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PubMed2002

Association of functional polymorphisms of matrix metalloproteinase (MMP)-1 and MMP-3 genes with colorectal cancer.

Matrix metalloproteinase (MMP)-1 and MMP-3 genes are associated with tumor cell invasion and metastasis with their promoter polymorphisms influencing the level of transcription. Our study explored the association of these polymorphisms with colorectal cancer risk in a Japanese population. DNA was extracted from peripheral blood of 101 patients with colorectal cancer and 127 age- and gender-matched healthy volunteers. Genotyping was carried out using PCR-RFLP and direct sequencing. In the MMP-1 gene polymorphism, the frequency of the 2G/2G genotype that is associated with higher enzyme activity was significantly increased in colorectal cancer patients when compared to controls (p = 0.0067; OR = 2.077; 95% CI = 1.221-3.534). With regard to the MMP-3 polymorphism, unexpectedly, the frequency of the 6A/6A genotype causing lower enzyme activity was significantly increased in patients (p = 0.0129; OR = 2.110; 95% CI = 1.165-3.822). Because the loci for the 2 MMP genes are closely linked, we examined linkage disequilibrium between the 2 loci using expectation-maximization algorithm. We found that the 2 loci were in linkage disequilibrium and that 2G-6A haplotype was significantly increased in patients compared to controls (p = 0.0010; OR = 1.949; 95% CI = 1.305-2.911). Our present data suggest that the MMP-1 and MMP-3 promoter polymorphisms may be associated with a colorectal cancer susceptibility in Japanese.

Adenocarcinoma↗
PubMed2005

Polymorphisms of the XRCC1, XRCC3, & XPD genes, and colorectal cancer risk: a case-control study in Taiwan.

BACKGROUND: Recent studies relating to the association between DNA repair-gene polymorphisms and colorectal cancer risk would, to the best of our knowledge, appear to be very limited. This study was designed to examine the polymorphisms associated with three DNA repair genes, namely: XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln, and investigate their role as susceptibility markers for colorectal cancer. METHODS: We conducted a case-control study including 727 cases of cancer and 736 hospital-based age- and sex-matched healthy controls to examine the role of genetic polymorphisms of three DNA-repair genes (XRCC1, XRCC3 and XPD) in the context of colorectal cancer risk for the Taiwanese population. Genomic DNA isolated from 10 ml whole blood was used to genotype XRCC1 Arg399Gln, XRCC3 Thr241Met and XPD Lys751Gln by means of polymerase chain reaction (PCR) and restriction fragment length polymorphism (RFLP) analysis. RESULTS: The risk for colorectal cancer did not appear to differ significantly amongst individuals featuring the XRCC1 399Arg/Arg genotype (OR = 1.18; 95% CI, 0.96-1.45), the XRCC3 241Thr/Thr genotype (OR = 1.25; 95% CI, 0.88-1.79) or the XPD 751Gln allele (OR = 1.20; 95% CI, 0.90-1.61), although individuals featuring a greater number of risk genotypes (genotype with OR greater than 1) did experience a higher risk for colorectal cancer when compared to those who didn't feature any risk genotypes (Trend test P = 0.03). Compared with those individuals who didn't express any putative risk genotypes, individuals featuring all of the putative risk genotypes did experience a significantly greater cancer risk (OR = 2.43, 95% CI = 1.21-4.90), particularly for individuals suffering tumors located in the rectum (OR = 3.18, 95% CI = 1.29-7.82) and diagnosed prior to the age of 60 years (OR = 4.90, 95% CI = 1.72-14.0). CONCLUSIONS: Our results suggest that DNA-repair pathways may simultaneously modulate the risk of colorectal cancer for the Taiwanese population, and, particularly for rectal cancer and younger patients.

Case-Control Studies↗
PubMed2003

Mutations in the p53 tumor suppressor gene in colorectal cancer in Taiwan.

Mutations in the tumor suppressor gene p53 have been reported as occurring prevalently in a wide range of human tumors. Detection of a mutated p53 is thought to provide useful information for the clinical management of colorectal neoplasm. In this study, we used polymerase chain reaction/single-strand conformation polymorphism (PCR/SSCP) and sequencing analysis to rapidly screen for mutations in p53 in colorectal cancer in Taiwan. Genomic DNA was purified from colorectal cancer specimens obtained from 80 patients at a teaching hospital in southern Taiwan. Primer sets were designed to amplify fragments within exons 4-8 of p53. We found p53 mutations in 38 of 80 patients. This is the first identification of a mutation at codon 143 of p53 in colorectal cancer in Taiwan. In addition, we found two insertions in exon 5 of p53. The p53 mutation rate among colorectal tumors in Taiwan, found in this study, is 43%. The results indicate that p53 mutation is not significantly associated with tumor grade, age, or gender (p > 0.05). We found that two-fifths of colorectal cancer patients in Taiwan have a p53 mutation, which could be used as a marker of colorectal cancer.

Adult↗
PubMedDate not supplied

Transitions and transversions in Ki-ras gene in colorectal cancers in Mexican patients.

AIMS & BACKGROUND: An important increase in the incidence of colorectal cancers has been detected in the last 15 years in Mexico. This fact has been attributed to several causes, including the change in diet acquired from industrialized countries. Various groups have studied the mutational pattern of oncogenes, including Ki-ras gene, in colorectal cancers from different human populations. The aim of this work was to study the prevalence of mutations at codons 12, 13 and 61 of the Ki-ras gene in 37 colorectal tumors from Mexican patients and to correlate them with clinical data. METHODS: Point mutations were studied in 37 colorectal cancers at codons 12 and 13 of the Ki-ras gene, using PCR followed by RFLP. We also performed PCR-SSCP to identify mutations at codon 61. We confirmed mutations by sequence analysis in all the altered codons. RESULTS: Our results indicated that 24.3% of the tumors presented mutations at codon 12, 5.4% at codon 13, and 2.7% at codon 61 of the Ki-ras gene. We found that 75% of these mutations were transitions and 25% transversions. The overall results indicated that the frequency of Ki-ras mutations in colorectal cancers in a sample of a Mexican population (Mexico City) was 32.4%, which is similar to that reported in other populations. We did not find a correlation between the Ki-ras mutations and gender, location of the tumor, or Dukes' stage, but survival of the patient without recurrence was statistically significant. CONCLUSIONS: The study of colorectal cancer indicated that in a Mexican population Ki-ras mutations were present in tumors of patients who survived without tumor recurrence. Most of them were transitions in the first and second base of codon 12.

Adult↗
PubMed1995

Allelic loss of the p53 gene in colorectal cancer.

The loss of specific chromosomal loci in cancers is indicative that the region contains a tumour suppressor gene. Allelic loss of chromosome 17p has been shown to occur in a wide variety of cancers such as lung, breast, colon, ovary and brain and, until recently, the gene believed to be involved was the p53 tumour suppressor gene. However, more recent studies have shown that the area deleted in some of these tumours does not include the structural gene for p53. For this reason it has been proposed that a tumour suppressor gene lying distal to p53 on chromosome 17p is the gene deleted in these cancers. As chromosome 17p has been shown to be deleted in approximately 75% of colorectal cancers, we set out to determine whether the target gene of these deletions was the structural gene for p53. Allelic loss was assessed by using restriction fragment length polymorphisms in 52 tumours. Deletions distal to p53 on chromosome 17p were assessed using the probe YNZ22.1 and allelic loss of p53 was assessed using probe pR4-2, a cDNA probe specific for the p53 gene. Out of the 21 tumours informative for both probes, 3 cases showed no allelic deletion of the chromosome 17p, 2 cases showed allelic deletion not encompassing the p53 gene and 16 cases (89%) showed allelic deletion including the p53 gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1996

[Differential expression of HSU17714 gene in colorectal cancer and normal colonic mucosa].

HSU17714 is a new gene discovered by subtractive hybridization. Its cDNA is 2,932 bp long and the gene is located at human chromosome 22 as defined by fluorescence in- situ hybridization combined fluorescence R-banding technique. Northern blot and RNA dot blot analyses showed that the expression level of HSU17714 gene was significantly lower in 15 cases of colorectal cancer than that in adjacent normal colonic mucosa. The defective expression of HSU17714 in colorectal cancer suggests that it is a new candidate tumor suppressor gene.

Adult↗
PubMed1996

Relaxation of imprinting of the insulin-like growth factor II gene in colorectal cancer.

The insulin-like growth factor II gene (IGF2) is imprinted in normal human tissues, and relaxation of imprinting (ROI) of IGF2 is thought to play an important role in human childhood tumors. Taking advantage of an Apa I polymorphism in this gene, allelic expression of IGF2 has now been examined in colorectal cancer. Thirteen of 33 patients studied were informative. Colorectal cancer tissue from 5 of the 13 informative patients exhibited ROI of IGF2; furthermore, normal mucosa from 3 of these 5 patients also showed weak biallelic expression of IGF2. ROI of IGF2 may thus also play a role in colorectal cancer.

Alleles↗
PubMed2004

Promoter CpG methylation of tumor suppressor genes in colorectal cancer and its relationship to clinical features.

Aberrant promoter methylation of CpG islands of tumor suppressor genes inhibits expression of the genes and may lead to tumorigenesis. We investigated the aberrant methylation profile of potential tumor suppressor genes of p15, p16, SOCS-1, and Wnt signaling pathway in colorectal cancers and correlated the data with clinical findings. Cancerous and nearby non-cancerous tissues of 185 sporadic colorectal cancer samples were studied. Methylation specific PCR was performed to explore the mechanism of inactivation in p15, p16, SOCS-1, E-cadherin, APC, GSK-3beta, and Axin1 genes. Aberrant promoter methylation in p15, p16, SOCS-1, E-cadherin, APC, GSK-3beta, and Axin1 genes were 5.9, 7.0, 3.8, 5.9, 12.4, 2.2, and 0% for cancerous tissues, respectively, whereas the frequencies were 3.8, 0, 0, 7.0, 2.7, 0.5, and 0% for nearby non-cancerous tissues, respectively. The frequency of aberrant promoter methylation of cancerous tissues was significant higher than non-cancerous tissues in p16, SOCS-1, and APC genes (p<0.05) and methylation status of these genes had no clear relationship with clinical parameters. Of the 66 patients who showed at least one aberrant promoter methylation in the tumor-suppressor genes, 5 (7.6%) patients demonstrated multiple methylation phenotype (methylation > or =3) and associated with increased lymph node metastasis (p=0.036). Our findings suggest that inactivation of some tumor suppressor genes through aberrant promoter methylation of CpG islands may play a role in the development of colorectal cancer and methylation inactivation of these genes except p16 and SOCS1 may occur at the precancerous stage. Multiple methylation pathways may be involved in the tumorigenesis of colorectal cancer and associated with aggressiveness of clinical disease.

Base Sequence↗
PubMedDate not supplied

Hypermethylation of the CDKN2A gene in colorectal cancer is associated with shorter survival.

Promoter hypermethylation of the CDKN2A gene has been suspected to be involved in the carcinogenesis of colorectal cancers. However, the relations between CDKN2A hypermethylation and clinicopathological findings, and patient prognosis, remain inconclusive. We analyzed the CDKN2A methylation status in primary colorectal cancers using real-time methylation specific PCR (MethyLight) which enables quantitative measuring of the methylation level. CDKN2A promoter methylation was detectable in 55 (61.1%) of 90 tumor samples and the median level of the methylation was 0.187 (range 0.00-197.9). The methylation value of CDKN2A was correlated with certain clinicopathological findings, including tumor differentiation (p=0.018), and Dukes stage (p=0.016). In survival analysis, the CDKN2A methylation level was correlated with a poor prognosis of the patient with colorectal cancer for either all cases (p=0.014) or Dukes C (p=0.004) cases that were analyzed. These results suggest that CDKN2A methylation status is a prognostic factor in colorectal cancer and may be of use for the patient specific design of therapy.

Aged↗
PubMed2006

Genetic analysis of caveolin-1 and eNOS genes in colorectal cancer.

Caveolae are involved in physical compartmentalization between different groups of signaling events. Its main component, CAV1, modulates different pathways in cellular physiology. The emerging evidence pointing to the role of CAV1 in cancer led us to study whether different alleles of this gene are associated with colorectal cancer (CRC). Since one of the most characterized enzymes regulated by CAV1 is eNOS, we decided to include both genes in this study. We analyzed five SNPs in 360 unrelated CRC patients and 550 controls from the general population. Two of these SNPs were located within eNOS and three within the CAV1 gene. Although haplotype distribution was not associated with CRC, haplotype TiA (CAV1) was associated with familiar forms of CRC (p<0.05). This was especially evident in CRC antecedents and nuclear forms of CRC. If both CG (eNOS) and TiA (CAV1) haplotypes were taken together, this association increased in significance. Thus, we propose that CAV1, either alone or together with eNOS alleles, might modify CRC heritability.

Aged↗
PubMed2005

Variance in the expression of 5-Fluorouracil pathway genes in colorectal cancer.

Although colorectal cancer has the third highest cancer mortality rate, the treatment remains far from optimized with patients showing variable responses to standard treatment. Molecular differences in pharmacologically relevant genes may contribute to the variability in response. This study used Taqman PCR to investigate the expression of 24 5-fluorouracil (5-FU) pathway genes in colorectal cancer using paired nontumor and tumor sample from 52 patients with Dukes' C colon cancer. In comparing tumor versus nonmalignant tissue, 14 of the 24 genes showed significant variation in gene expression. For 11 of these same genes (FPGS, DHFR, GGH, NME1, NME2, RRM2, UMPH2, UNG, UMPS, TP53, and TK1), a significant proportion of the patients showed an over expression of the particular gene in tumor tissue with a tumor-to-nonmalignant (T/N) ratio >1.2, whereas one gene (DPYD) showed the converse with a large number of patients showing a lower expression in the tumor tissue (T/N < 0.8). Multiple gene correlations for the genes of the 5-FU pathway were found with the Spearman rank correlation of >0.6 (all P > 0.001), suggesting possible coregulation mechanisms. Hierarchical clustering analysis created at least three groups of genes, which were consistent with groupings by the other statistical methods. Additionally, the hierarchical clustering showed two distinct groups of patients based on their gene expression. These variations in gene expression could provide valuable insights for optimizing treatment selection for patients with colorectal cancer.

Adult↗
PubMed1998

Reduced expression of mismatch repair genes in colorectal cancer patients in Egypt.

An Egyptian hospital-based pilot case-control study was conducted to investigate the relationship between the expression level of mismatch repair (MMR) genes and the risk of colorectal cancer. The relative expression of five known MMR genes, i.e., hMSH2, hMLH1, hPMS1, hPMS2, and GTBP/hMSH6, was measured by a multiplex reverse transcriptase (RT)-polymerase chain reaction (PCR) in peripheral blood lymphocytes from 31 colorectal cancer patients and 47 age- and-sex matched controls. The expression of hMSH2, GTBP/hMSH6, hPMS1 and hPMS2 tended to be lower in patients than controls, but only the difference in hPMS2 expression was statistically significant (p<0. 01). Although 50% of the cases had chemotherapy or radiotherapy within the last six months before the blood was drawn, their gene expression was not statistically different from those who had not undergone such therapies. After adjustment for age and sex, the odds ratios (OR) calculated from a logistical regression model, using the median levels of gene expression of controls as cut-off values, indicated that increased risk was associated with reduced expressions of both hPMS1 (OR = 3.97, 95% confidence interval (CI) = 1.04 to 7.65) and hPMS2 (OR = 2.86, 95% CI = 1.05 to 7.76). Although the results of this study were inconclusive because of the small sample size and use of prevalent cases, it is biologically plausible that patients with colorectal cancers may have a lower expression of MMR genes than healthy controls because malfunction of these genes has been shown in hereditary nonpolyposis colon cancer. The involvement of low hPMS2 expression in colon cancer risk seems to be unique in the Egyptian population. Further studies with newly diagnosed patients before they begin therapy will provide more convincing data about the role of MMR gene expression in the etiology of colorectal cancers in Egypt.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Somatic alterations of the SMAD-2 gene in human colorectal cancers.

The SMAD-2 gene, which is located at 18q21, has been identified as a candidate tumour-suppressor gene from work on colorectal cancers. The aim of the present study was to determine the clinical alterations and the significance of its mutations in a series of colorectal cancers previously examined for SMAD-4/DPC-4 gene. Mutation analyses of the SMAD-2 gene were carried out on cDNA samples from 36 primary colorectal cancer specimens using a combination of the polymerase chain reaction (PCR), single-strand conformation polymorphism (SSCP) and DNA sequencing. Only one missense mutation (2.8%), producing an amino acid substitution in the highly conserved region, and two homozygous deletions (5.5%) of the total coding region of the SMAD-2 gene were detected in the 36 cancers. The SMAD-2 gene may play a role as a candidate tumour-suppressor gene in a small fraction of colorectal cancers. However, allelic loss at 18q21 is very often seen in this type of tumour. Even in combination with changes in SMAD-4, the observed frequency was not sufficient to account for all 18q21 deletions in colorectal cancers. Thus, another tumour-suppressor gene, such as DCC, discovered as the first tumour-suppressor candidate in the region may also exist in this chromosome region.

Aged↗
PubMed2006

Polymorphisms within inflammatory genes and colorectal cancer.

BACKGROUND: Chronic inflammation is a risk factor for colorectal cancer and polymorphisms in the inflammatory genes could modulate the levels of inflammation. We have investigated ten single nucleotide polymorphisms (SNPs) in the following inflammation-related genes: TLR4 (Asp299Gly), CD14 (-260 T>C), MCP1 (-2518 A>G), IL12A (+7506 A>T, +8707 A>G, +9177 T>A, +9508 G>A), NOS2A (+524T>C), TNF (-857C>T), and PTGS1 (V444I) in 377 colorectal (CRC) cancer cases and 326 controls from Barcelona (Spain). RESULTS: There was no statistically significant association between the SNPs investigated and colorectal cancer risk. CONCLUSION: The lack of association may show that the inflammatory genes selected for this study are not involved in the carcinogenic process of colorectum. Alternatively, the negative results may derive from no particular biological effect of the analysed polymorphisms in relation to CRC. Otherwise, the eventual biological effect is so little to go undetected, unless analysing a much larger sample size.

Colorectal Neoplasms↗
PubMed2006

Meat, milk, saturated fatty acids, the Pro12Ala and C161T polymorphisms of the PPARgamma gene and colorectal cancer risk in Japanese.

The peroxisome proliferator-activated receptor gamma (PPARgamma) gene plays important roles in energy homeostasis. To examine interactions between consumption of foods and fatty acids and the Pro12Ala and C161T (His447His) polymorphisms for colorectal cancer, we performed two case-control studies in Japanese. In study 1, there were 128 colorectal cancer cases and 238 non-cancer controls, and in study 2 there were 257 cases and 771 (age- and sex-matched) non-cancer controls. Assessment of food and nutrients consumption in study 1 was via a nine-item questionnaire, while in study 2 assessment of consumption was according to a more detailed semiquantitative food frequency questionnaire. Consumption of foods and fatty acids was divided into low, moderate and high groups. The overall frequency of the Ala allele was <4%, and the frequencies of the Pro/Pro + C/C and Pro/Pro + (C/T + T/T) genotypes were 70-73% and 20-26%, respectively. Compared with subjects with low meat intake and the Pro/Pro + C/C genotype, those with high meat consumption and the same genotype had a stronger increased risk in study 1 [OR, 2.88; 95% CI, 1.14-7.30; P for trend = 0.02], but a positive association with processed meat consumption was greatest in those with the Pro/Pro + (C/T + T/T) genotype (P for trend = 0.05) in study 2. Likewise, high consumption of saturated fatty acids and milk appeared to confer marginal increased risk and stronger decreased risk, respectively, in those with the Pro/Pro and Pro/Pro + C/C genotypes (OR, 1.35 and 0.65; 95% CI, 0.93-1.96 and 0.43-1.00; P for trend = 0.10 and 0.06). Further large-scale studies are needed to determine colorectal cancer risk according to relationships between the PPARgamma gene polymorphisms and dietary intakes of meat, processed meat, milk and saturated fatty acids in Japanese with very low frequency of the Ala allele.

Adult↗
PubMed1994

Hereditary non-polyposis colorectal cancer--morphologies, genes and mutations.

Mutations in a human homologue of the yeast DNA mismatch repair gene MSH2 (equivalent to bacterial MutS) cause the condition hereditary non-polyposis colorectal cancer (HNPCC). Cancers in HNPCC originate within benign neoplastic polyps termed adenomas. Adenomas are clonal and each may serve as a marker of a single initiating mutation. The progression of adenomas is marked by increasing size, dysplasia and villosity. These characteristics can be taken as the morphological counterparts of the stepwise accumulation of mutations implicating oncogenes and tumour suppressor genes. The aim of this study was to link the morphogenesis of hereditary colorectal cancer with recent insights into the role of DNA mismatch repair genes. The frequency and anatomical distribution of adenomas in at-risk members of HNPCC families was the same as in an autopsy population. This suggests that the HNPCC gene does not initiate the process of neoplastic transformation. On the other hand, adenomas in at-risk members of HNPCC families were more likely to show villosity (p < 0.001), high grade dysplasia (p = 0.002) and probably increased size (p = 0.15). These findings are consistent with the observation that the HNPCC gene causes DNA replication errors to develop and accumulate within neoplastic but not normal tissues. The effect of the HNPCC gene is to accelerate the progression of adenoma to carcinoma, but not to initiate adenoma development.

Adenoma↗
PubMed2001

Adenovirus-mediated transfer of the p53 family genes, p73 and p51/p63 induces cell cycle arrest and apoptosis in colorectal cancer cell lines: potential application to gene therapy of colorectal cancer.

p53 gene therapy is being tested clinically for the treatment of human cancer, however, some cancer models (in vivo and in vitro) are resistant to p53. To explore the potential use of two p53 homologues, p73 and p51/p63, in cancer gene therapy, we introduced p53, p73 and p51/p63 into colorectal cancer cell lines via adenoviral vectors, and compared their effects on cell growth. Among 10 cell lines tested, six cell lines displayed a similar response following transduction of p53, p73beta or p51A/p63gamma; two lines underwent cell-cycle arrest, three lines exhibited apoptosis and one line showed no-effect following transduction. The effect on cell-cycle progression was variable in the other four cell lines. Interestingly, three cell lines were resistant to p53-mediated apoptosis, including two lines having endogenous wild-type p53 alleles, but underwent apoptosis after transduction of p73beta or p51A/p63gamma. Similar to p53, transduction of p51A/p63gamma induced extensive apoptosis when combined with adriamycin or X-radiation in SW480 cells, which are normally resistant to apoptosis. Transduction of p73beta and p51A/p63gamma also reduced the tumorigenicity of two colorectal cancer cells in vivo. These results suggest that adenovirus-mediated p73beta and p51A/p63gamma transfer are potential novel approaches for the treatment of human cancers, particularly for tumors that are resistant to p53 gene therapy.

Adenoviridae↗