PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “COLORECTAL CANCER GENES”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 361 records · Page 20Linked to original sources
PubMed2005

The AKT/I kappa B kinase pathway promotes angiogenic/metastatic gene expression in colorectal cancer by activating nuclear factor-kappa B and beta-catenin.

Our laboratory has delineated that the phosphatidylinositol 3' kinase (PI3K)/AKT/I kappa B kinase (IKK) pathway positively regulates NF kappa B and beta-catenin, both important transcriptional regulators in colorectal cancer (CRC). Therefore, we investigated the effect of inhibiting the PI3K/AKT/IKK alpha pathway in regulating the inappropriate constitutive activation of NF kappa B and beta-catenin in CRC cell lines. SW480 and RKO CRC cell lines demonstrate constitutive activation of AKT as well as both NF kappa B- and beta-catenin-dependent transcription. The constitutive activation of NF kappa B- and beta-catenin-dependent transcription is inhibited by transiently transfecting either kinase dead (KD) IKK alpha, which blocks IKK alpha kinase activity, KD AKT, which blocks AKT activity, or wildtype (WT) PTEN, which inhibits PI3K and AKT activity. The ability of KD IKK alpha, KD AKT or WT PTEN to decrease beta-catenin-dependent transcription is independent of their effects on NF kappa B. Inducible expression of either KD IKK alpha or WT PTEN strongly inhibits both the constitutive NF kappa B- and beta-catenin-dependent promoter and endogenous gene activation. Targeted array-based gene expression analysis of this inducible system reveals that many of the genes downregulated upon inhibition of this pathway are involved in tumor angiogenesis and metastasis. The activation of this pathway and the expression of the three most repressed genes was further analysed in samples of CRC. These results indicate a role of this pathway in controlling gene expression important in tumor progression and metastasis.

Colorectal Neoplasms↗
PubMed2006

The role of hereditary nonpolyposis colorectal cancer in the management of familial ovarian cancer.

PURPOSE: Familial ovarian cancer is most often associated with hereditary breast and ovarian cancer, implicating mutations in the BRCA1 and BRCA2 genes. Hereditary nonpolyposis colorectal cancer, another common syndrome, is also associated with ovarian cancer and is caused by DNA mismatch repair genes. We sought to identify the role of hereditary nonpolyposis colorectal cancer in women with family histories of ovarian cancer. METHODS: The likelihood of a genetic syndrome in 226 oophorectomized women in the Gilda Radner Familial Ovarian Cancer Registry was determined by pedigree analysis using clinical criteria and by calculating the probability of a mutation in genes responsible for hereditary breast and ovarian cancer and hereditary nonpolyposis colorectal cancer using available risk models. RESULTS: Some 86% had a BRCA gene mutation likelihood of 7.8% or higher, warranting consideration of hereditary breast and ovarian cancer. Of the 32 women below this threshold, 4 (12.5%) had family histories that met criteria for clinical diagnosis of hereditary nonpolyposis colorectal cancer. In addition, 16 women (7%) with a BRCA mutation likelihood greater than 7.8% met clinical criteria for hereditary nonpolyposis colorectal cancer or warranted its inclusion in the differential diagnosis. Among all study respondents, 9% had family histories warranting consideration of hereditary nonpolyposis colorectal cancer. CONCLUSION: Hereditary nonpolyposis colorectal cancer should be considered in the differential diagnosis of women with family histories of ovarian cancer.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed2006

Ets-1 and runx2 regulate transcription of a metastatic gene, osteopontin, in murine colorectal cancer cells.

Osteopontin (OPN) is a sialic acid-rich phosphoprotein secreted by a wide variety of cancers. We have shown previously that OPN is necessary for mediating hepatic metastasis in CT26 colorectal cancer cells. Although a variety of stimuli can induce OPN, the molecular mechanisms that regulate OPN gene transcription in colorectal cancer are unknown. We hypothesized that cis- and trans-regulatory elements determine OPN transcription in CT26 cells. OPN transcription was analyzed in CT26 cancer cells and compared with YAMC (young adult mouse colon) epithelial cells. Clonal deletion analysis of OPN promoter-luciferase constructs identified cis-regulatory regions. A specific promoter region, nucleotide (nt) -107 to -174, demonstrated a >8.0-fold increase in luciferase activity in CT26 compared with YAMC. Gel-shift assays sublocalized two cis-regulatory regions, nt -101 to -123 and nt -121 to -145, which specifically bind CT26 nuclear proteins. Competition with unlabeled mutant oligonucleotides revealed that the regions nt -115 to -118 and nt -129 to -134 were essential for protein binding. Subsequent supershift and chromatin immunoprecipitation assays confirmed the corresponding nuclear proteins to be Ets-1 and Runx2. Functional relevance was demonstrated through mutations in the Ets-1 and Runx2 consensus binding sites resulting in >60% decrease in OPN transcription. Ets-1 and Runx2 protein expression in CT26 was ablated using antisense oligonucleotides and resulted in a >7-fold decrease in OPN protein expression. Ets-1 and Runx2 are critical transcriptional regulators of OPN expression in CT26 colorectal cancer cells. Suppression of these transcription factors results in significant down-regulation of the OPN metastasis protein.

Animals↗
PubMed2006

Epidermal growth factor receptor and epidermal growth factor receptor variant III gene expression in metastatic colorectal cancer.

PURPOSE: The epidermal growth factor receptor (EGFR) variant type III (variously called EGFRvIII, de2-7 EGFR, or triangle upEGFR) has an in-frame deletion of the extracellular domain and is found in numerous types of human tumors. Because EGFRvIII has been reported to be tumor specific and has oncogenic potential, it is being investigated as a potential therapeutic target, but to our knowledge, there is only 1 previous report about EGFRvIII by immunohistochemistry in colorectal cancer. Our aim was to indicate the frequency of gene expressions of EGFRvIII and EGFR in metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Forty-five patients with mCRC who received the chemotherapy for metastatic disease were analyzed for the EGFRvIII variant. Paraffin-embedded tumor tissues were dissected using laser-captured microdissection and analyzed for the EGFR and EGFRvIII messenger RNA expression using a quantitative real-time reverse-transcriptase polymerase chain reaction method. Gene expression values (relative messenger RNA levels) are expressed as ratios (differences from the cycle threshold values) between the target gene and internal reference gene (beta-actin). Twenty-five women and 20 men with a median age of 55 years (range, 25-76 years) were included in this study. RESULTS: We did not find any expression of EGFRvIII in these 45 patients except for control cell lines as U87.EGFRvIII. However, EGFR gene expression was found in 43 of 45 (95.6%) with a range of 0.38-2.83. CONCLUSION: Our results demonstrate that the expression of EGFRvIII is rare, but most colon cancer demonstrates EGFR gene expression. We conclude that EGFRvIII does not play an important role in mCRC.

Adult↗
PubMed2001

Clinical and biologic heterogeneity of hereditary nonpolyposis colorectal cancer.

MMR gene mutations and MSI are not found in all clinically diagnosed HNPCC families. We evaluated whether MMR genotyping and tumor MSI analysis could identify distinct clinical subgroups among HNPCC families. Twenty-nine clinical HNPCC families were divided into 3 groups: A, families with hMLH1 or hMSH2 gene mutations; B, MMR gene mutations not present but MSI present in at least 50% of tumors tested; C, mutational and MSI analyses negative. We evaluated tumor spectrum, age at onset, risk of cancer in the follow-up and survival for CRC in the 3 groups. Tumors of the target organs in HNPCC (colon and rectum, endometrium, ovary, small bowel, stomach, renal pelvis and ureter) were more frequent in the first 2 groups than in the latter. Colon cancer was more frequently located in the proximal colon and showed an earlier age at onset in families with MMR gene mutation or with MSI than in families with stable tumors. Comparing the occurrence of tumors in the follow-up, in the first 2 groups patients younger than 50 years had a higher RR, which was particularly marked for CRC (RR = 18.6 for group A vs. group C, RR = 16.7 for group B vs. group C). CRC patients in the first 2 groups had a better clinical prognosis. The results of molecular analysis could distinguish, within clinically defined HNPCC families, different subgroups to which specific programs of surveillance could be addressed.

Adaptor Proteins, Signal Transducing↗
PubMed1995

Microallelotyping defines the sequence and tempo of allelic losses at tumour suppressor gene loci during colorectal cancer progression.

Microallelotyping of many regions from individual colorectal tumours was used to determine the sequence and tempo of allelic loss on 5q, 17p and 18q during neoplastic progression. No allelic losses were found in normal tissues surrounding colorectal neoplasms, but losses occurred abruptly on 5q at the transition from normal colonic epithelium to the benign adenoma, and on 17p at the transition from adenoma to carcinoma, indicating an essential role for these losses in tumour progression. Allelic losses were uniform throughout extensively microdissected benign adenomas and carcinomas. However, substantial allelic heterogeneity was found in high-grade dysplasia, the transition lesion between adenoma and carcinoma. Thus, allelic losses on 5q and 17p are associated with abrupt waves of clonal neoplastic expansion, and high-grade dysplasia is characterized by a high degree of allelic heterogeneity.

Adenocarcinoma↗
PubMed2005

Relationships between promoter polymorphisms in the thymidylate synthase gene and mRNA levels in colorectal cancers.

Thymidylate synthase (TS) intratumoural expression may be a prognostic marker and predict outcome of 5-fluorouracil (5-FU)-based chemotherapy in colorectal cancer patients. The TS gene promoter enhancer region contains two different polymorphisms which can influence TS mRNA transcriptional and translational efficiency: a polymorphic tandem repeat sequence (2 or 3 repeats; 2R and 3R) and a single nucleotide polymorphism (SNP), G > C, within the second repeat of the 3R alleles. We studied the relationship between tumoural TS mRNA expression levels and TS gene polymorphisms in the colonic mucosa of 48 colorectal cancer patients. The 3R/3R genotype was characterised by higher TS mRNA levels in the tumour than the 2R/2R-2R/3R genotypes (P = 0.071). Regarding the relationship with the SNP polymorphism, a statistically significant difference in TS gene expression between the 3RG/3RG genotype and 2R/2R-2R/3RC-2R/3RG genotype subset was observed (P = 0.017). No statistically significant correlation was observed between experimental data and baseline clinical-pathological characteristics as well as clinical outcome in the relatively small patient series investigated. This is the first study reporting an association between the TS intra-repeat SNP and gene expression levels in colorectal cancer patients. These results suggest that in 3R/3R patients, the G > C polymorphism may be an important factor in determining TS mRNA expression levels, and warrant further investigation of the role of TS promoter polymorphisms as predictors of sensitivity to 5-FU-based chemotherapy in larger case series.

Adult↗
PubMed2004

[Study on significance of single nucleotide polymorphisms in the redox domain of aprimidinic/apurinic endonuclease/redox factor-1 gene in Chinese sporadic colorectal cancer].

OBJECTIVE: To investigate the relationship between the single nucleotide polymorphisms(SNPs) in the redox domain of aprimidinic/apurinic endonuclease/redox factor-1(APEX) gene and the development of sporadic colorectal cancer. METHODS: One hundred and fifty cases of sporadic colorectal cancers and 143 peripheral blood samples from healthy population were screened for genetic polymorphisms or mutations in the redox domain by denaturing gradient gel electrophoresis followed by DNA sequencing. RESULTS: There were two SNPs identified in the redox domain of APEX gene, namely, 453G to T and 1247A to G. The gene frequencies of 453T and 1247G were 1.3% and 5.7%, respectively, in patient group, while 1.05% and 4.55%, respectively, in healthy population. The genotype distribution at the two sites in healthy population was consistent with Hardy-Weinberg equilibrium. There was no difference in gene frequencies at the two sites between cancer patients and healthy population. CONCLUSION: The polymorphisms in the redox domain of APEX gene are irrelevant to the development of sporadic colorectal cancer, but their distribution may vary greatly among tribes.

Aged↗
PubMed1999

Expression of the HMGI(Y) gene in human colorectal cancer.

Expression of HMGI(Y), a nucleoprotein that binds to A/T rich sequences in the minor groove of the DNA helix, is observable in neoplastically transformed cells but not in normal cells. We have analyzed HMGI(Y) expression in colorectal cancer and evaluated its clinicopathologic significance. HMGI(Y) mRNA was measured by CRT-PCR (competitive reverse transcription-polymerase chain reaction). Immunohistochemical staining for HMGI(Y), p53 and Ki-67 was performed in the same colon cancer tissues, and the results in colorectal tissues were similar to those of RT-PCR. HMGI(Y) expression evidenced by RT-PCR was observed in 63 of 64 (98.4%) colorectal cancer samples, and 2 of 5 (40%) adenomatous polyps, whereas 21 normal colon samples were negative (p<0.001). High HMGI(Y) expression using CRT-PCR was found in colon cancers with a high Ki-67 labeling index (p<0.001). There was no significant correlation between the levels of HMGI(Y) expression and stage, tumor size, lymph node metastasis, histologic grade and immunohistochemical status of p53. Our results indicate that the HMGI(Y) expression may occur at an early stage of carcinogenesis and correlate with cell proliferation. Int. J. Cancer (Pred. Oncol.), 84:376-380, 1999.

Adenomatous Polyposis Coli↗
PubMed1995

[Prognostic value of K-ras gene mutation in colorectal cancer].

Numerous acquired genetical mutations are now well described by molecular biology and seem to be related to tumour progression. K-RAS mutation is of interest in colorectal cancer where it could be correlated to an aggressive tumoral behaviour leading to a high risk of recurrence or metastasis.

Cell Transformation, Neoplastic↗
PubMed2000

Mutational analysis of the transforming growth factor beta receptor type II gene in hereditary nonpolyposis colorectal cancer and early-onset colorectal cancer patients.

Somatic mutations in the transforming growth factor beta receptor type II (TGF-beta RII) gene have been observed in various human cancers showing microsatellite instability. Most of the mutations observed were additions or deletions of the mononucleotide repeat sequence present in TGF-beta RII coding region, suggesting that the TGF-beta RII may be a target gene of genomic instability in tumorigenesis. Recently, we reported germ-line frameshift mutations in the mononucleotide repeat sequence of the hMSH6 gene, which is believed to be one of the target genes of genomic instability in tumorigenesis, suggesting the possibility of germ-line mutation in mononucleotide repeat sequences. Moreover, one case of germ-line mutation in the TGF-beta RII gene was identified in a hereditary nonpolyposis colorectal cancer (HNPCC) kindred, indicating the involvement of TGF-beta RII inactivation in tumorigenesis of HNPCC. However, germ-line mutation analysis of all of the coding sequences and the mononucleotide repeat sequence of the TGF-beta RII in HNPCC patients has not yet been fully elucidated. Therefore, to further investigate the presence of germ-line mutations, we screened all of the coding region sequences and mononucleotide repeat sequence of TGF-beta RII from 35 HNPCC, 44 suspected HNPCC, and 45 sporadic early-onset colorectal cancer patients. However, no pathogenic mutations other than silent mutations, introgenic mutation, and polymorphisms were identified. Two silent mutations at codons 309 (ACG to ACA) and 340 (CAT to CAC) in the kinase domain located in exon 4 were detected. A 1-bp cytidine deletion was observed 6 bases from the 3' end of intron. Two polymorphisms were identified at codon 389 (AAC to AAT) and at the fourth-to-last base in intron 3. The polymorphism at codon 389 was more frequent in HNPCC (20%; 7 of 35) and suspected HNPCC patients (18%; 8 of 44) than in nonmalignant control group (10%; 5 of 50). Moreover, the frequency was significantly higher in early-onset colorectal cancer patients (31%; 14 of 45). This is the first report of a different frequency of polymorphism in HNPCC, suspected HNPCC, early-onset colorectal cancer patients, and healthy normal individuals. This result suggests that: (a) germ-line mutation of the TGF-beta RII gene may be a rare event during tumorigenesis in HNPCC and sporadic early-onset colorectal cancer; (b) the mononucleotide repeat sequence of the TGF-beta RII gene is an apparent target of genomic instability but not of germ-line mutation; and (c) the polymorphism of codon 389 (AAC to AAT) is frequent, especially in early-onset colorectal cancer patients, in which it is more frequent than in control group.

Adult↗
PubMed1998

Moderate amplifications of the c-myc gene correlate with molecular and clinicopathological parameters in colorectal cancer.

C-myc gene activation is a common event in multiple types of neoplasia and has been associated with different cellular processes relevant to the malignant transformation of cancer cells. C-myc gene amplification has been analysed in colorectal carcinomas by means of an innovative DNA fingerprinting method based on the arbitrarily primed PCR. This method requires a low amount of DNA, uses multiple internal controls and appears sensitive and reproducible. Clinicopathological and molecular correlates have been investigated in a series of 70 colorectal carcinomas. The incidence of c-myc amplification was 26%, ranging from two- to fivefold increase in copy number. C-myc amplification occurrence was more frequent in more advanced stages of tumour invasion (P < 0.001) and was associated with mutations in the p53 tumour-suppressor gene (P = 0.048). The presence of c-myc amplification was indicative of a shorter disease-free survival period but, because of its strong association with Dukes' stage, its prognostic value is questionable.

Adult↗
PubMed2003

Genotyping of p53 codon 175 in colorectal cancer.

BACKGROUND: The gene encoding the tumor suppressor protein p53 is one of the most frequently mutated in human cancer. Over 8000 mutations of this gene have been identified. The spectrum of p53 mutations varies among tumor types. More than half of these mutations appear in three hotspot codons: 175, 248 and 273. The purpose of the present study was to evaluate the GgA transition in codon 175 of the p53 gene as a potential marker of colon cancer progression. MATERIAL/METHODS: The prognostic significance of alterations in codon 175 exon 5 of p53 gene was studied in 32 patients with colorectal cancer. The ASA-PCR method was used to assess GgA (ArggHis) transition in codon 175. RESULTS: The analyzed point mutation was identified in 56% of the tested cases of colorectal cancer. The frequency of codon 175 p53 gene mutation was found to increase with cancer aggressiveness. Screening for the studied point mutation in codon 175 showed no alteration in analyzed samples classified as Dukes' A stage, while variations were observed in 43%, 50% and 75% of the cases classified as Dukes' B, C, and D, respectively. In three cases the studied mutation was also found in some mucosal cells obtained from resectional borders. CONCLUSIONS: The GgA transition in codon 175 of the p53 gene may be useful as a potential marker of colorectal cancer progression and as a means of evaluating the margins of surgical resection.

Adult↗
PubMed2004

Housekeeping gene variability in normal and cancerous colorectal, pancreatic, esophageal, gastric and hepatic tissues.

Careful normalization is essential for the accurate quantitation of mRNA levels in biopsy-sized tissue samples. Commonly, normalization of the target gene with an endogenous standard, mainly housekeeping genes (HKGs), is applied. However, differences in the expression levels of endogenous reference genes have been reported between different tissues and pathological states. Therefore, we were challenged to identify a set of endogenous reference genes whose mRNA expression levels would not change significantly between normal and cancerous tissues. Quantitative real-time PCR (Q-RT-PCR) analysis was applied to evaluate the variability in gene expression among 21 classical housekeeping genes in colorectal, pancreatic, esophageal and gastric cancer as well as in liver metastases in comparison to the corresponding normal tissue. Our results indicated that some housekeeping genes were candidates with relatively stable gene expression in several of the investigated tissues but for most of the HKGs under investigation our data have revealed distinct differences in the extent of variability in gene expression between the different tissues and pathological states. However, for each of the five tissues investigated we found a group of genes that were expressed at a constant level thus representing a panel of candidates that we can recommend as housekeeping genes in the respective tissue types. In summary, our results can be used as guidance for other scientists studying various carcinomas for tissue-specific selection of the optimal housekeeping gene (HKG) to be used in normalizing target gene expression.

Colorectal Neoplasms↗
PubMed2005

Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer.

BNIP3 protein is a proapoptotic member of the Bcl-2 family that is expressed in hypoxic regions of tumors. To examine its role in the progression of gastrointestinal cancer, we examined the expression and DNA methylation status of BNIP3 gene in a panel of colorectal and gastric cancer cell lines. BNIP3 was not expressed in 14 of the 24 cell lines tested, and its absence was not caused by gene mutation or by altered expression of hypoxia inducible factor-1, a key transcription factor that regulates BNIP3 expression. On the other hand, methylation of the 5' CpG island of BNIP3 was closely correlated with silencing the gene. Moreover, treating methylated cells with the methyltransferase inhibitor 5-aza-2'-deoxycytidine restored hypoxia-induced expression of BNIP3 mRNA and protein, which in turn led to cell death. Aberrant methylation of BNIP3 was also detected in 66% of primary colorectal and 49% of primary gastric cancers, but not in normal tissue samples collected from areas adjacent to the tumors. Apparently, epigenetic alteration of BNIP3 is a frequent and cancer-specific event, which suggests that inactivation of BNIP3 likely plays a key role in the progression of some gastrointestinal cancers and that it may be a useful molecular target for therapy.

Acetylation↗
PubMed1999

Hypermethylation of the p16 gene in sporadic T3N0M0 stage colorectal cancers: association with DNA replication error and shorter survival.

Hypermethylation in the promoter region of the p16 gene was suspected to be involved in the tumorigenesis of colorectal cancers, although its clinical and biological significance remains obscure. In this study, we collected 84 T3N0M0 stage primary colorectal cancers that were curatively resected. The clinicopathologic data were reviewed. p16 hypermethylation was determined by a methylation-specific polymerase chain reaction (PCR). p53 overexpression was detected by immunocytochemistry (ICC). The point mutations in the 12 and 13 codons of the K-ras gene were screened by restriction enzyme analysis. Loss of heterozygosity (LOH) of the DCC (Deleted in Colorectal cancer) gene was examined by PCR using primers of the DCC (18q21) microsatellite marker. The DNA replication error (RER) was examined using 7 microsatellite markers at distinct chromosomal loci. p16 hypermethylation, regarded as an indication of p16 inactivation, was evident in 24 (28.6%) of the tumors. No correlation was found between p16 hypermethylation and various clinicopathologic factors, includinig age, sex, tumor location, tumor size, growth pattern, tumor differentiation, mucin production, vascular and/or lymphatic invasion, lymphocyte infiltration of the tumor, and serum level of carcinoembryonic antigen. There was no association between p16 hypermethylation of K-ras gene mutation, p53 overexpression and LOH of the DCC gene. However, p16 hypermethylation was significantly associated with DNA RER (p = 0.01). Survival analysis revealed a significant survival disadvantage of p16-hypermethylated versus non-p16-hypermethylated tumors (p = 0.0001). These findings indicate that p16 hypermethylation plays a role in the carcinogenesis of a subset of colorectal cancers; and the presence of p16 hypermethylation predicts shorter survival in T3N0M0 stage colorectal cancers.

Aged↗