverse events (AEs), progression-free survival (PFS) and overall survival (OS). Results: The majority of the patients experienced gastrointestinal toxicity (grade 1-2), with diarrhea (52%), mucositis (52%), and nausea/vomiting (20%) being largely observed. Neutropenia (16%) and febrile neutropenia (8%) were common grade 3-4 hematological events. Aflibercept-related toxicity was managed as per practice guidelines. No grade 5 event was reported. Median PFS was 6.12 months (95% CI, 4.80-7.20) and OS was 12 months (95% CI, 9.80-14.18). The partial response (PR), stable disease (SD), and progressive disease (PD) rates were 25% (95% CI: 23.4-27.0), 37.5% (95% CI: 31.6-43.3), and 37.5% (95% CI: 22.5-52.5), respectively. Conclusions: Aflibercept/FOLFIRI can be administered safely in a second line setting to Malaysian patients with mCRC, as the AEs experienced were generally reversible and manageable. The safety and efficacy outcomes were consistent with those observed in Western populations.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.14
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• pp.5941-5944
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• 2014

Purpose: To highlight the potential factors that could predict the response rate of patients with metastatic colorectal cancer (mCRC) treated with pemetrexed combined chemotherapy after first- or second-line chemotherapy using the FOLFOX regimen. Materials and Methods: Between January 2007 and July 2014, 54 patients diagnosed and pathologically-confirmed with advanced colorectal cancer in Jiangsu Cancer Hospital and Research Institute, were enrolled. They received pemetrexed at a dose of $500mg/m^2$ by 10 minute infusion on day 1, repeated every 3 weeks. Doses were modified depending on nadir counts of blood cells. Combined chemotherapeutic agents included irinotecan, lobaplatin, carboplatin, oxaliplatin, gemcitabine, cis-platinum or bevacizumab. Multiple variables (age, sex, hemoglobin, platinum drugs combined, metastasis sites, LDH, ALP, CEA>40 ug/ml) reported earlier were selected. We used logistic regression analysis to evaluate relationships between these and tumor response. Results: On multivariable analysis, we found that age was significant in predicting the responsiveness to pemetrexed (p<0.05) combined with oxaliplatin. We did not find any other factors which were significantly associated with the response rate to chemotherapy with pemetrexed and irinotecan. Conclusions: By multivariate analysis, we found that age had significant impact on the responsiveness of pemetrexed when combined with oxaliplatin. Additional research based on genomic properties of host and tumors are needed to clarify markers for better selection of patients who could benefit from pemetrexed combined chemotherapy.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.18
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• pp.7673-7677
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• 2014

Background: Patients with long-standing inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer (CRC). Colon cancer risk in IBD increases with longer duration and greater anatomic extent of colitis, the presence of primary sclerosing cholangitis, family history of CRC and degree of inflammation of the bowel. This study aimed to characterize the histopathological pattern of benign colorectal diseases among Saudi patients and to highlight age and gender variations of lesions as base line data for future studies to investigate the link between benign/IBD and colorectal cancers in the local population. Materials and Methods: The materials consisted of 684 biopsies, reported as benign (excluding malignancies and polyps) at the Department of Pathology, King Fahad Hospital, Madinah, Saudi Arabia from January 2006 to December 2013. Data collected and entered in MS-Excel and were analyzed using SPSS-20. Results: Of 684 colorectal tissues reviewed, 408 specimens (59.6%) were from male patients and 276 specimens (40.4%) were from females giving a male: female ratio of 1.5:1. Age of the patients ranged from 4 to 75 years with a mean of 39.6 years. The most frequent histologic diagnosis was a chronic non specific proctocolitis followed by ulcerative colitis, accounting respectively for 52.6% and 31.7% of all cases. These were followed by Crohn's disease 22 (3.2%), ischemic bowel disease 20 (2.9%), diverticular disease 14 (2%), eosinophilic colitis 12 (1.7%) and solitary rectal ulcer 12 (1.7%). A minority of 21 patients (3.1%) were cases of acute nonspecific proctocolitis, schistosomiasis, tuberculosis, volvulus and pseudomembranous colitis. Conclusions: These data show that although chronic non specific proctocolitis and ulcerative colitis were the dominant diagnoses, Crohn's disease, ischemic bowel disease and diverticular disease also existed to a lesser extent and should be considered in the differential diagnosis of benign colorectal diseases. This study provides a base line data for future studies which would be taken up to investigate the link between benign/IBD and colorectal cancers in the local population.