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PubMed1995

The deleted in colorectal cancer (DCC) gene: a candidate tumour suppressor gene encoding a cell surface protein with similarity to neural cell adhesion molecules.

Chromosome 18q is among the regions thought to harbour a tumour suppressor gene(s) that is frequently inactivated by LOH during the development of several cancer types, including those of the gastrointestinal tract. In addition, colorectal cancers with 18q LOH have been shown to have a more aggressive clinical behaviour than those without 18q LOH. A candidate tumour suppressor gene from 18q, called DCC, has been identified. The DCC gene is contained within the common region of LOH on 18q, its expression is markedly decreased or absent in the majority of colorectal cancers and cell lines and somatic mutations within the DCC gene have been identified in a subset of cases. Thus, DCC represents the strongest candidate tumour suppressor gene on 18q. At present, however, many questions remain regarding the mechanisms underlying the inactivation of DCC and its decreased expression in cancers. The predicted structural similarity of DCC to the NCAMs suggests that it may function through cell-cell and/or cell-extracellular matrix interactions; however, little is known regarding the specific cellular function(s) of DCC. Many reports have detailed the alterations in phenotype observed in cancer cells, including changes in cell morphology and tissue architecture, loss of differentiated phenotype, decreased cell adhesion and aggregation, increased motility and invasive behaviour. These altered properties are likely to account in part for the invasive and metastatic properties of cancer cells in the patient. It is hoped that further studies will identify the means by which DCC inactivation may contribute to the altered growth properties of advanced cancer cells.

Alternative Splicing↗
PubMed2005

Absence of mutation in the putative tumor-suppressor gene KLF6 in colorectal cancers.

The KLF6 gene encodes the Krüppel-like factor 6, a transcription factor that has been individualized as a tumor-suppressor gene involved in the regulation of cell proliferation and differentiation. Recently, high frequency (42%) of KLF6 mutations have been reported in colorectal cancers (CRC) as in prostate cancers, astrocytic gliomas and hepatocellular carcinomas. The aims of the study was to confirm the frequency of KLF6 mutations in a larger series of CRC than that previously published by using DNA extracted from frozen tissue samples, which have been proved to generate less mutational artefact than that extracted from formalin-fixed paraffin-embedded tissue samples, in order to compare KLF6 mutation frequency with that of other common genetic alterations and to determine genotype-phenotype correlations. Amplification and direct sequencing of KLF6 exon 2 of 76 CRC and matched normal frozen tissues was performed. Polymorphisms were observed in 14 cases, among which two (T35T and S116S) had not already been reported. No KLF6 somatic mutation was observed. Our data suggest a minor role of KLF6 mutation in colorectal carcinogenesis and underline the fact that the validity of sequence informations obtained from DNA extracted from formalin-fixed tissues may be limited.

Aged↗
PubMed1995

Coexpression of cdk2/cdc2 and retinoblastoma gene products in colorectal cancer.

The retinoblastoma gene (Rb gene) is a tumour-suppressor gene and its product (pRB) is known to act as a negative regulator of the cell cycle. Although lack of pRB expression resulting from gene alterations is considered to be responsible for the genesis of several human malignancies, increased expression of pRB has been demonstrated in a majority of colorectal cancer cases. In the present study, we investigated the expression of pRB as well as that of its related kinases, cdk2 and cdc2, in colorectal cancer, since these kinases have been reported to phosphorylate and inactivate pRB. Western blot analysis revealed that colorectal cancer expressed higher levels of cdk2 and cdc2 than did normal mucosa and that the ratio of the hyperphosphorylated form of pRB was higher in colorectal cancer. Furthermore, immunohistochemical studies showed that cdk2/cdc2 was expressed exclusively in the cancer cells positive for pRB. These results suggest that an increase in the expression of cdk2/cdc2 in colorectal cancer may have prevented pRB from braking the cell cycle through phosphorylation.

Blotting, Western↗
PubMed2003

Detection of point mutations of the Axin1 gene in colorectal cancers.

Axin is a recently identified tumor suppressor that plays an important role in liver and colon cancers. To gain further insights into the structure and function of Axin in controlling cell growth, we analyzed 54 colorectal cancer tissues for mutations in AXIN1 gene. We employed PCR amplification with 23 sets of primers against introns that encompassed the whole coding region of AXIN1 followed by single-strand conformation polymorphism (SSCP) analysis. After subcloning and sequencing analysis of the reamplified DNA from the aberrant bands, we found, in addition to 3 silent mutations, 6 missense point mutations in different functionally important regions. The missense mutation rate is hence 11%, suggesting that Axin deficiency may contribute to the onset of colorectal tumorigenesis.

Adenocarcinoma↗
PubMed1999

Hypermethylation of the MYF-3 gene in colorectal cancers: associations with pathological features and with microsatellite instability.

Myf-3 is the human homologue of the murine Myo-D1 gene involved in muscle-cell differentiation. Using Southern blot analysis, we examined methylation of Myf-3 in histologically normal colonic mucosae, adenomas and carcinomas from a large series of patients with primary colorectal cancer. Hypermethylation of this gene in comparison with normal mucosa was observed in 88% of adenomas and in 99% of carcinomas. The pattern of Myf-3 methylation was similar in different areas of the same tumour, suggesting that methylation imbalances occur before the bulk of clonal-cell expansion. Significantly increased levels of Myf-3 methylation were observed in tumours which were more invasive, located in the proximal colon or from older patients. Patients whose tumours had extensive methylation showed a trend for shortened survival, though this was probably related to their being more invasive. Extensive methylation was significantly more frequent in tumours with microsatellite instability. Further work is required to determine whether the hypermethylation of Myf-3 observed in colorectal cancers is a specific alteration with functional significance or whether it reflects non-specific methylation imbalances occurring early during tumorigenesis.

Adenoma↗
PubMed2006

[Role of the genetic polymorphism of p53 (codon 72) gene in colorectal cancer].

BACKGROUND: Polymorphisms are genetic variations that can occur in sequences of codons, leading to defective proteins. p53 is the most commonly gene affected in human cancer. The polymorphism of this gene occurs by a substitution of a base in codon 72 and may increase the risk of cancer. AIM: To investigate the possible association between p53 arginine/72 proline polymorphism and susceptibility to colorectal cancer. PATIENTS AND METHODS: This polymorphism was studied by polymerization chain reaction using specific primers in 100 patients with colorectal cancer paired by sex and age to 100 patients without cancer. Alcohol and tobacco used by all the patients and clinical aspects as stage, grade of differentiation and recurrence in the case group was compared with the genotype analyzed. RESULTS: The frequency of homozygosis for arginine was 56% in the cancer group and 58% in the control group. No significant difference was observed among both groups. This genotype was more frequent in colorectal cancer patients stage IV than in stage I (80% versus 14%). There was no significant difference between genotypes and alcohol, tobacco, grade of differentiation or recurrence. CONCLUSION: Homozygosity for arginine was the most prevalent genotype in both groups. The frequency of codon 72 proline/arginine p53 gene polymorphism was not correlated with a higher risk of colorectal cancer. Arginine/arginine genotype was more prevalent in advanced cancer patients (stage IV).

Adult↗
PubMed1992

Progression of colorectal cancer is associated with multiple tumor suppressor gene defects but inhibition of tumorigenicity is accomplished by correction of any single defect via chromosome transfer.

Carcinogenesis is a multistage process that has been characterized both by the activation of cellular oncogenes and by the loss of function of tumor suppressor genes. Colorectal cancer has been associated with the activation of ras oncogenes and with the deletion of multiple chromosomal regions including chromosomes 5q, 17p, and 18q. Such chromosome loss is often suggestive of the deletion or loss of function of tumor suppressor genes. The candidate tumor suppressor genes from these regions are, respectively, MCC and/or APC, p53, and DCC. In order to further our understanding of the molecular and genetic mechanisms involved in tumor progression and, thereby, of normal cell growth, it is important to determine whether defects in one or more of these loci contribute functionally in the progression to malignancy in colorectal cancer and whether correction of any of these defects restores normal growth control in vitro and in vivo. To address this question, we have utilized the technique of microcell-mediated chromosome transfer to introduce normal human chromosomes 5, 17, and 18 individually into recipient colorectal cancer cells. Additionally, chromosome 15 was introduced into SW480 cells as an irrelevant control chromosome. While the introduction of chromosome 17 into the tumorigenic colorectal cell line SW480 yielded no viable clones, cell lines were established after the introduction of chromosomes 15, 5, and 18. Hybrids containing chromosome 18 are morphologically similar to the parental line, whereas those containing chromosome 5 are morphologically distinct from the parental cell line, being small, polygonal, and tightly packed. SW480-chromosome 5 hybrids are strongly suppressed for tumorigenicity, while SW480-chromosome 18 hybrids produce slowly growing tumors in some of the animals injected. Hybrids containing the introduced chromosome 18 but was significantly reduced in several of the tumor reconstitute cell lines. Introduction of chromosome 5 had little to no effect on responsiveness, whereas transfer ot chromosome 18 restored responsiveness to some degree. Our findings indicate that while multiple defects in tumor suppressor genes seem to be required for progression to the malignant state in colorectal cancer, correction of only a single defect can have significant effects in vivo and/or in vitro.

Alleles↗
PubMed2002

Functional polymorphism of the thymidylate synthase gene in colorectal cancer accompanied by frequent loss of heterozygosity.

The thymidylate synthase (TS) gene has a polymorphic repeated sequence in its 5'-untranslated region. The repeat length is associated with TS protein expression, which suggests that we may be able to predict the efficacy of 5-fluorouracil (5-FU)-based chemotherapy from a patient's TS genotype determined through analysis of normal tissue obtained non-invasively. However, it is not yet elucidated whether the TS genotype is identical in tumor and normal tissue. In this study, we investigated the TS genotype in 151 matched tumor and normal DNA samples isolated from colorectal cancer and adjacent normal tissues by PCR analysis. The results showed that TS genotypes are identical in normal and tumor tissues of homozygous individuals, suggesting that the repeat sequence is stable through carcinogenesis. However, in heterozygous samples, an imbalance between the 2R and 3R alleles in the tumor DNA was frequently observed, suggesting loss of heterozygosity (LOH) at the TS locus. Detailed LOH analysis revealed that 62% (31 of 50) of 2R/3R-heterozygous samples had LOH. Frequent LOH at the TS locus was confirmed by RT-PCR of TS mRNA and microsatellite analysis using the marker D18S59, located on 18p11.3. There was no difference in the expressions of TS mRNA and TS protein between LOH and non-LOH samples. However, when the heterozygous genotype bearing LOH was subdivided according to the number of repeats, the cancer tissue with 2R/loss genotype expressed a significantly lower level of TS protein than did that with 3R/loss genotype. The results suggest that the difference in TS genotype between tumor and normal tissue due to LOH should be considered when the genotype is analyzed with normal tissue, such as peripheral blood cells, because it is important for TS protein expression.

Adult↗
PubMed2004

Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer.

Krüppel-like factor 4 (KLF4 or GKLF) is an inhibitor of the cell cycle. The gene encoding KLF4 is localized on chromosome 9q, previously shown to exhibit allelic loss in colorectal cancer (CRC). In this study, we show that the mean level of KLF4 mRNA in a panel of 30 CRC was 52% that of paired normal colonic tissues. Similarly, the levels of KLF4 mRNA and protein in a panel of six established CRC cell lines were significantly lower than those of an untransformed colonic epithelial cell line. Using highly polymorphic DNA markers that flank the KLF4 locus, we found evidence for loss of heterozygosity (LOH) in two of eight surgically resected CRC specimens. In addition, LOH was observed in five of six CRC cell lines with one additional cell line exhibiting hemizygous deletion in the KLF4 gene. We also found that the 5'-untranslated region of KLF4 was hypermethylated in a subset of resected CRC specimens and cell lines. Lastly, the open-reading frame of KLF4 in two of three CRC cell lines examined contained several point mutations that resulted in a diminished ability to activate the p21(WAF1/Cip1) promoter. These findings indicate that KLF4 is a potential tumor suppressor gene in CRC.

5' Untranslated Regions↗
PubMed1993

Expression of homeobox-containing genes in primary and metastatic colorectal cancer.

Homeobox genes are a network of genes encoding nuclear proteins functioning as transcriptional regulators. Human and murine homeobox genes of the HOX family are organised in four clusters on different chromosomes. Gene order within each cluster is highly conserved, perhaps in direct relation to their expression. Homeobox genes have recently been involved in normal development and oncogenesis. We have analysed HOX gene expression in normal human colon and in primary and metastatic colorectal carcinomas. The majority of HOX genes are active in normal adult colon and their overall expression pattern is characteristic of this organ. Furthermore, the expression of some HOX genes is identical in normal and neoplastic colon indicating that these genes may exert an organ-specific function. In contrast, other HOX genes exhibit altered expression in primary colon cancers and their hepatic metastases which may suggest an association with colon cancer progression.

Colon↗
PubMed2006

Colorectal cancer in a population with endemic Schistosoma mansoni: is this an at-risk population?

PURPOSE: Chronic infection with schistosomiasis has been clearly associated with the development of bladder cancer, and infestation is associated with a high incidence of colorectal cancer in endemic populations. Despite this association, the potential role of alterations in tumor suppressor genes colorectal cancers has never been evaluated in an endemically infected population. The aim of this paper was to compare histopathologic and genetic changes in schistosomal colitis-associated colorectal cancer (SCC) with colorectal cancer in a group of patients from the same population not affected by the disease (NDCC). MATERIALS AND METHODS: Sixty patients were included in this study: SCC-40, NDCC-20. Data collected included age, sex, clinical presentation, presence of synchronous tumors, histopathology, and clinical stage. p53, DCC (deleted in colorectal cancer gene), and mismatch repair genes (MLH1 and MSH2) were studied using immunohistochemical staining. RESULTS: Patients with SCC were significantly younger than the NDCC group (34.52+/-11.22 years vs 50.73+/-12.75 years, p=0.02). Mucinous adenocarcinoma occurred significantly more frequently in SCC (35 vs 10%, p=0.02). SCC tumors were more frequently stage III or IV, and significantly more synchronous tumors were present in the affected group (SCC-8/40 vs NDCC-1/20, p=0.05). p53 staining was far more frequent in SCC (SCC-32/40 vs NDCC-8/20, p=0.006). DCC expression was similar in two groups. There were only four cases, three in SCC and one in NDCC, that showed microsatellite instability. CONCLUSION: The data suggest that schistosomal colitis is more commonly associated with earlier onset of multicentric colorectal cancer, high percentage of mucinous adenocarcinoma, and presents at an advanced stage. The identification of a higher incidence of altered p53 expression in the SCC group raises the possibility of an association between schistosomiasis and alterations in p53 activation as an inciting event in colorectal cancer development.

Adenocarcinoma↗
PubMed1999

Inactivation of both alleles of the DPC4/SMAD4 gene in advanced colorectal cancers: identification of seven novel somatic mutations in tumors from Japanese patients.

Loss of heterozygosity (LOH) of loci on chromosome 18q occurs in a majority of colorectal cancers. The DPC4/SMAD4 gene, lying in close proximity to the DCC gene at 18q21.1, was recently identified as a candidate tumor suppressor for the genesis of pancreatic cancer as well as a predisposing gene for Juvenile Polyposis Syndrome (JPS). The gene product functions as a cytoplasmic mediator in the signaling pathway of transforming growth factor beta (TGF-beta). To investigate the potential role of DPC4/SMAD4 gene in colorectal cancers, we examined 73 tumors of clinical stages II or III from Japanese patients, for LOH at 18q21 and also for subtle mutations anywhere within the coding region of DPC4/SMAD4. LOH was identified in 50 (78%) of the 64 tumors that were informative for polymorphic markers in the region. Somatic mutations were identified in seven of those tumors: two frameshift mutations, a 1-bp deletion (326 del T) in exon 8 and a 1-bp insertion (50-51 ins A) in exon 1; two nonsense mutations, Arg445Ter in exon 10 and Glu538Ter in exon 11; and three missense mutations, Asn129Lys in exon 2, Tyr95Asn in exon 2, and Asp355Glu in exon 8. Three of the seven mutations were observed in the mad homology 1 (MH1) domain encoded by exons 1 and 2. In all of the tumors carrying intragenic mutations of one allele, LOH analysis had shown that the other allele was missing. The results demonstrated that inactivation of both alleles of the DPC4/SMAD4 gene occurs in a substantial proportion of advanced colorectal cancers, and that the DPC4/SMAD4 gene probably exerts a tumor-suppressor effect for colorectal carcinogenesis that fulfills the criterion of the two-hit concept proposed by Knudson [A.G. Knudson, Hereditary cancer, oncogenes, and anti-oncogenes, Cancer Res. 45 (1985) 1437-1443.].

Alleles↗
PubMed1999

Frequent frameshift mutations of the TCF-4 gene in colorectal cancers with microsatellite instability.

About 15% of sporadic colorectal cancers show microsatellite instability (MSI) due to the inactivation of mismatch repair genes and are termed MSI-H tumors. In these tumors, frameshift mutations in coding repeats have been found within the TGFbeta-RII, BAX, and IGFRII genes that are probably involved in their progression. In the present work, we report frequent mutations in TCF-4, another target gene for instability. TCF-4 codes for a transcription factor that is a crucial member of the adenomatous polyposis coil (APC)/beta-catenin/T-cell factor (TCF) pathway. Fifty percent (4 of 8) of human MSI-H colorectal cell lines and 39% (19 of 49) of MSI-H colorectal primary tumors were found to have a 1-bp deletion in an (A)9 repeat within the coding region of this gene. In contrast, a frameshift mutation was found in only 1 of 56 non-MSI colorectal tumors and in none of 16 non-MSI colorectal cancer cell lines. These results suggest that TCF-4 frameshift mutations are selected for and play a role in colorectal MSI-H tumorigenesis. Depending on different reading frames due to alternatively spliced TCF-4 mRNA, the (A)9 repeat normally codes for several isoforms that could serve as modulators of TCF-4 transcriptional activity. The deletion of one nucleotide in this repeat could change TCF-4 transactivating properties by modifying the respective proportions of the different isoforms.

Colorectal Neoplasms↗
PubMed2000

Microsatellite instability as a predictor of a mutation in a DNA mismatch repair gene in familial colorectal cancer.

Germline alterations in human DNA mismatch repair genes are associated with hereditary nonpolyposis colorectal cancer (HNPCC). Mutation analysis of the genes reveals carriers with a high risk of colorectal cancer, who will benefit from surveillance. We wanted to find the best predictive parameter of a germline mutation in those genes among patients with familial colorectal cancer. Affected members from a total of 83 unrelated colorectal cancer families previously analyzed for mutations in MSH2 and MLH1 were used to evaluate different parameters' ability to predict a germline mutation. We studied various clinical criteria such as family structure, age of onset, and prevalence of endometrial cancer, as well as microsatellite instability in the tumors from the families. In total, 124 tumors from 59 of the families were tested for microsatellite instability (MSI) using PCR-based mono- and dinucleotide markers to establish whether the families could be scored as MSI-positive or -negative. The finding of MSI-positive tumors in a family was the best predictor of a germline mutation, and was found in 73% of the MSI-positive, but in less than 3% of the MSI-negative families (P < 0.0001). In contrast, MSI in unselected colorectal cancer is not as useful, since most of these MSI-positive tumors are sporadic. The finding of microsatellite instability in colorectal tumors seems efficient enough even to select those with germline mutations among families fulfilling HNPCC Amsterdam criteria, once used in identification of the DNA mismatch repair genes. Genes Chromosomes Cancer 27:17-25, 2000.

Adult↗
PubMed2002

B-vitamin intake, metabolic genes, and colorectal cancer risk (United States).

OBJECTIVE: This population-based case-control study was designed to investigate the interrelationships between polymorphisms in the methylenetetrahydrofolate (MTHFR C677T and A1298C) gene and other genes (MTR A2756G; MTRR A66G and CBS 844ins68), intake of B-vitamins and colorectal cancer risk (CRC). METHODS: We interviewed 727 CRC cases of Japanese, Caucasian, or Native Hawaiian origin and 727 controls matched on sex, age, and ethnicity. RESULTS: Compared to the homozygous wild-type genotype, the odds ratios for subjects with one or two MTHFR 677T variant alleles were 0.8 (0.6-1.1) and 0.7 (0.5-1.1), respectively (p for gene-dosage effect: 0.04). The TT genotype was associated with a 50-60% decrease in CRC risk among subjects with high intake of folate or vitamin B6, compared to those with the CC genotype and low levels of intake. The MTHFR 1298C and CBS8 44ins68 variant alleles were also found to be weakly protective against CRC and to act jointly with the 677T allele. CONCLUSIONS: This study provides additional evidence for a decreased CRC risk for subjects with the MTHFR 677T allele, particularly at high levels of folate and vitamin B6 intake. Our data also suggest that the relationships between CRC and the MTHFR A1298C and CBS 844ins68 polymorphisms warrant further study.

Age Distribution↗