Polymorphism In Colorectal Cancer Research Articles

Abstract 781: Functional consequence of the p53 codon 72 polymorphism in colorectal cancer

Abstract Background: The codon 72 polymorphism in p53 has been implicated in colorectal cancer (CRC) and CRC health disparities. In this study, we determine the functional consequence of this polymorphism in CRC following both in-vitro cell based and in-vivo mouse model studies. Experimental Design: Plasmids (pCMV6) that express different phenotypes of p53 [p53 wild type (wt) at codon 72 (R72wt), R72wt with mutation at codon 273 cysteine (R72273Cys), p53 mutation at codon 72 (P72wt) and P72wt with mutation at codon 273 (P72273Cys)] were constructed. We selected a CRC cell line Caco2, which does not express p53 for in vitro studies. Severe combined immunodeficient mice were inoculated with CRC cells (HT29, SW480, and LS174) to establish tumor xenografts (tumors). Tumor angiogenesis was assessed in tumors by immunostaing for CD31. Sequencing analysis for codon 72 polymorphism of p53 was performed using genomic DNA purified from tumors. Western blot (WB) or immunostaining analyses for proteins of signaling mechanisms were performed to assess the functional consequence of P72 phenotype of p53. Results: Our study demonstrated that P72 tumors had well established vascularity, while R72 tumors had very poor vascularization. Indeed, the mean micro vessel density was higher in P72 tumors than in R72 tumors. WB analyses revealed that P72wt or mutant phenotypes effectively induced the activation of p38 and RAF/MEK/ extracellular signal-regulated kinase (ERK) MAP kinases. Up-regulation of phosphorylated SEK1/MKK4, an upstream kinase of p38 MAPK was associated with P72wt or mutant phenotypes. This activation was accompanied by up-regulation of phosphorylated-MAPKAPK-2, -Hsp27, and -CREB, downstream targets of p38 MAPK. Increased activation of CREB was found to be higher in tumors that exhibit P72 phenotype. Metastatic lesions of CRC expressed more phospho-CREB than non-metastatic lesions. Furthermore, suppression of RAF/MEK/ERK activation was significantly higher in cells that express R72wt phenotype compared to cells that express P72wt or mutant phenotypes. The expression of P72wt or mutant phenotypes displayed decreased expression of E cadherin and/or an increased expression of vimentin, fibrinectin, CD44, thereby promoting CRC metastasis. Conclusions: These findings offer significant novel insights into the mechanism by which P72 contributes to the aggressiveness of CRC. Because P72 is over-expressed in CRC, specifically in African-American patients, these studies suggest a role for P72 in cancer health disparities. This work was supported by NIH/NCI Workforce Diversity Grant R21-CA171251. Citation Format: Venkat R. Katkoori, Upender Manne, Harvey Bumpers. Functional consequence of the p53 codon 72 polymorphism in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 781. doi:10.1158/1538-7445.AM2017-781

Interleukin-1β (IL-1β) -31C/T and -511T/C promoter single nucleotide polymorphism in colorectal cancer in ethnic Kashmiri population - a case control study

BackgroundChronic inflammation is a vital component of colorectal cancer pathogenesis. Interleukin-1β (IL-1β) is one of the key regulators of GIT inflammatory homeostasis and plays a vital role in several pathophysiological processes in the GIT including inflammatory bowel diseases (IBDs) (Crohn's disease and ulcerative colitis) that are associated with an increased risk of CRC. Several studies have reported the association of IL1β-31C/T and IL1β-511T/C single nucleotide polymorphisms (SNPs) in human IL-1β gene with various cancers including colorectal cancer but the association of these SNPs with CRC risk in Kashmiri population is yet to be studied. Materials and methodsThe aim of this study was to analyze the association of IL1β-31C/T and IL1β-511T/C promoter SNPs with colorectal cancer (CRC) risk in ethnic Kashmiri population through a case-control study. The genotype frequencies of IL1β-31C/T and IL1β-511T/C promoter SNPs were analyzed in 142 CRC patients and 184 individually matched healthy controls by using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. The conditional logistic regression models adjusted for multiple possible confounding (third) variables were used to study the association between the IL1β-31C/T and IL1β-511T/C SNPs and CRC risk. The effect modification of the association between the relevant SNP genotypes and CRC risk by various CRC risk factors including age, gender and smoking status was also evaluated. Further, the associations between various clinico-pathological parameters, demographic variables and environmental factors within the case group subjects and the SNPs under study in relation to CRC risk were also analyzed. ResultsThe overall association between the IL1β-31C/T and IL1β-511T/C SNPs and the modulation of CRC risk was not found to be significant (p value=0.839 and p value=0.054 respectively). Further, we found no significant effect modification of CRC risk by relevant IL1β-31C/T and IL1β-511T/C SNP genotypes in presence of different possible risk factors (p>0.05).We found no significant association between the IL1β-31C/T promoter SNP with the subsets of various characteristics of the case group subjects (p>0.05) but IL1β-511T/C SNP was significantly associated with dwelling (p=0.0419), tumor grade (p=0.028) and lymph node status (p=0.049). ConclusionThis study has demonstrated that the association between the IL1β-31C/T and IL1β-511T/C promoter SNPs and risk of CRC in ethnic Kashmiri population is not significant. However, replicating this study with larger sample size and with other ethnically defined populations with comparable CRC incidence may substantiate and elaborate our findings in a more comprehensive manner.

Biology and therapeutic implications of VEGF-A splice isoforms and single-nucleotide polymorphisms in colorectal cancer.

Tumor growth, dissemination and metastasis are dependent on angiogenesis. The predominant vascular endothelial growth factor (VEGF) isoform that plays a major role in angiogenesis is VEGF-A. Indeed, VEGF-A is implicated in promoting angiogenesis of numerous solid malignancies, including colorectal cancer (CRC). A large body of preclinical and clinical evidence indicates that the expression of specific VEGF-A isoforms represents a predominant pro-angiogenic factor, which is associated with formation of metastases and poor prognosis in CRC patients. Different isoforms of human VEGF-A have been identified, all of which arise from alternative splicing of the primary transcript of a single gene. Notably, it has been recently demonstrated that expression of type 3 isoform pattern is significantly correlated with venous involvement in CRC as well as in progression to metastatic colorectal cancer (mCRC), although it remains unclear what proportion of CRC tumors express these isoforms. This review highlights the importance of investigating the genetic and the epigenetic variations in VEGF-A pathways in CRC, the functions of different VEGF-A isoforms and their potential application as prognostic markers and/or therapeutic targets. Better understanding of the mechanisms controlling angiogenesis in liver metastases is necessary to address the limitations of current anti-angiogenic therapies.

DPYD IVS14+1 G>A Polymorphism in Colorectal Cancer in Western India

DPYD IVS14+1 G>A Polymorphism in Colorectal Cancer in Western India

MiR-146a Polymorphism (rs2910164) Predicts Colorectal Cancer Patients' Susceptibility to Liver Metastasis.

miR-146a plays important roles in cancer as it directly targets NUMB, an inhibitor of Notch signaling. miR-146a is reportedly regulated by a G>C polymorphism (SNP; rs2910164). This polymorphism affects various cancers, including colorectal cancer (CRC). However, the clinical significance of miR-146a polymorphism in CRC remains unclear. A total of 59 patients with CRC were divided into 2 groups: a CC/CG genotype (n = 32) and a GG genotype (n = 27), based on the miR-146a polymorphism. cDNA microarray analysis was performed using 59 clinical samples. Significantly enriched gene sets in each genotype were extracted using GSEA. We also investigated the association between miR-146a polymorphism and miR-146a, NUMB expression or migratory response in CRC cell lines. The CC/CG genotype was associated with significantly more synchronous liver metastasis (p = 0.007). A heat map of the two genotypes showed that the expression profiles were clearly stratified. GSEA indicated that Notch signaling and JAK/STAT3 signaling were significantly associated with the CC/CG genotype (p = 0.004 and p = 0.023, respectively). CRC cell lines with the pre-miR-146a/C revealed significantly higher miR-146a expression (p = 0.034) and higher NUMB expression and chemotactic activity. In CRC, miR-146a polymorphism is involved in liver metastasis. Identification of this polymorphism could be useful to identify patients with a high risk of liver metastasis in CRC.

Investigation of <em>cyclin D1</em> rs9344 G>A polymorphism in colorectal cancer: a meta-analysis involving 13,642 subjects

The relationship between cyclin D1 (CCND1) rs9344 G>A polymorphism and colorectal cancer (CRC) risk is still ambiguous. To obtain a precise estimation of the relationship, we performed an extensive meta-analysis based on the eligible studies. Crude odds ratios with their 95% confidence intervals were harnessed to determine the strength of correlation between CCND1 rs9344 G>A polymorphism and CRC risk under the allele, the homozygote, the dominant, and the recessive genetic models, respectively (28 studies with 5,784 CRC cases and 7,858 controls). Our results indicated evidence of the association between CCND1 rs9344 G>A polymorphism and the increased risk of CRC in four genetic models: A vs G, AA vs GG, AA+GA vs GG, and AA vs GA+GG. In a stratified analysis by cancer type of CRC, there was an increased risk of sporadic CRC found in three genetic models: A vs G, AA vs GG, and AA+GA vs GG. In a stratified analysis by ethnicity, there was an increased CRC risk found among Asians in allele comparison genetic models, as well as Caucasians in two genetic models: AA+GA vs GG and A vs T. In summary, this meta-analysis demonstrates that CCND1 rs9344 G>A polymorphism may be a risk factor for CRC.

Tumor necrosis factor-α (TNF-α)-308G/A promoter polymorphism in colorectal cancer in ethnic Kashmiri population — A case control study in a detailed perspective

BackgroundInflammation constitutes one of the important components of colorectal cancer (CRC) pathogenesis. Tumor necrosis factor-α (TNF-α), a cytokine and an important inflammatory mediator plays a pivotal role in the malignant cellular proliferation, angiogenesis, tissue invasion and metastasis in CRC. The studies on association of various polymorphisms in human TNF-α gene including TNF-α-308G/A single nucleotide polymorphism (SNP) are limited, mixed and inconclusive. Materials and methodsThe aim of this study was to analyze the association of TNF-α-308G/A promoter SNP with colorectal cancer (CRC) susceptibility and development risk and also to evaluate the modifying effects of possible TNF-α-308G/A genotypes on different risk factors of CRC in ethnic population of Kashmir, India through a case–control setup. The genotype frequencies of TNF-α-308G/A promoter SNP were compared between 142 CRC patients and 184 individually matched healthy controls by using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method. The associations between the TNF-α-308G/A SNP and CRC risk were examined through conditional logistic regression models adjusted for multiple possible confounding (third) variables. Further, the associations between this SNP and various clinico-pathological parameters, demographic variables and environmental factors within the case group subjects with regard to CRC risk were also evaluated. ResultsThe association between the TNF-α-308G/A SNP and the modulation of risk of CRC was not found to be significant (p value=0.156). The effect of less common TNF-α-308A allele on the risk of colorectal cancer was also not found to be significant (p value=0.175). The variant genotype (AA) was nonexistent in the study population. Further, we found no significant effect modulation of CRC risk by wild and heterozygous TNF-α-308G/A SNP genotypes in presence of different possible risk factors (p>0.05). We also found no significant association of TNF-α-308G/A SNP with the subsets of various characteristics of the case group subjects under study (p>0.05). ConclusionsThis study indicates that there is no significant association between the TNF-α-308G/A promoter SNP and the risk of developing CRC in ethnic Kashmiri population. However, in order to substantiate our findings, this study needs to be replicated with bigger sample size and should involve other ethnically defined populations with high CRC risk.

Matrix metalloproteinase (MMP) -2, -7 and -9 promoter polymorphisms in colorectal cancer in ethnic Kashmiri population — A case–control study and a mini review

Matrix metalloproteinases (MMPs) are proteolytic enzymes that play a pivotal role in the transformation and progression of tumors at all stages, especially during the invasion and metastasis. The aim of this study was to determine the genetic association of MMP2, MMP7 and MMP9 promoter polymorphisms with colorectal cancer (CRC) susceptibility and development risk in ethnic Kashmiri population. The genotype frequencies of MMP2-1306C/T, MMP7-181A/G and MMP9-1562C/T SNPs were compared between 142 CRC patients and 184 healthy controls by using PCR-RFLP method. The association between all the three MMP promoter polymorphisms and the modulation of risk of CRC was found to be significant (p≤0.05). The heterozygous genotype (CT) of MMP2-1306C/T SNP and variant genotype (GG) of MMP7-181A/G SNP showed a significant association with decreased risk for the development of CRC [OR, 0.61 (95%CI, 0.37-1.01); p=0.05 and OR, 0.43 (95%CI, 0.20–0.90); p=0.02, respectively] whereas the heterozygous genotype (CT) of MMP9-1562C/T SNP showed a significant association with increased risk for the development of colorectal cancer [OR, 1.88 (95%CI, 1.11-3.18); p=0.02]. Further, the less common MMP9-1562T allele was found to be significantly associated with an increased risk of colorectal cancer [OR, 1.74 (95%CI, 1.15–2.62); p=0.007]. Our results suggest that these MMP2, MMP7 and MMP9 promoter polymorphisms play a role as one of the key modulators of the risk of developing colorectal cancer in Kashmiri population.

DNA repair gene XRCC7 G6721T variant and susceptibility to colorectal cancer

BackgroundThe human XRCC7 (MIM: 600899) is a DNA double-strand break repair gene, involved in non-homologous end joining (NHEJ). Polymorphism G6721T (rs7003908) is located in the intron 8 of the XRCC7. This polymorphism may regulate splicing and cause mRNA instability. AimThe aim of the present study was to determine an association of G6721T XRCC7 polymorphism in colorectal cancer. Subjects and methodsThe study included 166 patients with colorectal cancer and 260 age and gender frequency-matched controls. The patients and controls were Iranian (Caucasian/Muslims). ResultsOur data did not demonstrate any statistically significant association between the genotypes of XRCC7 G6721T polymorphism and risk of colorectal cancer. There was a significant association between family history of cancers among their first-degree relatives (FH) and risk of colorectal cancer (OR=3.69, 95% CI: 2.19–6.23, P<0.001). We further analyzed to see if the FH influenced the association of the XRCC7 G6721T polymorphism and colorectal cancer risk. The TT genotype among positive FH persons, remarkably increased the risk of colorectal cancer (OR=6.88, 95% CI: 2.27–20.8, P=0.001). ConclusionThe present study suggests the TT genotype of the XRCC7 G6721T polymorphism might be a risk factor for the development of colorectal cancer among persons with positive FH.

Genetic polymorphisms of the human cytomegalovirus UL144 gene in colorectal cancer and its association with clinical outcome.

Human cytomegalovirus (HCMV) has been increasingly detected in colorectal cancer (CRC), and genetic polymorphisms in HCMV affect its pathogenesis. This study aimed to investigate HCMV genetic polymorphisms in CRC and its correlation with the clinical outcomes. We performed PCR and sequencing of a viral immunomodulatory gene, UL144, in clinical isolates and CRC specimens. The nucleotide and amino acid sequences were aligned, and a phylogenetic tree was constructed. The clinical, pathological and survival data were compared among tumours with different UL144 genotypes. HCMV was detected in 49 (47.8 %) of the tumour specimens. Genotype A predominated in 43 samples (22/43; 51.2 %) with successful sequencing, followed by genotype B (13/43; 30.2 %) and genotype C (8/43; 18.6 %). The genotypic distribution was similar to that of the clinical isolates and those reported in other Asian populations. The amino acid sequence of genotype B was the most conserved. For stage II and III CRC patients with HCMV-positive tumours, disease-free survival (DFS) varied among the three major genotypes (P50.0046). The presence of genotype B virus in the tumours was associated with a shorter DFS and independently predicted tumour recurrence in a multivariate Cox proportional hazards model (hazard ratio, 5.79; 95 % confidence interval, 1.30–25.81; P50.021). By reverse transcription PCR, tumour samples with genotype B viruses had the highest rate of UL144 expression. Our results suggest that genetic polymorphisms of HCMV UL144 are associated with clinical outcome in CRC and that HCMV may play an immunomodulatory role in the tumour microenvironment of CRC.

Molecular and pathological characterization of the EZH2 rs3757441 single nucleotide polymorphism in colorectal cancer

BackgroundThe enhancer of zeste-homolog 2 (EZH2) is involved in cancer development through gene silencing by trimethylation of lysine 27 of histone 3 (H3K27me3). The C/C genotype for the EZH2 rs3757441 single-nucleotide polymorphism (SNP) is linked with poor prognosis in metastatic colorectal cancer (CRC), but molecular and pathological characterization of this SNP is lacking.Methods119 primary CRCs were analyzed. SNP was evaluated by real-time PCR from colonic healthy tissue, while EZH2 and H3K27me3 expression were studied by immunohistochemistry. We primarily looked for correlation between EZH2 rs3757441 genotypes and EZH2/H3K27me3 expression. Potential associations between EZH2/H3K27me3 expression and clinico-pathological features or KRAS exon 2 and BRAF exon 15 mutations were secondary endpoints. Statistical analysis was performed by chi-square test, T-test or ANOVA.ResultsThe C/C genotype was significantly associated with higher EZH2 (100 vs. 44 %; P = 0.019) and H3K27me3 (100 vs. 38 %; P = 0.009) staining intensity compared with C/T and T/T. EZH2 3+ staining significantly correlated with stronger H3K27me3 expression (P = 0.039). KRAS and BRAF mutations were not associated with EZH2 or H3K27me3 expression.ConclusionEZH2 rs3757441 C/C genotype is associated with stronger EZH2 and H3K27me3 immunoreactivity in primary CRC: this SNP may serve as a promising biomarker for EZH2-targeting agents and may add independent information to KRAS and BRAF testing.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1889-2) contains supplementary material, which is available to authorized users.

The Relationship Between Killer Cell Immunoglobulin-Like Receptors and HLA-C Polymorphisms in Colorectal Cancer in a Saudi Population.

We performed an association study to evaluate the contribution of 16 killer cell immunoglobulin-like receptor (KIR) genotype polymorphisms and the HLA-C1 and -C2 ligands in the development of colorectal cancer (CRC) in Saudi Arabian patients. A total of 52 patients with different stages of malignant CRC as well as 70 healthy Saudi controls were enrolled at the King Khalid University Hospital. Our results showed that the frequency of the activating mutations KIR2DS1, 2DS2, 2DS3, 2DS5, and 3DS1 was significantly higher in CRC patients compared to controls. The 3DS1 gene contributed to the highest risk of CRC (odds ratio [OR] = 16.25, p < 0.0001), followed by 2DS1 (OR = 8.6; p < 0.0001). The distributions of HLA-C1 and -C2 ligands were not significantly different between patients and controls. Analyses of different combinations of KIR genes with their HLA-C1 and -C2 ligands show that the frequency of 2DL3 in the presence of its ligand, the allotype C1, was significantly more prevalent in patients compared to controls. In addition, 2DL2 and 2DL3 that were aggregated in combination with the ligand, HLA-C1, were found to be more highly associated mainly with the homozygote HLA-C1/C1 (p = 0.03; OR = 2.6). The activating mutations 2DS1 and 2DS2 when combined with their respective ligands, HLA-C2 and -C1, showed highly significant associations with CRC development. This study supports a key role for KIR gene mutations in the development of CRC, especially in association with their ligands.

Evaluation of association studies and meta-analyses of MTHFR gene polymorphisms in colorectal cancer.

There is a discrepancy between the results of 89 original studies and 15 meta-analyses investigating the association of MTHFR rs1801133 and rs1801131 polymorphisms with colorectal cancer (CRC) risk. We examined this hypothesis through meta-analyses of both loci and their diplotypes as well as evaluation of previous meta-analyses. The present meta-analysis showed that rs1801133 and rs1801131 might be CRC susceptibility variants in Americans and Australians and rs1801133 in Brazilians and Japanese. A strong linkage disequilibrium was observed between both loci and their diplotypes were associated with CRC risk. Evaluation of 15 meta-analyses showed a high discrepancy among their findings, mainly caused by population stratification of original studies and data analysis strategies in meta-analysis. Population stratification was more dominant in the studies from Australia, America and Brazil leading to false positive or negative results. In conclusion, these loci alone might modify the development of CRC in some ethnicities.

Associations of the A66G Methionine Synthase Reductase Polymorphism in Colorectal Cancer: A Systematic Review and Meta-Analysis.

Inconsistency in the reported associations between the A66G polymorphism in the methionine synthase reductase (MTRR) gene and colorectal cancer (CRC) prompted a meta-analysis, so that we could obtain a more precise estimate. Databases searches of the published literature yielded 20 case–control studies from 17 articles (8,371 cases and 12,574 controls). We calculated pooled odds ratios (ORs) and 95% confidence intervals in three genetic comparisons (A allele, G allele, and A/G genotype). We found no evidence of overall associations between MTRR A66G and CRC risk (OR 0.96–1.05, P = 0.12–0.44). This was materially unchanged when reanalyzed without the Hardy–Weinberg equilibrium (HWE)-deviating studies (OR 0.97–1.06, P = 0.11–0.65). In the A allele comparison, however, outlier treatment generated significant protection (OR 0.91, P = 0.01). Combined removal of the outliers and HWE-deviating studies reflected this summary effect (OR 0.90, P = 0.01) as did the pooled OR from high-quality studies (OR 0.90, P = 0.01). Only the Asian subgroup showed significant (both at P = 0.05) A allele (OR 1.13) and A/G genotype (OR 0.88) associations. In conclusion, post-outlier A allele effects were protective. Our study also suggests ethnic-specific associations with Asian susceptibility and protection in the A allele and A/G genotype comparisons, respectively. Folate status showed no association of this polymorphism with CRC.

A case-control study of CYP2E1 (PstI) and CYP1A1 (MspI) polymorphisms in colorectal cancer.

Polymorphisms in genes encoding P450 cytochrome enzymes may increase the risk of sporadic colorectal cancer (SCRC). Here we investigated the association between SCRC and CYP2E1 (PstI) and CYP1A1 (MspI) polymorphisms in a case-control study. Moreover, we sought to determine any possible associations between this disease and the sociodemographic factors. We included 273 individuals (74 patients and 199 controls); the gender, age, tobacco usage, and alcohol consumption of the included subjects, and the clinico-histopathological parameters of the tumors, were analyzed. Molecular analyses were performed using PCR-RFLP. The effect of polymorphisms on SCRC development, and the association between this disease and sociodemographic factors were determined by multiple-logistic regression analyses. The combined genotype was also evaluated. Statistically significant differences between the patients and controls regarding the male gender (odds ratio, OR = 0.19, 95% confidence interval, CI = 0.08-0.46; P ≤ 0.05) and age ≥44 years (median = 44; OR = 96.84, 95%CI = 21.78-430.49; P ≤ 0.05) were observed. The evaluated polymorphisms were not associated with SCRC (PstI-CYP2E1: OR = 0.93, 95%CI = 0.30-2.85; P = 0.897; MspI-CYP1A1: OR = 0.75, 95%CI = 0.35-1.61; P = 0.463); the combined genotypes were not associated with the risk of disease. Thus, individuals aged ≥44 years are more sensitive to SCRC, while men are less susceptible. Additionally, polymorphisms in CYP2E1 (PstI) and CYP1A1 (MspI) were not associated with SCRC in the evaluated Brazilian population.

XRCC3 Thr241Met gene polymorphism and risk of colorectal cancer in Kashmir: a case control study.

XRCC (X-ray cross-complementing group) genes contribute to important DNA repair mechanisms that play roles in the repair of single strand breaks (SSBs) induced by a variety of external and internal factors, including ionizing radiation, alkylating agents and reactive oxygen species. These repair genes have a pivotal role in maintaining genomic stability through different pathways of base excision repair (BER). The aim of this study was to investigate the XRCC3 Thr241Met gene polymorphism in colorectal cancer (CRC) in Kashmir. We investigated the genotype distribution of XRCC3 gene in 120 CRC cases in comparison with 150 healthy subjects and found a significant association between XRCC3 genotypes and CRC (p≤0.05). Both heterozygous genotype (Thr/Met) as well as homozygous variant genotype (Met/Met) were moderately associated with elevated risk of CRC [OR=2.53; OR=2.29 respectively]. Also, Thr/Met and Met/Met genotypes demonstrated a significant association with the risk of CRC (p=0.003). This study displayed a significantly elevated risk for CRC in individuals with XRCC3 Thr/Met and Met/Met Genotype of about 2.5 times that with the Thr/Thr wild genotype.

CRP 1059 G/C and 1846G/A polymorphisms and cancer risk: A meta-analysis of 26,634 subjects

Previous studies have shown that C-reactive protein (CRP) 1059G/C and 1846G/A polymorphisms may play a role in cancer risk. However, the results from the published studies are conflicting. To derive a more precise estimation of the relationship between CRP 1059G/C and 1846G/A polymorphisms and cancer risk, we conducted a meta-analysis of 21 studies involving a total of 26,634 subjects. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the strength of the association. No significant association was found between CRP 1846G/A polymorphism and cancer risk. However, a significant association was found between CRP 1059G/C polymorphism and cancer risk (CC vs CG+GG: OR=3.60, 95% CI=1.63-7.92, PH=0.67; CC vs GG: OR=3.53, 95% CI=1.60-7.77, PH=0.69). In the subgroup analysis by ethnicity, a significant association was found for the CRP 1846G/A polymorphism among mixed population. Interestingly, when stratifying by cancer type, marginally increased risks were observed for CRP 1846G/A polymorphism in colorectal cancer (AA vs AG+GG: OR=1.17, 95% CI=1.00-1.36, PH=0.27) and significantly decreased risks were found for CRP 1846G/A polymorphism in breast cancer (AA vs GG: OR=0.73, 95% CI=0.56-0.95, PH=0.93; A vs G: OR=0.88, 95% CI=0.79-0.99, PH=0.54). For 1059G/C polymorphism, a significant association was found in colorectal cancer. This meta-analysis showed the evidence that CRP 1059G/C and 1846G/A polymorphisms were risk factors for the development of colorectal cancer, and CRP 1846G/A polymorphism is also a protective factor for decreasing breast cancer.

A-Kinase Anchoring Proteins 10 Expression in Relation to 2073A/G Polymorphism and Tumor Progression in Patients with Colorectal Cancer

The cAMP/PKA signalling events regulated by A-kinase anchoring proteins 10 (AKAP10) is involved in tumorigenesis. Previous study showed that AKAP10 polymorphism (2073 A/G, I646V) was associated with colorectal cancer risk. However, there was no literature reporting the role of AKAP10 in the pathogenesis of colorectal cancer. The aim of the study was to investigate the clinicopathologic significance of A-kinase anchoring proteins 10 (AKAP 10) expression and the relationship with its polymorphism in colorectal cancer. The expression of AKAP10 was determined by immunohistochemical staining (IHC) and western blot assay on colorectal cancer (n = 176), adenoma (n = 87) and distant normal mucosa (n = 72). 176 patients with colorectal cancer were genotyped for AKAP10 2073A/G polymorphism by TaqMan RT-PCR. We found that the positive expression rate of AKAP10 in colorectal cancer (59%) was significantly higher than those in adenoma (39%) and distant normal mucosa (42%) (P = 0.004). There was no significant difference between adenoma and distant normal mucosa (P = 0.741). Positive AKAP10 staining was correlated with deeper tumor invasion (P < 0.001), lymph nodes metastasis (P = 0.022), advanced tumor stage (P < 0.001) and poorly differentiated degree (P = 0.003). Compared with AA genotype (52%), positive expression of AKAP10 was significantly increased in colorectal cancer patients with the variant (AG+GG) genotypes (68%, P = 0.033). It was concluded that AKAP10 may play an important role in the development and progression of colorectal cancer.

Impact of the MTHFR C677T polymorphism on colorectal cancer in a population with low genetic variability

Methylenetetrahydrofolate reductase (MTHFR) plays a key role in folate metabolism, and folate is implicated in carcinogenesis by its role in DNA methylation, repair, and synthesis. We analyzed the impact of MTHFR C677T polymorphism in colorectal cancer in a region of the Tenerife Island whose population has a history of genetic isolation and a low genetic variability. This allows analyzing the effects of the polymorphism that are not due to interactions with different genetic variants. Genomic DNA of 50 Spanish sporadic colorectal cancer (CRC) patients and 103 controls was analyzed by PCR/RFLP and sequencing. The T allele is more frequent in controls than in patients (P < 0.01). The variant (T) carriers displayed significant odds ratio values for the CT heterozygotes (P = 0.026) and even when grouping heterozygote (CT) and homozygotes (TT) (P = 0.015). Patients carriers of the variant T (CT y TT) show a higher survival rate after chemotherapy than the CC homozygotes (log rank; P = 0.001). The MTHRF C677T variant has a protective effect on CRC development in a population with low allelic variability and an optimal intake of folic acid. Moreover, patients carrying the variant (T) show a better prognosis after 5-fluorouracil/folinic acid-based chemotherapy.

Lack of association between the interleukin 6 gene -174G&gt;C polymorphism and colorectal cancer: evidence from a meta-analysis

Interleukin 6 (IL6) is a pleiotropic cytokine involved in physiological processes and in a variety of human malignancies. It is thus a logical candidate for being a causative factor underlying colorectal cancer (CRC). The association between the IL6 -174G>C polymorphism and CRC has been widely evaluated; yet, there is a lack of agreement between studies on the role of this polymorphism in CRC. We performed a meta-analysis to evaluate this association signal. Articles published before May 10, 2012 were included in the meta-analysis. A total of 11 populations incorporating 6481 cases and 7935 controls were included in our analysis. A random-effect model was applied irrespective of between-study heterogeneity. Data and study quality were assessed in duplicate. Overall, the association of the -174G>C polymorphism with CRC was not significant in an allelic comparison model [odds ratio (OR) = 0.99; 95% confidence interval (95%CI) = 0.90-1.09; P = 0.827], a homozygote model (OR = 0.98; 95%CI = 0.83-1.15; P = 0.805), a dominant model (OR = 0.99; 95%CI = 0.87-1.13; P = 0.906), or a recessive model (OR = 0.97; 95%CI = 0.88-1.08; P = 0.610). Furthermore, the analyses of subgroups created based on common study design, genotyping methods, and ethnicity failed to find a significant association of this polymorphism with CRC. Therefore, our results collectively suggest that the IL6 -174G>C polymorphism might not be a potential candidate for CRC risk.