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PubMed1998

DNA mismatch repair genes and their association with colorectal cancer (Review).

Mismatch repair genes are involved in increasing the fidelity of replication by specific repair of DNA polymerase incorporation errors. In Escherichia coli, the best studied mismatch repair (MMR) pathway is the methyl-directed long patch repair system which is mediated by three gene products; MutS, MutL and MutH. These are conserved in higher eukaryotes. Mutations in human homologues of these proteins have been shown to be implicated in hereditary non-polyposis colorectal cancer (HNPCC). Alterations in the coding regions of MMR genes result in a mutator phenotype with marked instability of microsatellite sequences, indicative of a deficiency in DNA repair.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed1999

Polymorphism of GSTM1 gene in patients with colorectal cancer and colonic polyps.

The frequency of the GSTM1 gene in patients with nonpolyposis colorectal cancer (CRC) (n = 70) and in subjects with colonic polyps (n = 27) was evaluated and compared with healthy individuals (n = 145). Patients with CRC were divided into the three groups: patients coming from the families with hereditary nonpolyposis colorectal cancer (HNPCC) (n = 17); patients with a high risk of HNPCC who were referred to as suspected of HNPCC (n = 25); patients with sporadic colorectal cancer without clinical features of hereditary tumours (n = 28). A simple polymerase chain reaction (PCR) - based assay to identify GSTM1 nulled and positive (non-nulled) genotype was used. No significant differences in frequency of nulled individuals were observed in both patients with HNPCC and patients suspected of HNPCC as well as in subjects with colonic polyps. The most interesting observation was made in the group of patients with sporadic CRC. Twenty individuals (71.4 %) of the group were GSTM 1 deficient which was significantly different from the control population (p < 0.04). The above data indicate that the absence of the GSTM1 gene is associated with a greater risk of sporadic colorectal cancer. There is an increase in the overall risk of approximately 2.5 as compared with the control population.

Adolescent↗
PubMed2006

[Hereditary colorectal cancer: Molecular analysis of APC and MLH1 genes].

BACKGROUND: Among colorectal cancer hereditary variants, two syndromes show a predisposition to the disease based on germline mutations: Familial Adenomatous Polyposis (FAP) and Hereditary Nonpolyposis Colorectal Cancer (HNPCC). AIM: To screen mutations in FAP and HNPCC families in Chile. MATERIALS AND METHODS: Two FAP and one HNPCC families were studied. The APC gene (for FAP patients) and the MLH1 gene (for HNPCC patients), were screened for mutations on genomic DNA. The molecular analysis was performed through polymerase chain reaction, Single Strand Conformer Polymorphism (SSCP) and DNA sequencing. Mutations were defined as changes in the DNA sequence leading into a stop codon and a truncated protein. RESULTS: In the two FAP families the analysis revealed a mutation consisting in the deletion of five nucleotides named c.3927_3931delAAAGA. The genetic study of the HNPCC family demonstrated the insertion of one adenine in codon 168 of exon 6, named c.504insA. DISCUSSION: Germ-line mutations were identified in the three families. The relevance of these studies in a better knowledge of cancer susceptibility, and the possibility of identifying in relatives in risk by molecular diagnosis.

Adenomatous Polyposis Coli↗
PubMedDate not supplied

Distribution of angiogenin and its gene message in colorectal cancer patients and their clinical relevance.

BACKGROUND: [corrected] The distribution of angiogenin (ANG) in normal colorectal and colorectal cancer tissues has not been precisely elucidated, while studies on the clinical significance of ANG have been scanty at best. PATIENTS AND METHODS: We investigated the distribution of ANG and its gene message in 58 colorectal cancer and 58 corresponding normal colorectal tissue pairs by immunohistochemistry and in situ hybridization, the circulating ANG levels in sera by ELISA from 94 colorectal cancer patients and 52 healthy volunteers, as well as the clinical significance of ANG expression. RESULTS: Strong, moderate and weak ANG immunoreactivity of cancer cells was observed in 22, 31 and 5 patients, respectively. ANG immunoreactivity was also observed in interstitial cells in the vicinity of and at the invasion front of cancer cells, as well as in normal superficial epithelial cells and in some interstitial cells. The distribution of the ANG gene message was coherent with the ANG protein localization. The mean serum ANG concentration was significantly (p =0.00005) higher in cancer patients as compared with that in the healthy volunteers and the degree of its elevation was more significant in the more progressed cancer subgroups. The degrees of ANG protein and mRNA expression correlated with serum ANG concentration (p<0.05). Survival analyses revealed a significant correlation between higher serum ANG concentrations (> or = 400ng/ml) and worse disease-free (p=0.003) or disease-specific (p=0.03) survivals. CONCLUSION: These results suggest that ANG is expressed in colorectal cancer cells and in normal colorectal superficial cells as well as in interstitial cells and that serum levels of ANG reflect the degree of tissue ANG expression that could be a predictor of postoperative outcome.

Adult↗
PubMed2004

In vivo recombinant adenovirus-mediated p53 gene therapy in a syngeneic rat model for colorectal cancer.

The p53 gene has a significant role in controlling genomic stability of cancer. The purpose of this study was to evaluate the tumor response of allograft colorectal tumor treated with Ad5CMV-p53 in a syngeneic rat model. Two weeks after the inoculation of WB-2054-M5 tumor cells in the flank of rats, rats were randomly assigned by tumor size to one of three groups (n=18 in each): phosphate buffered saline (PBS), Ad5CMV, and Ad5CMV-p53. Recombinant adenovirus or PBS was administered through intratumoral injection at three divided doses every other day for 4 weeks. Apoptosis of the tumors was evaluated using TUNEL assay. After 2 and 4 weeks of treatment, the volume (cm(3)) of tumors in PBS, Ad5CMV, and Ad5CMV-p53 was as follows: 2 week: 1.66 +/-0.43, 1.40 +/-0.47, 0.75 +/-0.26 (p<0.001), 4 week: 4.41 +/-0.88, 3.93 +/-1.86, 2.33 +/-0.51 (p<0.001). Tumor growth showed no statistically significant difference between the PBS and Ad5CMV groups (6-week vol. p=0.32). The TUNEL assay results revealed more apparent apoptotic cells in Ad5CMV-p53-treated tumors than in other groups. Growth of allograft colorectal cancer in the syngeneic rat model was significantly suppressed by intratumoral Ad5CMV-p53 gene therapy. These results demonstrate that gene replacement therapy with p53 may provide a novel modality of treatment in conjunction with other present treatments for metastatic colorectal cancer.

Adenocarcinoma↗
PubMed2005

Analysis of progressively overexpressed genes in tumorigenesis of colorectal cancers using cDNA microarray.

The identification of differentially expressed genes has important implications in understanding the biology of colorectal tumorigenesis and progression, as well as developing new diagnostic and therapeutic strategies. In this study, cDNA microarray technology was used to identify colorectal tumor-related functional genes, which are overexpressed continuously from colorectal adenoma to adenocarcinoma. A set of 23 genes with progressive overexpression in the development of colorectal cancer (CRC) was identified by cDNA microarray, then analyzed by sequencing and Northern blot analysis. Validation of our array results was simultaneously performed by exploring the SAGEmap database. Furthermore, the gradually over-expressed genes from adenoma to adenocarcinoma were validated by Northern blot analysis with additional samples from three patients with synchronous colorectal adenocarcinoma and adenoma and four patients with CRC. Of these 23 genes, one was a function-unknown gene, designated as Homo sapiens chromosome 21q22.1 anonymous mRNA sequence (Genbank accession no. AF003738), and 22 were function-known genes. Searching through the Gene Ontology Browser at the Cancer Genome Analysis Project website revealed that the biological roles of these 22 function-known genes are involved in cell motility, cell adhesion, chemokine activity, signal transduction, cytoskeleton organization, proteolysis, apoptosis, and cell proliferation. The genes identified in the present study offer valuable information on colorectal carcinogenesis and metastasis, and represent a potential source of novel targets for new strategies for CRC diagnosis and therapy.

Blotting, Northern↗
PubMed2003

Polymorphisms in the cytochrome P450 CYP1A2 gene (CYP1A2) in colorectal cancer patients and controls: allele frequencies, linkage disequilibrium and influence on caffeine metabolism.

AIMS: Several single nucleotide polymorphisms (SNPs) of the cytochrome P450 enzyme 1A2 gene (CYP1A2) have been reported. Here, frequencies, linkage disequilibrium and phenotypic consequences of six SNPs are described. METHODS: From genomic DNA, 114 British Caucasians (49 colorectal cancer cases and 65 controls) were genotyped for the CYP1A2 polymorphisms -3858G-->A (allele CYP1A2*1C), -2464T-->delT (CYP1A2*1D), -740T-->G (CYP1A2*1E and *1G), -164A-->C (CYP1A2*1F), 63C-->G (CYP1A2*2), and 1545T-->C (alleles CYP1A2*1B, *1G, *1H and *3), using polymerase chain reaction-restriction fragment length polymorphism assays. All patients and controls were phenotyped for CYP1A2 by h.p.l.c. analysis of urinary caffeine metabolites. RESULTS: In 114 samples, the most frequent CYP1A2 SNPs were 1545T-->C (38.2% of tested chromosomes), -164A-->C (CYP1A2*1F, 33.3%) and -2464T-->delT (CYP1A2*1D, 4.82%). The SNPs were in linkage disequilibrium: the most frequent constellations were found to be -3858G/-2464T/-740T/-164A/63C/1545T (61.8%), -3858G/-2464T/-740T/-164C/63C/1545C (33.3%), and -3858G/-2464delT/-740T/-164A/63C/1545C (3.51%), with no significant frequency differences between cases and controls. In the phenotype analysis, lower caffeine metabolic ratios were detected in cases than in controls. This was significant in smokers (n = 14, P = 0.020), and in a subgroup of 15 matched case-control pairs (P = 0.007), but it was not significant in nonsmokers (n = 100, P = 0.39). There was no detectable association between CYP1A2 genotype and caffeine phenotype. CONCLUSIONS: (i) CYP1A2 polymorphisms are in linkage disequilibrium. Therefore, only -164A-->C (CYP1A2*1F) and -2464T-->delT (CYP1A2*1D) need to be analysed in the routine assessment of CYP1A2 genotype; (ii) in vivo CYP1A2 activity is lower in colorectal cancer patients than in controls, and (iii) CYP1A2 genotype had no effect on phenotype (based on the caffeine metabolite ratio). However, this remains to be confirmed in a larger study.

Aged↗
PubMed1999

Correlations between p53-protein accumulation, serum antibodies and gene mutation in colorectal cancer.

Only half of colorectal-cancer patients elicit serum antibodies in response to intratumoral p53-gene mutations. Our study was designed to compare cellular events (p53-protein accumulation and gene mutations) with the presence of circulating anti-p53 antibodies (p53-Ab). Thirty-five colorectal-cancer patients were studied for their intratumoral p53-protein accumulation and circulating p53-Ab. Tumour DNA was analyzed for genomic mutations in a sub-set of 28 patients. In all, 18 tumours (51.4%) were positive by immunohistochemistry, and 17 tumour extracts were shown to contain "mutant" conformation p53 protein, 16 of them being were concordant by both methods. Of the 28 tumours tested by DGGE, 16 contained alterations in p53 exons 5 to 8 (57.1%). Of 12 tumours without detectable mutations, 10 were "mutant"-conformation-negative by immunohistochemistry and ELISA. Paradiploid tumors presented more frequently wild-type p53 genes and were significantly less frequently immunohistochemistry- or p53-Ab-positive than polyploid tumors. Circulating p53-Ab were detected in the serum of 11 patients (31%). In 9/11 cases, a gene mutation was found in the corresponding tumour. Three of four mutations in exon 8 and 3/3 mutations in exons 5-6 were associated with p53-Ab, in contrast with only 3/9 mutations in exon 7. We found good agreement in the detection of p53-gene alterations by different methods. However, our data suggest that all gene mutations may not be equivalent in term of immunogenicity.

Adenocarcinoma↗
PubMedDate not supplied

Identification of differentially expressed genes associated with colorectal cancer liver metastasis.

The molecular mechanisms underlying successful metastasis of primary colorectal tumour to the liver remain unknown. We have used suppression subtractive hybridisation (SSH) and reverse Northern dot blot analysis to profile the mRNA expression patterns of a primary colorectal cancer and its liver metastasis. After SSH and reverse Northern dot blot analysis, differential expression was confirmed in 17 clones from the forward, and 13 clones from the reverse subtracted cDNA library. Four clones showed no significant sequence identities with any known sequences in the GenBank data base and likely to represent novel genes whose up- or down-regulation is associated with colorectal liver metastasis. Interestingly, one of the 13 down-regulated clones displayed 99% sequence identity with the BRCA1 tumour suppressor gene. Since promoter methylation is a direct cause of transcription silencing of the BRCA1 gene in approximately 10-20% of human breast cancer we further investigated its promoter methylation status in ten primary colorectal tumour samples, but revealed no evidence of promoter methylation.

Adult↗
PubMed2004

Identification of APC gene mutations in colorectal cancer using universal microarray-based combinatorial sequencing-by-hybridization.

Familial adenomatous polyposis (FAP) is an autosomal dominant inherited form of colorectal cancer, caused mostly by mutations in the APC gene. Due to the wide variety of mutations found and the large size of the APC gene, several methods of mutation detection are used, which can be time consuming and costly. Here we demonstrate a new method of mutation detection in the APC gene using an array-based approach termed combinatorial sequencing-by-hybridization (cSBH). In cSBH, a universal probe set is attached to a support and a second one is in solution. Two-probe ligation occurs when a DNA strand from the target PCR product consecutively anneals to both unlabeled array-bound and solution-phase dye-labeled probe, creating all target-complementary long-labeled probes attached to the surface. A standard array reader scores fluorescent signals at each array position. Cell lines and patient DNA with known APC gene mutations were analyzed using a cSBH-based HyChip trade mark product. Results show that this universal hexamer (6-mer) chip can successfully detect a range of mutations. Results are very robust for a continuous readout of 3.6 kb from a PCR target, with 99.97% accuracy on a single HyChip trade mark slide. cSBH is a fast, cost-efficient method for first stage mutation screening in the APC or any other gene.

Adenomatous Polyposis Coli↗
PubMed2004

Gene expression profiling of colorectal cancer and metastases divides tumours according to their clinicopathological stage.

Gene expression profiling of matched colorectal carcinomas and metastases could reveal key molecular events involved in tumour progression and metastasis. Expression profiles have been created from 25 colorectal carcinomas (CRCs, pT1-4), corresponding normal colonic mucosa, and 14 liver metastases using cDNA arrays containing 1176 cancer-related genes (Clontech). Hierarchical clustering clearly distinguished carcinomas from non-cancerous tissues, separated tumours into high-stage (pT4 and extensive lymph node or distant metastases) and low-stage (< or =pT3) groups, and correlated with the histopathological classification in 87% (33/38 cases). Most primary tumours and matched liver metastases clustered on terminal branches of the dendrogram. Statistical analysis (Mann-Whitney U-test) revealed 40 tumour-specific genes (29 up-regulated, 11 down-regulated) which allowed identification of malignant tissue samples by cluster analysis. A specific expression signature in matching metastases was not found, but a set of 23 classifier genes with statistically significant expression patterns in high- and low-stage tumours was identified. These genes may represent important targets in colorectal carcinogenesis and might provide useful clinicopathological tools in the management of colorectal cancer.

Adenocarcinoma↗
PubMed2002

Low-penetrance genes and their involvement in colorectal cancer susceptibility.

This report focuses on low-penetrance genes that are associated with colorectal adenoma and/or cancer or that are in strong linkage disequilibrium with colorectal adenoma and/or cancer causing variants. A pooled analysis was performed for 30 polymorphisms in 20 different genes that have been reported in more than one colorectal adenoma or cancer study. An association with colorectal cancer was found for seven polymorphisms in seven genes reported in more than one study; no associations were found with colorectal adenoma. Four of the polymorphisms exhibited an increased colorectal cancer risk [GSTT1, NAT2 (phenotype), HRAS1, and ALDH2]. Two others [MTHFR, Tp53 (intron 3)] exhibited a decreased risk. For the tumor necrosis factor (TNF)a polymorphism of the TNF-alpha gene, one allele was associated with an increased risk (a2 allele) and two other TNFa alleles with decreased risks (a5 and a13 allele). No association with colorectal adenoma and/or cancer was detected for 23 other polymorphisms in 15 genes. However, of all 30 polymorphisms, only three pooled analyses had sufficiently large samples to confirm (MTHFR) or to exclude (GSTM1 and NAT2 genotype) the association with a P < 0.0026 and a power of 90%. Eighteen polymorphisms in 15 genes were each described in only one study, all with very small sample sizes. For 11 polymorphisms in 10 of these genes, an association with colorectal adenoma and/or cancer was found. Only simultaneous genotyping and combined analysis of different polymorphisms in large numbers of patients and controls, stratified by ethnicity, gender, and tumor localization and taking relevant dietary and lifestyle habits into account, will make it possible to describe the exact relations between polymorphisms and colorectal cancer susceptibility with an adequate power.

Adenoma↗
PubMed1996

p53 gene therapy in vivo of herpatocellular and liver metastatic colorectal cancer.

Tumor suppressor genes such as p53 contribute to the oncogenic process via loss-of-function mechanisms such as genetic mutation or complex formation with other cellular or viral proteins. p53 is mutated in approximately 50% of human tumors and has an important role in the genesis or progression of both colorectal and hepatocellular cancers. Colorectal cancer is leading cause of cancer mortality in the United States, whereas hepatocellular cancer is the leading worldwide cause of cancer death; the liver is a primary site of morbidity in both diseases. Because systemic tumor suppressor gene therapy is currently not feasible, we have chosen to develop a regional form of such therapy directed at primary or metastatic liver neoplasms. Gene replacement therapy with p53 is a promising new strategy to treat advanced human cancers.

Adenoviridae↗
PubMed2005

The role of cytokine gene polymorphisms in colorectal cancer and their interaction with aspirin use in the northeast of Scotland.

The reduced risk of colorectal cancer associated with cyclooxygenase enzyme inhibitors, such as aspirin and other nonsteroidal anti-inflammatory drugs, strongly suggests that chronic inflammation is a key mediator in the development of colorectal cancer. This complements recent molecular evidence demonstrating an association between a number of proinflammatory genetic polymorphisms and risk of colorectal cancer. We assessed polymorphisms in the IL-1, IL-10, TNF-A, and TGF-B genes in a population-based case-control study of colorectal cancer cases (n = 264) and frequency-matched controls (n = 408) in the Northeast of Scotland and analyzed their interaction with regular aspirin use. There was no evidence of a relation between any of the individual polymorphisms, or pairs of polymorphisms, and risk of colorectal cancer. There was a significant interaction between the IL-10-592 C/A polymorphism and aspirin use (Pinteraction = 0.03). Carriers of the variant IL-10-592 (A) allele, who produce less of the anti-inflammatory cytokine interleukin-10, had a statistically significant 50% reduced risk of colorectal cancer when taking regular aspirin (odds ratio, 0.5; 95% confidence interval, 0.25-0.97), whereas risk was not reduced in carriers of the A allele who did not use aspirin, or among aspirin users with the CC genotype. It is possible that carriers of the mutant IL-10-592 allele are more likely to derive anti-inflammatory and chemopreventive benefits from aspirin in the presence of a lower production of their own endogenous anti-inflammatory interleukin-10. These results suggest that host genetics may play a role in predicting response to chemopreventive strategies. Confirmation of these findings in other populations is required.

Aged↗
PubMed2003

A better cell cycle target for gene therapy of colorectal cancer: cyclin G.

The purpose of this study was to evaluate the overexpression of cyclin G in colorectal neoplasia, which may be a more frequent event than cyclin D1 during the cell cycle and thus may have a more enhanced therapeutic potential in treating colorectal cancer. Ninety formalin-fixed, paraffin-embedded human colon and rectal specimens were obtained from the Pathology Department of Norris Cancer Center/University of Southern California. The tissues had been obtained after surgical resection between 1995 and 2001, and had been processed by routine clinical histopathologic methods. Ninety-one percent of colorectal tumors had cyclin G overexpression. These cyclin-positive patients were evenly distributed between men and women, and between tumor locations, that is, 36% rectal tumors and 34% right-sided tumors. Thirty-two percent were well differentiated, and 66% were moderately differentiated. Thirty patients (38%) had stage I disease, 16 (20%) had stage II disease, 25 (32%) had stage III, and seven (9%) had stage IV disease. Eight patients (10%) in this group had recurrent disease during follow-up. There was no correlation between cyclin G overexpression and clinical and pathologic characteristics. Cyclin D1 overexpression was found to be present in only 42% of colorectal adenocarcinomas. There was no correlation between cyclin D1 overexpression and clinical and pathologic characteristics. The present study demonstrates that cyclin G overexpression is a frequent event in colorectal cancer. This frequent event in colorectal carcinogenesis may facilitate new therapeutic approaches acting as a target for gene therapy, possibly directed at downregulating cyclin G in colorectal cancer.

Adenocarcinoma↗
PubMed2003

Allelic imbalance in colorectal cancer at the CRAC1 locus in early-onset colorectal cancer.

A susceptibility gene to colorectal adenomas and carcinoma (CRAC1) on chromosome region 15q14 approximately q22 has been proposed on the basis of linkage in a single family. Allele-specific loss of heterozygosity (LOH) in tumors of affected family members suggests that the causative gene functions as a tumor-suppressor gene. The genes that are mutated in inherited cancer syndromes are often involved in the pathogenesis of sporadic cancer. To determine whether CRAC1 plays a role in colorectal carcinogenesis in general, we have studied 277 cases of early-onset colorectal cancers for allele loss at 15q14 approximately q22 using four microsatellite markers (D15S970, D15S117, D15S971, and D15S1028) that define the region of maximal linkage. The frequency of LOH detected was between 14% and 22%, but there was no significant association between LOH at each adjacent marker. Most cancers caused by loss of expression of a tumor suppressor involve large-scale deletion of one allele. On this basis, our findings suggest that CRAC1 is unlikely to be implicated in the development of colorectal cancer in general or, if involved, it is through small somatic mutations or other loss of function mechanisms rather than allele loss.

Allelic Imbalance↗
PubMed2002

SMAD4 is a predictive marker for 5-fluorouracil-based chemotherapy in patients with colorectal cancer.

The gene for the transducer of transforming growth factor-beta/bone morphogenetic protein signalling SMAD4, a potential suppressor of colorectal carcinogenesis, is located at the chromosomal region 18q21. In order to evaluate the clinical relevance of SMAD4 deletion, gene copy alterations were determined by copy dosage using real-time quantitative PCR in 202 colorectal tumour biopsies from a previous randomised study of adjuvant chemotherapy. Patients with normal SMAD4 diploidy turned out to have a three-fold higher benefit of 5-fluorouracil-based adjuvant chemotherapy with a border line significance (overall survival: 3.23, P=0.056; disease-free survival: 2.89, P=0.045). These data are consistent with the previous observation that patients whose cancer had retention of the 18q21 region had a significantly higher benefit from 5-fluorouracil-based therapy. Moreover, these results may provide a refinement at the gene level of the clinical relevance of 18q21 deletion, thereby suggesting SMAD4 as a predictive marker in colorectal cancer. This data also indicate that integrity of this component of the transforming growth factor-beta/bone morphogenetic protein signalling pathway may be a critical factor for benefit of chemotherapy in patients with colorectal cancer.

Antimetabolites, Antineoplastic↗