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PubMed1997

Conserved region mutations of the p53 gene are concentrated in distal colorectal cancers.

Distal colorectal cancers, especially those in the rectum, are more aggressive and more commonly recurrent than proximal cancers. We studied the possible relationship between p53-gene mutation type and location of the tumour, since mutations in the conserved areas of the p53 gene have been suggested to result in a poorer outcome of colorectal cancer than mutations outside these areas. Exons 5 to 8 of the p53 gene were studied in specimens from 72 colorectal-cancer patients. Polymerase-chain-reaction-amplified products of tumour DNA were analyzed by automated direct sequencing. Of the mutations detected in distal cancers, 71% were located in conserved regions of the gene, while only 42% of the mutations in proximal cancers were in these areas. In rectal cancers, 81% of the mutations were located in conserved regions. The tumours with mutations in the conserved regions were more often poorly differentiated (23%) than those with other mutations (0%). Our results indicate that mutations in the conserved regions of the p53 gene accumulate in distal but not in proximal tumours. This difference may be related to the more aggressive behaviour and to different aetiological factors associated with distal tumours.

Adult↗

PubMed2005

Interleukin-1 receptor antagonist gene polymorphism in human colorectal cancer.

Several studies indicate that local immunoregulation and associated cytokines have a putative role in the development of cancer. There is evidence that pro-inflammatory cytokines such as interleukin-1 (IL-1) are critically involved with tumour progression. IL-1 receptor antagonist (IL-1Ra) is known to down-regulate and limit the inflammatory response. Therefore we attempted to examine the influence of the known polymorphism of the IL-1Ra gene on the development of human colorectal cancer (CRC). The study included 125 patients with CRC and 134 controls. Variable number tandem repeat (VNTR) polymorphism in intron 2 of the IL-Ra gene was analysed by the polymerase chain reaction method. There was a significant difference in genotype distribution between CRC patients and controls (P=0.025) and also in allelic frequencies (P=0.012). In detail the carriage rate of allele 3 in CRC patients was significantly increased compared with controls (P=0.007). We also found that the allelic distribution differs significantly between colon and rectum (P=0.041) and that allele 3 was overabundant in colon. The frequency of allele 1 in CRC patients with localized disease (Dukes A+B) was higher compared with disseminated disease (Dukes C+D), (P=0.035). These findings therefore suggest that the IL-1Ra polymorphism is associated with colorectal carcinogenesis.

Aged↗

PubMed2001

Absence of post-transcriptional RNA modifications of BCL10 in human malignant mesothelioma and colorectal cancer.

The BCL10 gene, located at 1p22, has been implicated in a number of human malignancies, including malignant mesotheliomas (MMs) and colorectal carcinomas. Subsequent reports, however, have revealed an absence of BCL10 mutations in genomic DNA from such tumors. It has been proposed that some abnormalities of this gene may be found only in RNA and not in genomic DNA, suggesting that BCL10 may be mutated post-transcriptionally, rather than at the genomic level. To explore this possibility, we performed SSCP mutation analysis and direct sequencing of cDNA from 17 MM cell lines displaying LOH in 1p22, 12 MM tumor specimens, and 11 colon carcinoma cell lines. SSCP revealed several different band shifts in these samples. The nucleotide changes observed in the cDNA samples were also seen in matched genomic DNA and corresponded to known polymorphisms in the general population. Thus, we conclude the BCL10 mutations are absent at the cDNA level, and that this gene does not undergo "molecular misreading." Since BCL10 also does not possess mutations at the genomic DNA level, it can be ruled out as a gene involved in the pathogenesis of MM and colorectal cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Expression profiling by microarrays in colorectal cancer (Review).

Genome-wide gene profiling studies using microarrays have the potential to improve diagnosis and treatment of human cancers. Microarrays have identified many genes that are deregulated in colorectal cancer compared to normal tissue. Groups of genes that are predictive of tumor stage or presence of metastases, hence putatively associated with cancer progression have also been revealed. Microarray studies have identified genes whose expression are impacted by chemotherapies for colorectal cancer, thus could potentially be used to predict response to treatments. Unique gene expression profiles have also been used to classify metastases of uncertain origin. The wide application of microarrays generates exciting prospects in translational research. However, to date overlaps of candidate gene lists associated with specific clinical/biological phenotypes remain disturbingly poor between studies. Overfitting, bias, reporting of only the best results, and fidelity of probe annotations could present limitations for the interpretation of results shown in microarray publications. Making raw data from these microarray experiments publicly available for analysis by other investigators using different analytical algorithms or for in silico studies may facilitate the most thorough mining of data from these expensive studies. Validations of the results using other more precise techniques and at the biological level represent critical follow-up goals for microarray studies.

Adenoma↗

PubMed2003

[Gene therapy in the treatment of colorectal cancer liver metastases].

In the early 1990s gene therapy had the promise of a new therapeutic modality for many types of cancer including colorectal liver metastases. At the end of that decade the outlook was less encouraging following the death of a patient receiving adenovirus in Pennsylvania. Today the prospect is very bleak following the discovery of leukaemia in children treated for SCiD syndrome in France. Does this mean the start and fall of gene therapy? In this article the concept of gene therapy for colorectal liver metastases will be reviewed. Studies in this field will be cited. It is clear that there are several obstacles to surmount. It is difficult to foresee whether gene therapy will succeed in the clinics in patients with colorectal liver metastases. In this article the author will describe the systematic approach which might lead to success of gene therapy in these patients. In short, gene therapy so far has failed in patients with colorectal liver metastases. However it might succeed in the future. The jury is still out!

Adenoviridae↗

PubMed1996

p53 gene alterations and protein accumulation in colorectal cancer.

Aim-To correlate immunohistochemical staining with single strand conformation polymorphism (SSCP) analysis of the p53 gene in colorectal cancer in order to understand how the findings provided by the two techniques complement each other in defining p53 functional status.Methods-Frozen tumour tissue from 94 patients with colorectal cancer was studied for p53 protein accumulation and gene mutations. Accumulation of p53 protein was detected by immunohistochemistry using PAb1801 and BP53-12-1 monoclonal antibodies. The findings were then compared with SSCP analysis of exons 5 to 8 of the p53 gene. All cases with a positive result by SSCP analysis were confirmed by sequencing.Results-Nuclear staining was observed in 51 (54.2%) cases. SSCP analysis of the DNA amplified by PCR revealed that the electrophoretic pattern had shifted in 30 cases; sequence analysis confirmed the occurrence of a mutation in 29 cases and of a polymorphism in one. In 27 cases both assays gave a positive result, and in 40 both were negative; therefore, concordance between PCR-SSCP and immunohistochemistry was seen in 72% of cases.Conclusion-The data indicate that positive immunostaining corresponds with the presence of a mutation in most, but not all, cases studied; other mechanisms could be responsible for stabilisation and accumulation of p53 protein in the nucleus. Nonsense mutations which do not confer stability on the protein will not be detected by immunohistochemistry and false negative results can also occur with SSCP analysis.

Journal Article↗

PubMed1996

Genetic counseling in hereditary nonpolyposis colorectal cancer.

Recent identification of gene mutations responsible for hereditary nonpolyposis colorectal cancer (HNPCC) has made possible the presymptomatic diagnosis of at-risk family members. If DNA testing shows that a family member is a gene carrier, that individual's lifetime cancer risk is approximately 90%. If the test is negative, the family member's cancer risk drops to that of the general population. Presymptomatic DNA-based diagnosis consists of pretest counseling, the actual DNA test, and posttest counseling. Pretest counseling focuses on the benefits, limitations, and possible adverse effects of testing, and the advantages and drawbacks of screening methods. Posttest counseling sessions explore the test result, and family members' reactions to it. A multidisciplinary team approach is necessary for the management of HNPCC families.

Colorectal Neoplasms, Hereditary Nonpolyposis↗

PubMed2005

Dietary fibre and colorectal cancer: a model for environment--gene interactions.

As environmental factors are clearly associated with risk for colorectal cancer, we set out to model how dietary fibre, or the effects of its ingestion, might impact upon the complex events that characterise colorectal oncogenesis. The diverse nature of dietary fibre and its resultant fate in the gut is outlined. The evidence indicates that different types of fibre create different conditions in different regions of the gut. This is reflected in different effects on oncogenesis especially in animal models. Data from animal models show that insoluble fibre is protective. Evidence from human studies are not consistent, especially considering the interventional studies. However, all such studies have been dependent on biomarkers short of cancer formation, for measurement of an effect. The biological and molecular events characteristic of colorectal oncogenesis are reviewed in an effort to identify how fibre ingestion might regulate oncogenesis. While several mechanisms might account for protection, the results of fermentation and especially butyrate production provide examples of how genomic instability might be controlled. Activation of apoptosis and cell cycle arrest seem likely to be mechanisms that would enable correction of genomic events that drive oncogenesis. Butyrate itself can regulate gene expression by both epigenetic and direct effects.

Adenoma↗

PubMed2005

Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer.

CONTEXT: The accurate identification and interpretation of germline mutations in mismatch repair genes in colorectal cancer cases is critical for clinical management. Current data suggest that mismatch repair mutations are highly heterogeneous and that many mutations are not detected when conventional DNA sequencing alone is used. OBJECTIVE: To evaluate the potential of conversion analysis compared with DNA sequencing alone to detect heterogeneous germline mutations in MLH1, MSH2, and MSH6 in colorectal cancer patients. DESIGN, SETTING, AND PARTICIPANTS: Multicenter study with patients who participate in the Colon Cancer Family Registry. Mutation analyses were performed in participant samples determined to have a high probability of carrying mismatch repair germline mutations. Samples from a total of 64 hereditary nonpolyposis colorectal cancer cases, 8 hereditary nonpolyposis colorectal cancer-like cases, and 17 cases diagnosed prior to age 50 years were analyzed from June 2002 to June 2003. MAIN OUTCOME MEASURES: Classification of family members as carriers or noncarriers of germline mutations in MLH1, MSH2, or MSH6; mutation data from conversion analysis compared with genomic DNA sequencing. RESULTS: Genomic DNA sequencing identified 28 likely deleterious exon mutations, 4 in-frame deletion mutations, 16 missense changes, and 22 putative splice site mutations. Conversion analysis identified all mutations detected by genomic DNA sequencing--plus an additional exon mutation, 12 large genomic deletions, and 1 exon duplication mutation--yielding an increase of 33% (14/42) in diagnostic yield of deleterious mutations. Conversion analysis also showed that 4 of 16 missense changes resulted in exon skipping in transcripts and that 17 of 22 putative splice site mutations affected splicing or mRNA transcript stability. Conversion analysis provided an increase of 56% (35/63) in the diagnostic yield of genetic testing compared with genomic DNA sequencing alone. CONCLUSIONS: The data confirm the heterogeneity of mismatch repair mutations and reveal that many mutations in colorectal cancer cases would be missed using conventional genomic DNA sequencing alone. Conversion analysis substantially increases the diagnostic yield of genetic testing for mismatch repair mutations in patients diagnosed as having colorectal cancer.

Adaptor Proteins, Signal Transducing↗

PubMed2005

Gene expression signatures for colorectal cancer microsatellite status and HNPCC.

The majority of microsatellite instable (MSI) colorectal cancers are sporadic, but a subset belongs to the syndrome hereditary non-polyposis colorectal cancer (HNPCC). Microsatellite instability is caused by dysfunction of the mismatch repair (MMR) system that leads to a mutator phenotype, and MSI is correlated to prognosis and response to chemotherapy. Gene expression signatures as predictive markers are being developed for many cancers, and the identification of a signature for MMR deficiency would be of interest both clinically and biologically. To address this issue, we profiled the gene expression of 101 stage II and III colorectal cancers (34 MSI, 67 microsatellite stable (MSS)) using high-density oligonucleotide microarrays. From these data, we constructed a nine-gene signature capable of separating the mismatch repair proficient and deficient tumours. Subsequently, we demonstrated the robustness of the signature by transferring it to a real-time RT-PCR platform. Using this platform, the signature was validated on an independent test set consisting of 47 tumours (10 MSI, 37 MSS), of which 45 were correctly classified. In a second step, we constructed a signature capable of separating MMR-deficient tumours into sporadic MSI and HNPCC cases, and validated this by a mathematical cross-validation approach. The demonstration that this two-step classification approach can identify MSI as well as HNPCC cases merits further gene expression studies to identify prognostic signatures.

Adenocarcinoma↗

PubMed2001

[Expression level of c-erbB-2 protein correlates with the prognosis of patients with colorectal cancer].

OBJECTIVE: To study the expression level of c-erbB-2 gene in colorectal cancer and its correlation to prognosis. METHODS: In 173 colorectal carcinoma patients, c-erbB-2 protein was examined immunohistochemically and patients' prognosis was evaluated by retrospective analysis combined with follow-up data. RESULTS: The immunohistochemical staining of c-erbB-2 protein was found in the cytoplasm and membrane with a positive rate of 52% in tumor tissue. The 1-, 3-, 5- and 10-year survival rate of patients with negative c-erbB-2 expression was 98.7%, 92.4%, 87.1% and 84.1% respectively; that of the patients with weakly positive c-erbB-2 expression was 94.5%, 76.1%, 72.3% and 68.3%, respectively. In contrast, that of patients with strongly positive c-erbB-2 expression was 91.0%, 43.5%, 36.8% and 23.4%, respectively. The survival rates among the three groups of patients were statistically different. Multivariate survival analysis by Cox regression model showed that c-erbB-2 expression level was a risky prognostic factor for colorectal cancer. CONCLUSION: The expression level of c-erbB-2 protein is an independent prognostic factor in colorectal carcinoma.

Adult↗

PubMed2000

Alterations of the PPP2R1B gene located at 11q23 in human colorectal cancers.

BACKGROUND/AIMS: In 1998 the PPP2R1B gene encoding the A subunit of the serine/threonine protein phosphatase was identified as a putative tumour suppressor gene in lung and colon cancer in the chromosome region 11q22-24. The aim of the present study was to determine the type of alterations in primary rectal cancers as well as colon cancers and the correlation between these alterations and clinicopathological data. METHODS: Mutation analyses of the PPP2R1B gene sequence encoding the binding sites of the catalytic C subunit (Huntington elongation A subunit TOR (HEAT) repeats 11-15) and partial binding sites of the regulatory B subunit were carried out on cDNA samples from 30 primary colorectal cancer specimens and corresponding normal tissues using a combination of the polymerase chain reaction and subsequent direct DNA sequencing. RESULTS: Five missense mutations producing amino acid substitutions were detected in the four colon cancer cases (13.3%; four of 30 colorectal cancers): (15)glycine (GGT) to alanine (GCT) and (499)leucine (TTA) to isoleucine (ATA) in the same case, and (498)valine (GTG) to glutamic acid (GAG), (500)valine (GTA) to glycine (GGA), and (365)serine (TCT) to proline (CCT). Of these five mutations, three (60%) were located in HEAT repeat 13 and four (80%) showed T to other nucleotide substitutions. In addition, a normal polymorphism, (478)leucine, was found. No correlation was found between these mutations and clinicopathological data. CONCLUSION: Our results suggest that the PPP2R1B gene is one of the true targets at 11q23, and its inactivation is involved in the development of all types of colorectal cancers.

Adult↗

PubMed2000

Enzyme/prodrug gene therapy for human colon cancer cells using adenovirus-mediated transfer of the Escherichia coli cytosine deaminase gene driven by a CAG promoter associated with 5-fluorocytosine administration.

Escherichia coli cytosine deaminase (CD), which is a prokaryotic enzyme, converts nontoxic prodrug 5-fluorocytosine (5-FC) into the toxic chemotherapeutic agent 5-fluorouracil (5-FU). To investigate an enzyme/prodrug gene therapy for colorectal cancer, using adenoviral gene transfer of the E. coli CD gene associated with administration of 5-FC, we constructed replication-defective adenovirus vectors expressing the E. coli CD gene or lacZ gene driven by a CAG promoter (composed of a cytomegalovirus immediate early enhancer and a chicken beta-actin promotor). The present study demonstrated that an adenoviral gene transfer system using a CAG promoter induced sufficient gene expression of CD to confer the cytotoxicity of 5-FC to HT29 human colon cancer cells by converting it into 5-FU even at an moi of one. Furthermore, experimental gene therapy using intratumoral injection of the CD-expressing adenovirus with systemical administration of 5'-FC successfully suppressed the growth of established HT29 subcutaneous tumors in nude mice. These results suggest that enzyme/prodrug gene therapy using the adenoviral gene transfer of the E. coli CD gene with concomitant administration of 5-FC may be an effective strategy in the local control of colorectal cancer.

Adenoviridae↗

PubMed2005

Genetic and epigenetic alterations of the candidate tumor-suppressor gene MYO18B, on chromosome arm 22q, in colorectal cancer.

Allelic imbalance (AI) on chromosome arm 22q has been detected in 20%-40% of colorectal cancers, suggesting that this chromosome arm has a tumor-suppressor gene involved in colorectal carcinogenesis. Recently, we isolated a candidate tumor-suppressor gene, MYO18B, at 22q12.1, that is deleted, mutated, and hypermethylated in more than 50% of lung cancers. In the present study, we analyzed genetic and epigenetic alterations of the MYO18B gene in colorectal cancers. AI at the MYO18B locus was detected in 16 of 43 (40%) informative cases. Mutations of the MYO18B gene were detected in 2 of 11 (18%) cell lines and 1 of 47 (2%) surgical specimens. Nine of 11 (82%) cell lines showed reduced MYO18B expression, which was restored in all 9 by treatment with 5-aza-2'-deoxycytidine and/or trichostatin A (TSA). Although hypermethylation of the promoter CpG island for MYO18B was not detected, a significant correlation was observed between the level of MYO18B expression and the level of acetylation of histones H3 and H4 in 6 cell lines with and without TSA treatment. Thus, it was suggested that MYO18B is inactivated in a considerable fraction of colorectal cancers by several mechanisms, especially silencing by histone deacetylation and/or AI. Furthermore, restoration of MYO18B expression in colorectal cancer cell lines HT29 and DLD-1 suppressed anchorage-independent growth, whereas it did not affect the growth rate in vitro. These results suggest that genetic and epigenetic inactivation of the MYO18B gene play an important role in colorectal carcinogenesis.

Acetylation↗

PubMed2006

[The expression of mutation p53 gene from circulating cancer cells of peripheral blood and the clinical significance in detecting the patients with colorectal cancer].

OBJECTIVE: To study the clinical significance of detecting p53 gene mutation expression in colorectal cancer cells of peripheral blood. METHODS: Flow cytometry (FCM) was used to detect p53 gene mutation expression in peripheral blood cancer cells of 128 patients with colorectal cancer. Experimental data were analyzed by SPSS (v.11.0) software. RESULTS: The lymph node metastasis showed the significant difference statistically (P<0.01) between p53 positive and negative expression in the colorectal cancer patients. The mutation p53 expression associated with existing histological differentiation (r=0.8476, P<0.05). A lymph node metastasis difference was observed between left and right colorectal cancers of mutation p53 positive expression. CONCLUSION: Detecting the mutation p53 expression in cancer cells of peripheral blood might be helpful to the early diagnosis of colorectal cancer.

Adult↗

PubMed1998

Absence of somatic alterations of the EB1 gene adenomatous polyposis coli-associated protein in human sporadic colorectal cancers.

The human EB1 gene product was recently found, by a yeast two-hybrid screening, to be associated with the carboxy terminus of the APC (adenomatous polyposis coli) protein, the product of a tumour-suppressor gene thought to act as a gatekeeper in colorectal carcinogenesis. Because virtually all of the APC mutations result in the synthesis of carboxy-terminal truncated proteins, mutant APC proteins are expected to lose their ability to interact with EB1 gene product. Thus, the interaction between APC and EB1 proteins may be important for the tumour-suppressor activity of APC protein, and raises the hypothesis that EB1 is also involved in sporadic colorectal tumorigenesis. To investigate this hypothesis, somatic mutations in the entire coding sequence of EB1 cDNA were searched by reverse transcriptase single-strand conformational polymorphism (SSCP) analysis in 21 sporadic colorectal cancers and seven adenomas. None of these tumours contained somatic mutation, whereas a silent cDNA variant was identified in 14% of alleles. Furthermore, to investigate whether EB1 locus was included within a region subjected to losses of heterozygosity, four polymorphism markers surrounding EB1 locus were surveyed. Only one out of 28 colorectal tumours contained a loss of heterozygosity at the D20S107 marker. In conclusion, the present findings strongly suggest that EB1 gene is not involved in somatic colorectal carcinogenesis.

Adenomatous Polyposis Coli↗

PubMed2005

High frequency of hereditary colorectal cancer in Newfoundland likely involves novel susceptibility genes.

PURPOSE: Newfoundland has one of the highest rates of colorectal cancer in North America. The most common hereditary form of colorectal cancer is hereditary nonpolyposis colorectal cancer caused by mutations in genes involved in mismatch repair. Our purpose was to determine the proportion of hereditary colorectal cancer and to determine the genetic basis of disease in both population and clinically referred cohorts from Newfoundland. EXPERIMENTAL DESIGN: Seventy-eight colorectal cancer patients were accrued over a 2-year period from the Avalon Peninsula of Newfoundland. We also examined 31 hereditary nonpolyposis colorectal cancer-like families, which had been referred to the Provincial Medical Genetics Program. Tumors from probands were tested by immunohistochemistry for deficiencies in MLH1, MSH2, and MSH6 proteins and tested for DNA microsatellite instability. Mutation analyses of MLH1, MSH2, and MSH6 were undertaken by direct sequencing and an assay to detect deletions, amplifications, and rearrangements in MSH2 and MLH1. RESULTS: We identified eight population-based families that fulfill the Amsterdam I or II criteria, 4 (50%) of which seem to have hereditary cancer not attributable to the most commonly mutated mismatch repair genes. In addition, in 16 of 21 (76%) referred families fulfilling Amsterdam I or II criteria, no mutations were found in the three most commonly altered mismatch repair genes, and tumor analyses corroborated these findings. CONCLUSIONS: It seems that strong and novel genetic causes of hereditary colorectal cancer are responsible for a high proportion of colorectal cancer in this population. Conditions are suitable for the identification of these genes by linkage studies of large Newfoundland cancer families.

Adaptor Proteins, Signal Transducing↗

PubMed1991

A novel point mutation at codon 146 of the K-ras gene in a human colorectal cancer identified by the polymerase chain reaction.

In this report, point mutations of the K-ras gene at codon 146 were analyzed in 25 cases of colon cancer, 4 cases of lung cancer, and 41 cases of lymphoid malignancy. A codon 146 mutation substituting threonine (ACA) for alanine (GCA) was detected in the tumor tissue of a patient with colon cancer and was not detected in the normal tissue of the same patient. Any additional mutations of the ras gene family were not detected in this patient. These results suggest that the codon 146 mutation of the K-ras gene could be involved in the development of naturally occurring human malignancies.

Antisense Elements (Genetics)↗