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PubMed2002

Deletion of the FHIT gene in human colorectal cancer is independent of high-risk HPV infection.

BACKGROUND AND AIMS: The fragile histidine triad (FHIT) gene, which is frequently lost in many cancers, has been identified as a candidate tumor suppressor gene at chromosome 3p locus 14.2. Human papillomaviruses (HPVs) are the major cause of cervical carcinoma and have been found to be able to integrate its genes into the chromosome 3 fragile site of cultured cells, deleting a piece of DNA which includes the FHIT gene. MATERIALS AND METHODS: We used nested reverse transcriptase PCR and DNA sequencing to evaluate 32 cases of colorectal adenocarcinoma and matched nearby normal tissues for aberrant transcripts of FHIT and infection of high-risk HPVs. RESULTS: Aberrant transcripts of the FHIT gene were observed in 34.4% of colorectal adenocarcinoma and in 6.3% of matched nearby normal tissues. The HPV(16) DNA was detected in 21.9% of colorectal adenocarcinomas and 3.1% of matched nearby normal tissues using PCR. Only two cases of colorectal adenocarcinoma contained both aberrant transcripts of FHIT and HPV(16) infection. No HPV(18) infection was detected in the present study. CONCLUSION: Our results indicate that alteration of the FHIT gene and HPV(16) infection are important genetic events associated with colorectal adenocarcinoma. However, there is no correlation between FHIT abnormalities, clinicopathological features, and HPV(16) infection in colorectal adenocarcinoma.

Acid Anhydride Hydrolases↗

PubMed2004

Impact of GSTT1, GSTM1, GSTP1 and NAT2 genotypes on KRAS2 and TP53 gene mutations in colorectal cancer.

Which carcinogens are of influence in the development of human colorectal cancers remains a question; one answer could be the finding that specific polymorphisms in xenobiotic metabolizing enzymes are related to particular mutations in cancer genes. KRAS2 and TP53 gene mutations as well as genotypes for GSTM1, GSTP1, GSTT1 and NAT2 were determined in an exploratory series of 165 stable colorectal cancers. Mutations in KRAS2 and TP53 were found in 34% and 57.5% of cases, respectively. The KRAS2 mutation frequency was significantly lower in patients with a GSTT1 null genotype than in those with a GSTT1 non-null genotype (18% vs. 38%, p = 0.03). The overall risk of KRAS2 mutation for patients with distal colorectal cancer and GSTT1 null genotype was 0.3 (95% CI 0.1-0.9) compared to patients with distal colorectal cancer and non-null GSTT1 genotype. The overall risk of KRAS2 mutation was similarly reduced (OR = 0.4, 95% CI 0.2-0.9) for patients with distal colorectal cancer and GSTP1 mutated genotypes compared to patients with distal colorectal cancer and wild-type genotype. Patients with GSTP1 wild-type genotype appeared to be at significantly lower risk for TP53 mutation compared to patients with mutated genotypes (p = 0.023). Our results suggest that GSTT1 and GSTP1 could play a role in the occurrence of KRAS2 and TP53 mutations in colorectal cancer and generate a hypothesis on the dietary factors that could be incriminated.

Adult↗

PubMed1997

K-ras and p53 gene mutations in colorectal cancer in 57 Japanese patients.

Fifty-eight tissue specimens from 57 Japanese patients with colorectal cancer were analyzed for the K-ras and p53 gene mutations by polymerase chain reaction-single strand conformation polymorphism analysis and direct sequencing. K-ras mutations were detected in 21 cases (36.2%) and p53 mutations in 20 cases (34.5%). Eight specimens had both gene mutations. The K-ras mutation was associated with higher degrees of differentiation (p = 0.0019). The P53 mutation was associated with Duke B to D staging (p = 0.028), lymph vessel invasion (p = 0.021), and venous invasion (p = 0.03). Interestingly, a mutation in only exon 7 of the P53 gene was associated with lymph node metastasis. These results suggest the important effect of the mutations of the K-ras and p53 genes, especially p53 gene on colorectal carcinogenesis in Japanese patients. The grades of malignancy of the specimens with the mutations in both genes were not different significantly from those with a single (K-ras or p53) or no mutation, suggesting no cooperation between K-ras and p53 gene mutations on carcinogenesis or tumorigenesis.

Adenocarcinoma↗

PubMed2000

Mutations of the bak gene in human gastric and colorectal cancers.

The Bcl-2 homologue Bak is a potent inducer of apoptosis. We performed PCR-based single-strand conformational polymorphism and sequencing analysis of the entire coding region of the bak gene (exons 2-6) in 24 primary gastric cancers (6 early-stage and 18 advanced-stage cancers) and 20 primary colorectal cancers (6 early-stage and 14 advanced-stage cancers). The data herein demonstrate, for the first time, the mutation of the bak gene in gastric and colorectal cancers. Missense bak gene mutations were observed in 3 of 24 (12.5%) gastric cancers and 2 of 20 (10.0%) colorectal cancers. Sequence alterations without amino acid alteration were observed 1 of 24 (4.2%) gastric cancers and 2 of 20 (10.0%) colorectal cancers. Mutations in the bak gene were observed only in advanced-stage gastrointestinal cancers but not in early-stage cancers. Our observations suggest that mutations in this gene predispose bearers to the development of gastrointestinal malignancies in at least a subset of the cases.

Colorectal Neoplasms↗

PubMed2001

Glutathione-S-transferase gene polymorphisms in colorectal cancer patients: interaction between GSTM1 and GSTM3 allele variants as a risk-modulating factor.

The distribution of polymorphisms in the glutathione S-transferase (GST) family genes has been studied in 355 healthy controls and 206 cancer (59 proximal and 147 distal) patients. All controls were subjected to flexible sigmoidoscopy. Odds ratios (OR) after stratification by age, gender and smoking were slightly higher in the cancer group as a whole for GSTM1-null (*0/*0), GSTT1-null (*0/*0) and GSTM3 *A/*B or *B/*B when compared with the control group, but the differences did not reach statistical significance. GSTP1 variants had no effect. Separate analysis of patients with proximal and distal tumours has shown stronger associations for the distal cancers, the GSTM3*B allele presence being significantly more frequent in these patients [OR = 1.77; 95% confidence interval (CI) = 1.15-2.74]. Taking into account strong linkage between the GSTM1*A and GSTM3*B alleles, a separate analysis of the GSTM1-nulled individuals was undertaken. The combination of GSTM1-null genotype with GSTM3*B allele presence (*A/*B or *B/*B) was significantly overrepresented among patients with proximal and distal tumours taken together (OR = 2.12; 95% CI = 1.24-3.63), and especially in distal cancer patients (OR = 2.75; 95% CI = 1.56-4.84). Male individuals displayed a stronger association between the presence of the GSTM1-null in combination with GSTM3 *A/*B or *B/*B and distal tumours with a higher odds ratio (OR = 3.57; 95% CI = 1.73-7.36). In contrast, the frequency of GSTM1 *B/*0 or *B/*B combined with GSTM3 *A/*A was significantly lower in patients with distal colorectal cancer, especially in males (OR = 0.37; 95% CI = 0.15-0.92). Neither of these combinations was associated with proximal tumours. Our findings suggest that interactions of polymorphic genotypes within the GSTM gene cluster affect individual susceptibility to colorectal carcinogenesis, the GSTM3*B variant presence being a risk factor especially in combination with the GSTM1-null genotype.

Alleles↗

PubMed2006

Single-nucleotide polymorphisms of mismatch repair genes in healthy Chinese individuals and sporadic colorectal cancer patients.

Mismatch repair (MMR) genes are among of the most important genes associated with colorectal cancer (CRC). Single-nucleotide polymorphisms (SNPs) are generally thought to provide important information across a wide spectrum of life sciences; however, no study of association between SNPs of MMR genes and Chinese sporadic colorectal cancer (SCRC) is available. We chose 29 reported single-nucleotide variants that have rarely been verified in a population-based study. We identified SNPs and the genotype-phenotype association in Chinese populations of 150 healthy individuals and 160 SCRC patients. We extracted the genomic DNA from the blood of these individuals and used sequencing to determine these SNPs. Three SNPs (MLH1 394G-->C, 655A-->G, 1151T-->A) occurred with a frequency of 8.8-11.2% in the Chinese population. These SNPs formed a series with combined effects. The haplotype of concurrent MLH1 655 and 1151 SNPs and the haplotype combinations of MLH1 1151, MLH1 394 occurred exclusively in SCRC. None of the other 26 variants were detected in the Chinese population.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Frequent rearrangements and amplification of the CDX2 homeobox gene in human sporadic colorectal cancers with chromosomal instability.

The expression of the CDX2 gene, a crucial regulator of gut homeostasis, is altered in human colorectal cancers in parallel with de-differentiation. Here, we have investigated the chromosomal status of CDX2 in human sporadic colorectal cancers with the phenotype of chromosomal instability. Allelic imbalance determination showed frequent rearrangements at the CDX2 locus. The rearrangements correlated with CDX2 gene amplification, as assessed by quantitative PCR analysis. However, they were not predictive of the Cdx2 protein pattern. These data suggest that mechanisms other than structural alterations at the CDX2 locus account for the change of expression in colorectal cancers.

Base Sequence↗

PubMed1991

[Prevalence of K-ras gene mutations in human colorectal cancers].

It has been reported that mutations in the human ras gene family convert these genes into active oncogenes. In the present study using in vitro gene amplification by the polymerase chain reaction (PCR) and mutation detection by the oligonucleotide hybridization assay, a total of 86 colorectal cancers were analyzed for the point mutations at codon 12 and 13 of K-ras genes. Mutations were present in 33 of the 86 colorectal cancers examined; 32 of the 33 mutations were at codon 12 of this gene and one of them was at codon 13. There was no apparent correlation between the presence of a ras gene mutation in a carcinoma and its anatomical location, level of differentiation, depth of invasion, degree of lymphnode metastasis or stage of progression, however, the high incidence of K-ras mutations was observed in early stage carcinomas (depth m and sm). This results support the concept that the point mutation of K-ras gene is early event in tumorigenesis of colorectal cancer.

Base Sequence↗

PubMed2003

Differential gene expression profiles and identification of the genes relevant to clinicopathologic factors in colorectal cancer selected by cDNA array method in combination with principal component analysis.

The clinical outcome of patients with colorectal cancer frequently varies even if they are at the same clinicopathologic stage. Alternative superior tumor markers of colorectal cancer are needed for prediction of clinical outcome. To clarify the regulatory factors in colorectal cancers, we examined differential expression profiles using cDNA macroarray technique with surgically resected specimens obtained from the patients with colorectal cancer. The gene profiles by an average-linkage hierarchical clustering analysis were found to be almost separable into two groups: tumor group and normal mucosa group. The relationship between several clinicopathologic factors and cancer related genes were investigated by using statistical analyses including principal component analysis (PCA). c-myc-binding protein MM-1, and c-jun proto-oncogene were identified as possible markers of tumor histology and clinical prognosis and early growth response protein 1 (EGR1) was selected to play an important role in progression of clinical stage. We conclude that, with PCA method, we successfully selected the genes relevant to clinicopathologic factors using limited population of clinical samples.

Aged↗

PubMed2002

Analysis of gene expression in human colorectal cancer tissues by cDNA array.

BACKGROUND: The development and progression of cancer are accompanied by complex changes in patterns of gene expression. The purpose of this study was to clarify the relevance of macroarray analysis of human colorectal cancer tissues. METHODS: Hybridization of cDNA macroarray filters on which 550 genes had been spotted was performed with biotin-labeled cDNA targets that were prepared from mRNA extracted from 20 pairs of colorectal cancer and corresponding noncancerous tissues. Expression of differentially expressed genes was further studied by semiquantitative RT-PCR. RESULTS: Fourteen (2.5%) of the 550 genes were differentially expressed and up- or downregulated in cancer tissues by at least threefold compared with matched noncancerous tissues in 10 or more of the 20 patients. The genes that were upregulated in cancer tissues were associated with transcription, cell cycle, growth factor receptor, cell adhesion, extracellular matrix-degrading enzymes, and angiogenesis, and the downregulated genes were those involved in apoptosis and immune recognition. Semiquantitative RT-PCR analysis of these differentially expressed genes gave results consistent with those by cDNA array analysis. CONCLUSIONS: Although the macroarray used in this study contained only a small number of genes, our results support the feasibility and usefulness of this approach to study variation in gene expression patterns in human colorectal cancer tissues. The results also suggest the possibility of a diagnostic application of cDNA macroarrays in daily clinical settings.

Biopsy, Needle↗

PubMed1997

An intronic germline transition in the HNPCC gene hMSH2 is associated with sporadic colorectal cancer.

The aim of this study was to determine whether an intronic germline substitution in the hereditary non-polyposis colorectal cancer (HNPCC) gene hMSH2 represents a genetic risk factor for sporadic CRC. Possible effects of this substitution were investigated by assessment of microsatellite instability and hMSH2 cDNA sequencing. Constitutional DNA from patients with sporadic CRC and healthy controls from the same region in Germany was analysed for the intronic germline T-->C transition six bases upstream of exon 13 of hMSH2. 29 of 106 patients (27%) were found to harbour the germline T-->C transition as opposed to only 13 of 125 controls (10%; P < 0.001; OR 3.2, CI 1.58-6.63). CRCs from patients with the substitution displayed neither clinical HNPCC-like features nor an increased rate of microsatellite instability. No abnormal cDNA sequence was found at the exon 12-13 border. These data suggest a 3.2-fold increased risk of sporadic CRC for individuals with the intronic hMSH2 transition. However, this substitution might not be pathogenic itself, but may be linked to a locus nearby that is.

Adult↗

PubMed1996

Frequent coordinated overexpression of the MRP/GS-X pump and gamma-glutamylcysteine synthetase genes in human colorectal cancers.

We have recently shown that multidrug resistance-associated protein (MRP) and gamma-glutamylcysteine synthetase (gamma-GCS) heavy subunit genes are coordinately overexpressed in cisplatin-resistant human leukemia cells (T. Ishikawa et al. J. Biol. Chem., 271: 14981-14988, 1996). Using the RNase protection assay, we examined expression levels of these genes in colon tumor and nontumorous biopsy specimens from 32 cancer patients who had not been treated with chemotherapy. Increased mRNA levels (P < 0.001) of MRP and gamma-GCS genes were observed in 16 (50%) and 20 (62%) tumor samples, respectively. More importantly, all of the 16 (100%) MRP-overexpressing tumor specimens also exhibited higher levels of gamma-GCS mRNA than those in the matched nontumorous specimens. The correlation coefficient between MRP and gamma-GCS mRNA levels was r = 0.78 for all of the tumor samples studied. These results strongly suggest that MRP and gamma-GCS genes are coordinately up-regulated during colorectal carcinogenesis.

ATP-Binding Cassette Transporters↗

PubMed2005

Effect of SNC19/ST14 gene overexpression on invasion of colorectal cancer cells.

AIM: To study the effect of SNC19/ST14 gene overexpression on invasion in vitro of colorectal cancer cells. METHODS: The adhesion of SNC19/ST14 gene-transfected cells to ECM was measured by MTT assay. The cell movement was evaluated by wound healing assay. Cell invasion and migration were determined by invasion assay in vitro. RESULTS: SNC19/ST14 gene overexpression could enhance invasion of colorectal cancer cells in vitro significantly and influence early cell adherence to ECM, but could not change cell movement significantly. CONCLUSION: SNC19/ST14 gene overexpression increases the local invasion of colorectal cancer cells in vitro.

Cell Adhesion↗

PubMed2024

Identification and analysis of key genes related to efferocytosis in colorectal cancer.

UNLABELLED: The impact of efferocytosis-related genes (ERGs) on the diagnosis of colorectal cancer (CRC) remains unclear. In this study, efferocytosis-associated biomarkers for the diagnosis of CRC were identified by integrating data from transcriptome sequencing and public databases. Finally, the expression of biomarkers was validated by real-time quantitative polymerase chain reaction (RT-qPCR). Our study may provide a reference for CRC diagnosis. BACKGROUND: It has been shown that some efferocytosis related genes (ERGs) are associated with the development of cancer. However, it is still uncertain how ERGs may influence the diagnosis of colorectal cancer (CRC). METHODS: In our study, the CRC cohorts were gained from transcriptome sequencing and the gene expression omnibus (GEO) database (GSE71187). Efferocytosis related biomarkers with diagnostic utility for CRC were identified through combining differentially expressed analysis, machine learning algorithms, and receiver operating characteristic (ROC) analysis. Then, infiltration abundance of immune cells between CRC and control was evaluated. The regulatory networks (including mRNA-miRNA-lncRNA and miRNA/transcription factors (TF)-mRNA networks) were created. Finally, the expression of biomarkers was validated via real-time quantitative polymerase chain reaction (RT-qPCR). RESULTS: There were 3 biomarkers (ELMO3, P2RY12, and PDK4) related diagnosis for CRC patients gained. ELMO3 was highly expressed in CRC group, while P2RY12 and PDK4 was lowly expressed. Besides, the infiltrating abundance of 3 immune cells between CRC and control groups was significantly differential, namely activated CD4 memory T cells, macrophages M0, and resting mast cells. We then constructed a mRNA-miRNA-lncRNA network containing 3 mRNAs, 33 miRNAs, and 22 lncRNAs, and a miRNA/TF-mRNA network including 3 mRNAs, 33 miRNAs, and 7 TFs. Additionally, RT-qPCR results revealed that the expression trends of all biomarkers were consistent with the transcriptome sequencing data and GSE71187. CONCLUSION: Taken together, this study provides three efferocytosis related biomarkers (ELMO3, P2RY12, and PDK4) for diagnosis of CRC, providing a scientific reference for further studies of CRC.

Humans↗

PubMed2003

High frequency of DAP-kinase gene promoter methylation in colorectal cancer specimens and its identification in serum.

Death-associated protein (DAP)-kinase is frequently inactivated by promoter methylation in human cancers. To understand the involvement of the DAP-kinase gene in colorectal cancer (CRC), we investigated the methylation of the DAP-kinasegene in primary CRC to define the frequency of this epigenetic aberration and the clinicopathological significance. For this reason, methylation-specific polymerase chain reaction (MSP) was used to detect DAP-kinase gene methylation in DNA from 122 cases of CRC and 18 paired serum samples. Methylation of the DAP-kinase gene was found in 67 of 122 (55%) cases of primary CRC. Study of the serum DNA from 14 patients exhibiting methylated DAP-kinase gene revealed aberrant methylation in three patients (21%). False positives were not obtained in any of the patients who did not exhibit methylation. No association was found between the promoter methylation of the DAP-kinase gene in primary CRC and gender, localization, tumor differentiation, invasion depth, regional lymph node involvement, or tumor stage. In conclusion, methylation of the DAP-kinase gene is common in CRC. The detection of the methylation of the DAP-kinase gene has a potential clinical application as a diagnostic tumor marker for CRC.

Apoptosis Regulatory Proteins↗

PubMed2006

5-fluorouracil-related gene expression levels in primary colorectal cancer and corresponding liver metastasis.

Gene expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP) and orotate phosphoribosyl transferase (OPRT) have been shown to be associated with response to 5-fluorouracil-based therapies. Analyzing these gene expression levels in liver metastases is important to obtain the best prediction of therapy. Our aim was to determine how TS, DPD, TP and OPRT gene expression levels in primary colorectal cancer (CRC) were related to those in liver metastases. Formalin-fixed, paraffin-embedded tumor specimens from 31 pairs of primary CRC and corresponding liver metastases were dissected by using laser-captured microdissection. RNA was extracted and cDNA was prepared by reverse-transcription. Quantitation of target gene and internal reference gene was performed using real-time PCR. No significant difference was seen between median mRNA expression levels of TS, DPD, TP and OPRT in primary cancer and those in corresponding liver metastases (median value: TS 1.48 vs. 1.43; p=0.92, DPD 0.19 vs.0.12; p=0.10, TP 1.20 vs. 0.98; p=0.39, OPRT 1.17 vs. 0.95; p=0.10). When matched tissue sets were compared on an individual basis, there was a significant correlation for TS mRNA expression between primary cancer and corresponding liver metastases (rs=0.52, p=0.0026). However, no correlation was seen between matched sets for DPD, TP or OPRT. Significant correlation was seen between DPD and TP expression levels in both primary CRC (rs=0.38, p=0.03) and liver metastases (rs=0.72, p<0.0001). A good prediction of TS mRNA levels in liver metastases can be obtained by measuring those of primary CRC, although no correlation was seen for DPD, TP and OPRT.

Aged↗

PubMed1999

Absence of prolactin gene expression in colorectal cancer.

AIMS: Previous studies documenting hyperprolactinaemia in patients with colorectal cancer have suggested that the tumour is the source of hormone production. The aim of this study was to determine the frequency of hyperprolactinaemia in patients with colorectal cancer before, during, and after surgery, and also to determine whether prolactin is produced by these tumours. METHODS: Serum prolactin concentrations were measured in 20 patients with colorectal cancer before, during, and after surgical resection of their tumours. Samples taken during surgery included peripheral venous blood and blood taken from the main veins draining the tumour. To determine whether the tumour was responsible for the production of prolactin in these patients, paraffin wax embedded sections of tumour specimens were subjected to immunohistochemistry and western blotting using a monoclonal antibody to prolactin. RESULTS: Five patients (three women, two men) had preoperative prolactin concentrations above the normal reference range, although this increase was of clinical importance in only two. After surgical resection of their tumours, prolactin concentrations remained high in both patients. All 20 patients had greatly raised prolactin values at the time of surgery, irrespective of whether this was measured in peripheral blood or in blood taken from veins draining the tumour. All 20 colorectal cancer tissue samples, including those with raised preoperative and/or postoperative prolactin concentrations, were negative for prolactin staining. Frozen tissue was also available in four cases. The absence of prolactin gene expression in these four tumours was confirmed both by repeat immunohistochemistry and by western blotting. A further 50 colorectal cancer cases examined by immunohistochemistry alone were also unreactive for prolactin. CONCLUSIONS: The results of this study suggest that serum prolactin concentrations may occasionally be raised in colorectal cancer patients, but that the tumour is not the source of hormone production.

Blotting, Western↗

PubMed2002

Gene expression in colorectal cancer.

Understanding molecular alterations in colorectal cancer (CRC) is needed to define new biomarkers and treatment targets. We used oligonucleotide microarrays to monitor gene expression of about 6,800 known genes and 35,000 expressed sequence tags (ESTs) on five pools (four to six samples in each pool) of total RNA from left-sided sporadic colorectal carcinomas. We compared normal tissue to carcinoma tissue from Dukes' stages A-D (noninvasive to distant metastasis) and identified 908 known genes and 4,155 ESTs that changed remarkably from normal to tumor tissue. Based on intensive filtering 226 known genes and 157 ESTs were found to be highly relevant for CRC. The alteration of known genes was confirmed in >70% of the cases by array analysis of 25 single samples. Two-way hierarchical average linkage cluster analysis clustered normal tissue together with Dukes' A, clustered Dukes' B with Dukes' C, and clustered Dukes' D separately. Real-time PCR of 10 known genes and 5 ESTs demonstrated excellent reproducibility of the array-based findings. The most frequently altered genes belonged to functional categories of metabolism (22%), transcription and translation (11%), and cellular processes (9%). Fifteen nuclear encoded mitochondrial proteins were all down-regulated in CRC. We identified several chromosomal locations with clusters of either potential oncogenes or potential tumor suppressors. Some of these, such as aminopeptidase N/CD13 and sigma B3 protein on chromosome 15q25, coincided with a high frequency of loss of heterozygosity. The genes and ESTs presented in this study encode new potential tumor markers as well as potential novel therapeutic targets for prevention or therapy of CRC.

Biomarkers, Tumor↗