Colorectal Cancer Susceptibility Research Articles

The association between SMAD7 polymorphisms and colorectal cancer susceptibility as well as clinicopathological features in the Iranian population.

Our aim was to investigate the association between two single nucleotide polymorphisms (SNPs) of SMAD7 and the risk of CRC among Iranian individuals. Genome-wide association studies (GWAS) have identified 18q21 as a risk locus for colorectal cancer (CRC), which maps to the SMAD7 gene. This case-control study was conducted on 109 CRC cases and 109 controls in the Iranian population to evaluate the influence of two SNPs of SMAD7, rs2337106 and rs6507874, on the risk of CRC as well as on clinicopathological features. Genotype determination was performed by TaqMan assay via an ABI 7500 Real Time PCR System (Applied Biosystems) for the DNA of peripheral blood. Descriptive analysis and logistic regression model were used for statistical analyses. Genotyping of the SNPs in the SMAD7 gene revealed that the frequency of G allele of rs2337106 was 53.7% in controls and 56.4% in cases (p-value=0.564) while the frequency of C allele of rs6507874 was 55.5% in controls and 56.3% in cases (p-value=0.772). Further, there were no significant differences in genotype frequencies of these SNPs between CRC patients and controls. The SMAD7 genotypes were not associated with the risk of CRC or with any clinicopathological characteristics such as tumor site, tumor grade, and stage TNM in CRC patients (p-value>0.05), even after adjustment for sex, age, and smoking status. Our results provided the first evidence that SMAD7 genotypes, rs2337106 and rs6507874, could not be predisposing markers in genetic susceptibility to CRC in an Iranian population, at least in the studied population.

Genetic Fine Mapping and Genomic Annotation Defines Causal Mechanisms at A Novel Colorectal Cancer Susceptibility Locus in Han Chinese.

Genome-wide association studies of colorectal cancer (CRC) have identified two risk SNPs. The characterization of these risk regions in diverse racial groups with different linkage disequilibrium structure would aid in localizing the causal variants. Herein, fine mapping of the established CRC loci was carried out in 1,508 cases and 1,482 controls obtained from the Han Chinese population. One distinct association signal was identified at these loci, where fine mapping implicated rs1010208 as a functional locus. Next, the candidate target genes of functional SNP rs1010208 were analyzed using data from TCGA databases by expression quantitative trait loci analysis method; the data from Peking University People's Hospital were utilized for verification. The dual-luciferase reporter system analysis confirmed that rs1010208 is a regulatory region that can be mutated to decrease the expression of HINT1, resulting in proliferation and invasiveness of CRC.

Molecular Basis of Inherited Colorectal Carcinomas in the Macedonian Population: An Update.

Hereditary factors are assumed to play a role in ~35.0-45.0% of all colorectal cancers (CRCs) with about 5.0-10.0% associated with high penetrant disease-causing mutations in genes correlated to hereditary polyposis (HP) or hereditary non polyposis syndromes (HNPCC). Although inherited germline mutations in mismatch repair (MMR) and the APC genes contribute significantly to CRC, genetic diagnosis cannot yet be obtained in more than 50.0% of familial cases. We present updated data of 107 probands from the Macedonian population with clinically diagnosed HP (n = 41) or HNPCC (n = 66) obtained by next generation sequencing (NGS) with three different gene panels covering the coding, flanking and promoter regions of 114 cancer predisposition genes. Using this approach, we were able to detect deleterious mutations in 65/107 (60.7%) patients, 50.4% of which were in known well-established CRC susceptibility genes and 10.2% in DNA repair genes (DRG). As expected, the highest frequencies of deleterious variants were detected in familial adenomatous polyposis (FAP) and in HNPCC patients with microsatellite instability (MSI) tumors (93.8 and 87.1%, respectively). Variants of unknown significance (VUS) were detected in 24/107 (22.4%) patients, mainly in HNPCC patients with microsatellite stable (MSS) tumors or patients with oligopolyposis. The majority of VUS were also found in DRG genes, indicating the potential role of a doble-strand brake DNA repair pathway deficiency in colorectal cancerogenesis. We could not detect any variant in 18/107 (16.8%) patients, which supports the genetic heterogeneity of hereditary CRC, particularly in HNPCC families with MSS tumors and in families with oligopolyposis.

Single nucleotide polymorphisms associated with susceptibility for development of colorectal cancer: Case-control study in a Basque population.

Given the significant population diversity in genetic variation, we aimed to investigate whether single nucleotide polymorphisms (SNPs) previously identified in studies of colorectal cancer (CRC) susceptibility were also relevant to the population of the Basque Country (North of Spain). We genotyped 230 CRC cases and 230 healthy controls for 48 previously reported CRC-susceptibility SNPs. Only the rs6687758 in DUPS10 exhibited a statistically significant association with CRC risk based on the crude analysis. The rs6687758 AG genotype conferred about 2.13-fold increased risk for CRC compared to the AA genotype. Moreover, we found significant associations in cases between smoking status, physical activity, and the rs6687758 SNP. The results of a Genetic Risk Score (GRS) showed that the risk alleles were more frequent in cases than controls and the score was associated with CRC in crude analysis. In conclusion, we have confirmed a CRC susceptibility locus and the existence of associations between modifiable factors and the rs6687758 SNP; moreover, the GRS was associated with CRC. However, further experimental validations are needed to establish the role of this SNP, the function of the gene identified, as well as the contribution of the interaction between environmental factors and this locusto the risk of CRC.

Genetic variants in circTUBB interacting with smoking can enhance colorectal cancer risk.

Circular RNAs (circRNAs) are an intriguing class of regulatory RNAs involved in the tumorigenesis of many cancers, including colorectal cancer. Mechanistically, circRNAs sponge microRNAs (miRNAs) with specific miRNA response elements (MREs) and compete for regulatory target genes downstream. However, the genetic effects of MREs on colorectal cancer susceptibility remain unclear. The MREs of colorectal cancer-associated circRNAs (CRC-circRNAs) and corresponding single nucleotide polymorphisms (SNPs) were identified by the transcriptome of cancer cells and the 1000 Genomes Project. The association between candidate SNPs and colorectal cancer risk was evaluated in a Chinese population (1150 cases and 1342 controls) and two European populations (9023 cases and 386,896 controls) using logistic regression analysis. Among the 197 candidate SNPs within MREs of 186 CRC-circRNAs, rs25497 in circTUBB was significantly associated with colorectal cancer risk in a Chinese population after false discovery rate (FDR) correction [odds ratio (OR)=1.78, 95% confidence interval (CI)=1.44-2.21, P = 1.42 × 10-7, PFDR = 2.80 × 10-5] and even reached significance in a genome-wide association study (GWAS) under the dominant model (P = 1.28 × 10-8). Similar results were found in the European populations (ORmeta=1.30, 95% CI=1.10-1.53). Both stratification and interaction analyses revealed that rs25497 interacting with smoking affected the colorectal cancer risk (Pinteraction = 1.48 × 10-2). Here, we first comprehensively identified genetic variants in MREs of CRC-circRNAs and evaluated their effects on colorectal cancer risk in both Chinese and European populations. These findings provide basis for a comprehensive understanding of colorectal cancer etiology.

Polymorphisms of a novel long non-coding RNA RP11-108K3.2 with colorectal cancer susceptibility and their effects on its expression.

RP11-108K3.2 was recently identified as a novel long non-coding RNA (lncRNA) transcript, and several single nucleotide polymorphisms (SNPs) have been identified in its coding region. This study aimed to explore the associations of tagSNPs in RP11-108K3.2 with the risk of colorectal cancer and their effects on its expression. A total of 821 colorectal cancer cases and 857 healthy controls were enrolled into this two-stage case-control study. Demographic characteristics and lifestyle information were collected by a validated questionnaire. Six tagSNPs were genotyped by using Sequenom MassARRAY platform. A total of 71 additional colorectal cancer cases were recruited, of which the genotypes of potential polymorphisms and the RP11-108K3.2 expression levels were determined. In the discovery set, only the rs2470151 C/T polymorphism was found to have a promising association with the risk of colorectal cancer, and this polymorphism was further replicated in the validation set with a significantly decreased risk of colorectal cancer (adjusted odds ratio 0.73; 95% confidence interval 0.55, 0.97). Combined discovery set and validation set together, this negative association was found both in the heterozygote codominant model and the dominant model. Furthermore, colorectal cancer patients carrying rs2470151 CT/TT genotypes had a marginally lower RNA expression of RP11-108K3.2 than those carrying the CC genotype. Stratified analyses showed the association between rs2470151 and the risk of colorectal cancer were influenced by family history of cancer, smoking, alcohol consumption, and tea drinking. These findings suggest that RP11-108K3.2 rs2470151 had a significant association with the risk of colorectal cancer; this may help to predict the susceptibility of colorectal cancer in Chinese populations.

Evaluation of gene-environment interactions for colorectal cancer susceptibility loci using case-only and case-control designs

BackgroundGenome-wide association studies (GWAS) have identified more than 40 colorectal cancer susceptibility loci, but only a small fraction of heritability was explained. To account for missing heritability, we investigated gene-environment interactions (G × Es) between GWAS-identified single-nucleotide polymorphisms (SNPs) and established risk or protective factors for colorectal cancer using both case-only and case-control study designs.MethodsData on 703 colorectal cancer cases and 1406 healthy controls from the National Cancer Center in Korea were used. We tested interactions between 31 GWAS-identified SNPs and 13 established risk or protective factors for colorectal cancer (family history, body mass index, history of colorectal polyps, inflammatory bowel disease, and diabetes mellitus, alcohol drinking, smoking, regular exercise, regular aspirin use, postmenopausal hormone replace therapy, red meat and processed meat intake, and dairy consumption). Logistic regression models were used to assess G × Es for colorectal cancer risk.ResultsThe SNP rs4444235 at 14q22.2 interacted with regular exercise in colorectal cancer (pcase-only = 2.4 × 10− 3, pcase-control = 1.5 × 10− 3). The risk allele (C) of rs4444235 increased the risk of colorectal cancer in regularly exercising individuals (OR = 1.47, 95% CI = 1.02–2.10) but decreased the risk in non-exercising individuals (OR = 0.76, 95% CI = 0.62–0.94). Furthermore, the G × E between the SNP rs2423279 at 20p12.3 and regular aspirin use was statistically significant (pcase-only = 7.7 × 10− 3, pcase-control = 1.6 × 10− 3). The additive effect of the risk allele (T) of rs2423279 on colorectal cancer risk was increased among regular aspirin users (OR = 4.62, 95% CI = 1.97–10.80).ConclusionOur results suggest that SNP rs4444235 at 14q22.2 and SNP rs2423279 at 20p12.3 may interact with regular exercise and aspirin use in colorectal carcinogenesis.

Inactivation of Interferon Regulatory Factor 1 Causes Susceptibility to Colitis-Associated Colorectal Cancer

The mechanisms linking chronic inflammation of the gut (IBD) and increased colorectal cancer susceptibility are poorly understood. IBD risk is influenced by genetic factors, including the IBD5 locus (human 5q31), that harbors the IRF1 gene. A cause-to-effect relationship between chronic inflammation and colorectal cancer, and a possible role of IRF1 were studied in Irf1-/- mice in a model of colitis-associated colorectal cancer (CA-CRC) induced by azoxymethane and dextran sulfate. Loss of Irf1 causes hyper-susceptibility to CA-CRC, with early onset and increased number of tumors leading to rapid lethality. Transcript profiling (RNA-seq) and immunostaining of colons shows heightened inflammation and enhanced enterocyte proliferation in Irf1−/− mutants, prior to appearance of tumors. Considerable infiltration of leukocytes is seen in Irf1−/− colons at this early stage, and is composed primarily of proinflammatory Gr1+ Cd11b+ myeloid cells and other granulocytes, as well as CD4+ lymphoid cells. Differential susceptibility to CA-CRC of Irf1−/− vs. B6 controls is fully transferable through hematopoietic cells as observed in bone marrow chimera studies. Transcript signatures seen in Irf1−/− mice in response to AOM/DSS are enriched in clinical specimens from patients with IBD and with colorectal cancer. In addition, IRF1 expression in the colon is significantly decreased in late stage colorectal cancer (stages 3, 4) and is associated with poorer prognosis. This suggests that partial or complete loss of IRF1 expression alters the type, number, and function of immune cells in situ during chronic inflammation, possibly via the creation of a tumor-promoting environment.

KRAS SNPs are related to colorectal cancer susceptibility and survival in Chinese people.

Aim:KRAS SNPs may increase KRAS transcription and KRAS levels. SNPs of KRAS 3'UTR can affect carcinoma risk and prognosis. Materials & methods: The rs8720 and rs7960917 in KRAS 3'UTR for colorectal carcinoma (CRC) risk and survival were investigated in a case-control study. Association between SNPs and CRC risk, survival analysis were analyzed by an unconditional logistic regression model, log-rank test, Kaplan-Meier estimation, Cox regression model and one-way analysis of variance. Results & conclusion: The genotype CT of rs8720 was significantly increased risk of CRC, decreased overall survival and event-free survival, and KRAS mRNA and protein expressions were significantly increased in individuals with rs8720 CT, TT genotype. rs8720 may be an important factor in CRC development and prognosis.

Comprehensive analysis of colorectal cancer-risk loci and survival outcome: A prognostic role for CDH1 variants

PurposeGenome-wide association studies have identified common single nucleotide polymorphisms (SNPs) at 83 loci associated with colorectal cancer (CRC) risk in European populations. Because germline variation can also influence patient outcome, we studied the relationship between these SNPs and CRC survivorship. Experimental designFor the 83 risk loci, 10 lead SNPs were directly genotyped, 72 were imputed and 1 was not genotyped nor imputed, in 1948 unrelated patients with advanced CRC from the clinical trials COIN and COIN–B (oxaliplatin and fluoropyrimidine chemotherapy ± cetuximab). A Cox survival model was used for each variant, and variants classified by pathway, adjusting for known prognostic factors. We imposed a Bonferroni threshold of P = 6.6 × 10−4 for multiple testing. We carried out meta-analyses of published risk SNPs associated with survival. ResultsUnivariate analysis identified six SNPs associated with overall survival (OS) (P < 0.05); however, only rs9939049 in CDH1 remained significant beyond the Bonferroni threshold (Hazard Ratio [HR] 1.44, 95% Confidence Intervals [CI]: 1.21–1.71, P = 5.0 × 10−5). Fine mapping showed that rs12597188 was the most significant SNP at this locus and remained significant after adjustment for known prognostic factors beyond multiple testing thresholds (HR 1.23, 95% CI: 1.13–1.34, P = 1.9 × 10−6). rs12597188 was also associated with poor response to therapy (OR 0.61, 95% CI: 0.42–0.87, P = 6.6 × 10−3). No combinations of SNPs within pathways were more significantly associated with survival compared with single variants alone, and no other risk SNPs were associated with survival in meta-analyses. ConclusionsThe CRC susceptibility SNP rs9939049 in CDH1 influences patient survival and warrants further evaluation as a prognostic biomarker.

Association of CD44 gene rs187115 polymorphism with colorectal cancer risk and prognosis in Chinese Han population: a case-control study.

The cell surface adhesion receptor CD44 reportedly affects the development and progression of cancers. Moreover, CD44 gene rs187115 polymorphism appears to be genetic determinant of cancer susceptibility. We investigated whether CD44 rs187115 polymorphism is associated with colorectal cancer (CRC) risk and prognosis. We enrolled 669 CRC cases and 826 controls in this three-center case-control study in a Chinese Han population. All individuals were genotyped by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Cross-over analysis, multivariate logistic regression, Kaplan-Meier method, and Cox regression analysis were used for analysis. In this study, CD44 rs187115 polymorphism was associated with increased risk for CRC. Stratified analyses revealed that CD44 rs187115 polymorphism was correlated with increased risk for CRC in females, drinkers, smokers, and those aged ≥ 60 years. In addition, rs187115 polymorphism was significantly associated with TNM III+IV stage, lymph node metastasis and tumor size in CRC patients. Combined effects of CD44 rs187115 polymorphism (GG/AG vs. AA) and environmental factors (smoking and drinking) further increased the risk of CRC. GG genotype carriers showed poorer overall survival than AA genotype carriers. Cox regression analysis showed that drinking, CD44 rs187115 polymorphism, and TNM stage were independent prognostic factors affecting CRC. These findings show that CD44 rs187115 polymorphism may be a potential biomarker predictive of CRC susceptibility and prognosis.

Genetic Variants in CircTUBB Interacting Smoking Enhance Colorectal Cancer Risk

Background: Circular RNAs (circRNAs) are an intriguing class of regulatory RNAs involved in the tumorigenesis of many cancers, including colorectal cancer. Mechanistically, circRNAs sponge microRNAs (miRNAs) with specific miRNA response elements (MREs) and compete for regulatory target genes downstream. However, the genetic effects of MREs on colorectal cancer susceptibility remain unclear. Methods: The MREs of colorectal cancer-specific circRNAs (CRC-circRNAs) and corresponding single nucleotide polymorphisms (SNPs) were identified by the transcriptome of cancer cells and the 1000 Genomes Project. The association between candidate SNPs and colorectal cancer risk was evaluated in a Chinese population (1,150 cases and 1,342 controls) and two European populations (9,023 cases and 386,896 controls) using logistic regression analysis. Findings: Among the 197 candidate SNPs within MREs of 186 CRC-circRNAs, rs25497 in circTUBB was significantly associated with colorectal cancer risk in a Chinese population after false discovery rate (FDR) correction [odds ratio (OR) = 1.78, 95% confidence interval (CI) = 1.44-2.21, P = 1.42×10-7, PFDR = 2.80×10-5] and even reached significance in a genomewide association study (GWAS) under the dominant model (P = 1.28×10-8). Similar results were found in the European populations (ORmeta = 1.30, 95% CI = 1.10-1.53). Both stratified and interaction analyses revealed that rs25497 interacting with smoking affected the colorectal cancer risk (Pinteraction = 1.48×10-2). Interpretation: We first comprehensively identified genetic variants in MREs of colorectal cancer-associated circRNAs (CRC-circRNAs) and evaluated their effects on colorectal cancer risk in both Chinese and European populations. These findings provide basis for comprehensive understanding of colorectal cancer etiology. Funding Statement: This study was partly supported by National Natural Science Foundation of China (81703307, 21575064) and the Natural Science Foundation of Jiangsu Province (BK20181371) and the project of National Key Research and Development Plan of China (2017YFC1309201). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: This study was approved by the Institutional Review Board of Nanjing Medical University.

LncRNA-PCAT1 rs2632159 polymorphism could be a biomarker for colorectal cancer susceptibility.

Background: Single-nucleotide polymorphisms (SNPs) in lncRNAs could be biomarkers for susceptibility to colorectal cancer (CRC), but the association of PCAT1 polymorphisms and CRC susceptibility is yet to be studied. Methods: Five tagSNPs covering the PCAT1 gene were detected through Kompetitive Allele-Specific PCR among 436 CRC patients and 510 controls. An expression quantitative trait locus (eQTL) bioinformatic analysis was then performed. Results: In the present study, PCAT1 rs2632159 polymorphism increased CRC risk by 1.37-fold and 2.19-fold in the dominant and recessive models, respectively (P=0.040 and 0.041). When the CRC cases were divided into colon cancer and rectal cancer, we found that this polymorphism affected colon cancer risk under the dominant model (P=0.022, OR = 1.51) and affected rectal cancer susceptibility under the recessive model (P=0.009, OR = 3.03). A more pronounced effect was observed in the male subgroup in that PCAT1 rs2632159 SNP increased rectal cancer risk by 3.97-fold (P=0.017). When PCAT1 rs2632159 was present, epistatic effects were observed with rs1902432 and rs785005 (P=0.011 and 0.008, respectively). eQTL analysis showed that rs2632159 could influence binding with the transcription factors EBF, LUN-1, and TCF12. Conclusion: PCAT1 rs2632159 SNP could be a biomarker for CRC risk. And the rs1902432 SNP might only have potential to be a biomarker for colon cancer risk.

Evaluation of the association between P53 codon 72 and P21 codon 31genetic polymorphisms within gastric and colorectal cancer risk in a Moroccan Cohort

AimThe aim of the current study was to explore the association between the p53 (Arg > Pro) (rs1042522) and p21 (Ser > Arg) (rs1801270) polymorphisms and gastric and colorectal cancers susceptibility among Moroccan population. MethodsThis case control study was conducted on 70 gastric cancer, 70 colorectal cancer patients and 70 healthy patients. The p53 (Arg > Pro) and p21 (Ser > Arg) polymorphisms were analyzed by polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) assay. ResultsFor the P53 codon 72 the genotype frequencies were 27.1% for Arg/Arg, 65,7% for Arg/Pro and 7,1% for Pro/Pro in control group, and 40%; 17,1% for Arg/Arg, 34.3%; 42,9% for Arg/Pro and 25,7%; 40% for Pro/Pro respectively in the gastric and colorectal cancer patients. Genotype frequencies of the p21 codon 31 were 17.1% for Arg/Arg, 71.4% for Ser/Arg and 11.4% for Ser/Ser in control group, and 22.9%; 25.7% for Arg/Arg, 35.7%; 41.4% and 41.4%; 32.9% for Ser/Ser respectively in the patient with gastric and colorectal cancer. This difference was statistically significant for the Pro/Pro genotype. The same trend as observed in the Pro allele distribution for colorectal cancer patients (P = 0.0004). No statistically significant correlation was found between p21 (Ser > Arg) and the development of gastric and colorectal cancers. ConclusionOur results have demonstrated that the P53 (rs1042522) polymorphism may contribute to the risk of colorectal cancer development while the P21 (rs1801270) polymorphism does not contribute to this susceptibility for both cancers in the Moroccan population.

Determining the clinical validity of hereditary colorectal cancer and polyposis susceptibility genes using the Clinical Genome Resource Clinical Validity Framework

PurposeGene–disease associations implicated in hereditary colorectal cancer and polyposis susceptibility were evaluated using the ClinGen Clinical Validity framework. MethodsForty-two gene–disease pairs were assessed for strength of evidence supporting an association with hereditary colorectal cancer and/or polyposis. Genetic and experimental evidence supporting each gene–disease relationship was curated independently by two trained biocurators. Evidence was reviewed with experts and assigned a final clinical validity classification. ResultsOf all gene–disease pairs evaluated, 14/42 (33.3%) were Definitive, 1/42 (2.4%) were Strong, 6/42 (14.3%) were Moderate, 18/42 (42.9%) were Limited, and 3/42 (7.1%) were either No Reported Evidence, Disputed, or Refuted. Of panels in the National Institutes of Health Genetic Testing Registry, 4/26 (~15.4%) contain genes with Limited clinical evidence. ConclusionClinicians and laboratory diagnosticians should note that <60% of the genes on clinically available panels have Strong or Definitive evidence of association with hereditary colon cancer or polyposis, and >40% have only Moderate, Limited, Disputed, or Refuted evidence. Continuing to expand the structured assessment of the clinical relevance of genes listed on hereditary cancer testing panels will help clinicians and diagnostic laboratories focus the communication of genetic testing results on clinically significant genes.

Analysis of MIR155HG variants and colorectal cancer susceptibility in Han Chinese population.

Background MIR155HG plays an important role in malignant tumors, but it is rarely reported in the occurrence and development of colorectal cancer (CRC). This study investigated the effects of MIR155HG polymorphisms on CRC susceptibility from the perspective of molecular genetics.MethodsEight SNPs in MIR155HG were selected and genotyped among 514 CRC cases and 510 healthy controls using the Agena MassARRAY platform. The associations between these SNPs and the CRC risk were evaluated under genetic models using conditional logistic regression analysis. The HaploReg v4.1 database was used for SNPs functional prediction.ResultsThe allele “C” of rs12482371 (p = 0.047), allele “C” of rs1893650 (p = 0.025), and the allele “A” of rs928883 (p = 0.037) in MIR155HG were significantly associated with CRC risk. Genetic model analysis revealed that rs12482371 and rs1893650 increased CRC risk; whereas rs928883 was associated with reduced CRC risk. Stratification analysis showed that rs9383938 was a protective factor in CRC patients under 60 years old. Rs12482371 and rs1893650 were associated with the CRC risk in females. Rs11911469 and rs34904192 may affect the clinical stage and lymph node metastasis. Moreover, the haplotypes CTT and GTC of LD block rs4143370|rs77218221|rs12482371, and the haplotypes CATGA and CACGG of LD block rs77699734|rs11911469|rs1893650|rs34904192|rs928883 were significantly associated with CRC risk.ConclusionThis study revealed that MIR155HG SNPs were associated with CRC susceptibility and could be predictive biomarkers for CRC risk.

Contribution of Genetic Polymorphisms of Inflammation Response Genes on Sporadic Colorectal Cancer Predisposition Risk in Malaysian Patients - A Case Control Study.

AIM:To investigate the frequencies and association of polymorphic genotypes of IL-8 -251 T>A, TNF-α -308 G>A, ICAM-1 K469E, ICAM-1 R241G, IL-6 -174 G>C, and PPAR-γ 34 C>G in modulating susceptibility risk in Malaysian colorectal cancer (CRC) patients. Methods:In this case-control study, peripheral blood samples of 560 study subjects (280 CRC patients and 280 controls) were collected, DNA extracted and genotyped using PCR-RFLP and Allele Specific PCR. The association between polymorphic genotype and CRC susceptibility risk was determined using Logistic Regression analysis deriving Odds ratio (OR) and 95% CI. Results:On comparing the frequencies of genotypes of all single nucleotide polymorphisms ( SNPs ) in patients and controls, the homozygous variant genotypes IL-8 -251 AA and TNF-α -308 AA and variant A alleles were significantly higher in CRC patients. Investigation on the association of the variant alleles and genotypes singly, with susceptibility risk showed the homozygous variant A alleles and genotypes IL-8 -251 AA and TNF-α -308 AA to be at higher risk for CRC predisposition. Analysis based on age, gender and smoking habits showed that the polymorphisms IL8 -251 T>A and TNF – α 308 G>A contribute to a significantly higher risk among male and female who are more than 50 years and for smokers in this population.Conclusion:We observed an association between variant allele and genotypes of IL-8-251 T>A and TNF-α-308 G>A polymorphisms and CRC susceptibility risk in Malaysian patients. These two SNPs in inflammatory response genes which undoubtedly contribute to individual risks to CRC susceptibility may be considered as potential genetic predisposition factors for CRC in Malaysian population.

Correlation between the rs7101 and rs1063169 polymorphisms in the FOS noncoding region and susceptibility to and prognosis of colorectal cancer.

Background:The FOS gene is located on human chromosome 14q21–31 and encodes the nuclear oncoprotein c-Fos. This study analyzed the correlation between the FOS noncoding region rs7101 and rs1063169 polymorphisms and colorectal cancer susceptibility and prognosis.Methods:We analyzed the FOS genotypes in 432 colorectal cancer patients and 315 healthy subjects by PCR/Sanger sequencing. Survival was analyzed by Kaplan–Meier and Cox regression analysis. Western blot was used to detect the expression of c-Fos protein in cancer tissues and adjacent tissues in colorectal cancer patients with different genotypes.Results:The presence of a T allele at rs7101 and a T allele at rs1063169 in FOS carried a higher risk of colorectal cancer [adjusted odds ratio (OR) = 1.237, 95% confidence interval (95% CI) = 1.131–1.346, P ≤ .001 and adjusted OR = 1.218, 95% CI = 1.111–1.327, P ≤ .001, respectively]. c-Fos protein levels were significantly higher in variant cancer tissues than in normal mucosa tissues (P < .05), and c-Fos proteins levels were also higher in homozygous variant cancer tissues than in heterozygous variant cancer tissues. The 3-year survival rate of patients with wild-type FOS was higher than that of patients with variant FOS (P < .05).Conclusion:The rs7101 and rs1063169 polymorphisms in the noncoding region of FOS are associated with the risk of developing colorectal cancer and the progression of colorectal cancer, which may be because the mutation enhances the expression of c-Fos protein to promote the incidence and development of colorectal cancer.

Contribution of Caspase-8 Genotypes to Colorectal Cancer Risk in Taiwan.

The aim of this study was to examine the role of caspase-8 rs3834129 polymorphism on colorectal cancer (CRC) risk in Taiwanese CRC patients and healthy controls. The caspase-8 rs3834129 (-652 6N insertion/deletion) polymorphic genotypes were analyzed in 362 patients with CRC and the same number of age- and gender-matched healthy subjects. The interaction of caspase-8 rs3834129 genotypes with personal behaviors and clinicopathological features were also examined. The percentage of variants ID and DD for caspase-8 rs3834129 genotype were 37.6 and 5.8% in CRC group and 39.0 and 6.6% in the control group, respectively (p for trend=0.7987). The allelic frequency distribution analysis showed that caspase-8 rs3834129 D allele conferred a non-significant lower susceptibility for CRC compared with I allele (OR=0.92, 95%CI=0.74-1.20, p=0.5063). There was no obvious link between caspase-8 rs3834129 genotype and CRC risk among ever-smokers, non-smokers, non-alcohol drinkers or alcohol drinkers. No statistically significant correlation was observed between caspase-8 rs3834129 genotypic distribution and age, gender, tumor size, location or metastasis status. Overall, caspase-8 rs3834129 genotypes may not serve as predictors for CRC risk or prognosis.

Interleukin-17A polymorphisms predict the response and development of tolerance to FOLFOX chemotherapy in colorectal cancer treatment.

Polymorphic variants in IL-17A gene were differentially associated with colorectal cancer (CRC) susceptibility but their link with response and toxicity to CRC treatment have not yet been evaluated. We investigated association between seven IL-17A variants with the response and toxicity to CRC treatment in 294 patients with CRC. IL-17A genotyping was done by real-time PCR. MAF of rs3748067 was significantly higher in CRC cases resistant to FOLFOX treatment (R+) than non resistant (R-). Significantly higher rs3804513 MAF was noted in R+ versus R- colon cancer (CC). Higher rs2275913 and rs10484879, and reduced rs3804513 MAF were seen in rectal cancer (RC) tolerant to FOLFOX (T+) compared to (T-) patients. Strong association of rs3819025, rs3804513, and rs7747909 was found with tolerance to RC treatment. rs3748067 was associated with FOLFOX tolerance in CC but not RC. Significant higher frequency of AGGCAGG and GAGCAGG haplotypes was seen among R + CC, thus assigning non-favorable nature to these haplotypes. Higher and lower frequencies of GAGTAAG and AGGCTGA haplotypes, respectively, were observed in T + RC, thereby assigning FOLFOX-tolerant and non-tolerant nature to these haplotypes. The obtained results suggest that IL-17A variants and haplotypes may be a target for future management of CRC treatment.