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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Colorectal cancer represents the major cause for excess morbidity and mortality by malignant disease in ulcerative colitis as well as in Crohn's disease. The risk for ulcerative colitis associated colorectal cancer is increased at least 2-fold compared to the normal population and colorectal cancer is observed in 5.5-13.5% of all patients with ulcerative colitis and 0.4-0.8% of patients with Crohn's disease. Established risk factors include long duration of the disease, large extent of the disease, low activity of the disease, young age at onset, presence of complicating primary sclerosing cholangitis or stenotic disease and possibly lack of adequate surveillance, inadequate pharmacological therapy, folate deficiency and non-smoking. Crohn's disease is associated with an increased risk of colorectal carcinoma in patients with long-standing disease, strictures and fistulae under the condition that the colon is involved, tumors of the small intestine may occur occasionally. Extracolonic malignancies are rare, with the exception of biliary tract cancer. Ulcerative colitis associated colorectal cancer typically can occur in the entire colon, is often multifocal and of undifferentiated histology. Stage distribution and prognosis of ulcerative colitis associated colorectal cancer appears to be similar to that of sporadic colorectal cancer with an overall survival of about 40% (15-65%) after 5 years with tumor stage at diagnosis being the most important predictive parameter for survival. Tumor markers helpful for the diagnosis of sporadic colorectal cancer fail to differentiate between inflammatory response and malignant transformation. In contrast the histologic evidence of dysplasia was shown to be a strong indicator of underlying carcinoma or developing malignant transformation. The presence of a surface projection termed dysplasia associated lesion or mass is highly indicative of underlying or associated cancer. While the routinely performed search for dysplasia is hampered by high interobserver variation the demonstration of DNA-aneuploidy or genetic changes which may confirm the ongoing malignant transformation has not yet become clinical routine. The genetic alterations found in ulcerative colitis associated colorectal cancer involve many of the same targets found in sporadic colorectal tumors and include multiple sites of allelic deletion, microsatellite instabilities, and mutations of APC, p53, Ki-ras as well as MSH2 and other genes. The progression of dysplasia to carcinoma is generally accompanied by an accumulation of these mutations and the similarities in the biology of colorectal cancer associated with ulcerative colitis and sporadic colorectal cancer appear to outweigh their difference. In regard to the management of dysplasia and cancer, the role of surveillance programs for the early detection of ulcerative colitis associated colorectal cancer at a curable stage is still under debate. Although these programs failed at tumor prevention and lethal carcinomas are still found inadvertently in patients under surveillance, the majority of surveillance programs could reduce mortality by detecting more cancers at a still curable stage. Current recommendations for surveillance include, therefore, biennial colonoscopy with extensive biopsies after 8-10 years of total colitis or after 15-20 years of left-sided colitis. In the presence of cancer or unequivocal high-grade dysplasia and/or dysplasia associated lesion or mass proctocolectomy is considered adequate. The evidence of low-grade dysplasia should be confirmed before proctocolectomy is considered.
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PMID:Chronic inflammatory bowel disease and cancer. 1069 May 86

Activation of the ras family gene has been implicated in colorectal tumorigenesis, K-ras being the most frequently altered gene. The frequency of K-ras codon 12, 13 and 61 point mutations in patients with colorectal neoplasias was examined. We employed a polymerase chain reaction-restriction fragment length polymorphism assay and single-strand conformational polymorphism to detect mutations. We found that point mutations at codons 12 and 13 were present in 53% and 39% of the tumors, respectively, but none at codon 61. These results agree with previous reports. Point mutations were more frequent in adenomas than in carcinomas, with villous adenomas presenting a higher incidence of mutations than other adenomas. The association between clinical and histopathological parameters was investigated. Our study is the beginning of a new research line in molecular epidemiology of colorectal cancer and is the first to be carried out in one part of the Mexican population.
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PMID:Frequency and clinicopathology associations of K-ras mutations in colorectal cancer in a northeast Mexican population. 1075 62

Patients with long-standing ulcerative colitis (UC) have an increased risk for developing colorectal cancer (CRC) compared to the general population. For investigation of the mechanisms and prevention of UC and UC-related CRC, establishment of a promising animal model for such disease is important. 1-hydroxyanthraquinone (1-HAQ) present in certain medicinal plants such as Rubia tinctorum L. is a genotoxic and rodent colon carcinogen. Long-term feeding of 1-HAQ induced hyper-cell proliferation in rat colonic crypts with ulcerative changes, crypt abscess, severe inflammation and erosion before the occurrence of tumors, which are similar to those found in human UC. In addition, 1-HAQ has a synergistic effect with methylazoxymethaol (MAM) acetate on colon carcinogenesis. The polymerase chain reaction-single strand conformation polymorphism analysis revealed no mutations in Ki-ras and p53 in colonic neoplasms induced by MAM acetate + 1-HAQ, MAM acetate alone or 1-HAQ alone. Also, no mutations of APC were found in these tumors. These findings are similar to those found in human ulcerative colitis-associated colon cancer in contrast with sporadic colon cancers. A previous study revealed that induced colonic tumors had beta-catenin mutation with high frequency, suggesting tumor development by activation of the beta-catenin-Tcf signaling pathway. Increased expression in TNF-alpha and IL-1alpha was found in these induced colonic neoplasms, and the expression was more remarkable in colonic mucosa of rats exposed to MAM acetate + 1-HAQ, MAM acetate or 1-HAQ when compared with that in untreated rats. Thus, these cytokines may act as growth factors in rat colon carcinogenesis by MAM acetate and 1-HAQ and the synergistic effect of 1-HAQ with MAM acetate might be related to the biological effects of the cytokines expressed in the inflammatory conditions induced by 1-HAQ.
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PMID:Colitis-related rat colon carcinogenesis induced by 1-hydroxy-anthraquinone and methylazoxymethanol acetate (Review). 1076 59

Previously we have demonstrated a reciprocal deregulation of various homeobox genes (HOXB6, B8, C8 and C9 vs Cdx-1) in human colorectal cancer (CRC). In the present study, using RT-PCR, we have investigated the expression pattern of these homeobox genes in various human colon cell lines, representing various stages of colon cancer progression and differentiation. Thus, we have tested polyposis coli Pc/AA adenoma cells, Caco-2, HT-29 and LS174T adenocarcinoma cell lines. All cell lines, except LS174T, demonstrated a pattern of deregulated homeobox gene expression which resembled that of CRC. In contrast, the pattern of expression of these genes in the highly oncogenic LS174T cells, as well as in Caco-2 cells transfected with activated Ha-ras or Polyoma middle T oncogene, resembled that of the normal mucosa. The reciprocal deregulation of HOX and Cdx-1 genes in CRC and in CRC-derived cell lines suggests a possible role in human CRC development.
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PMID:Deregulated expression of homeobox-containing genes, HOXB6, B8, C8, C9, and Cdx-1, in human colon cancer cell lines. 1083 44

Alterations in gene structure and functions involving the c-Ki-ras and p53 genes have been shown to play an important role in the various stages of human colorectal carcinogenesis. However, how these gene alterations cooperate with tumoral mechanisms at an immunological level is not known. To this aim an immunological study of a group of healthy subjects, patients with p53 gene deletions (53D), with c-Ki-ras mutations (KrM) and no gene alterations (53D-KrM-) have made. In a previous study we found that a disregulation between TH1/Th2 cell functions seems to be implicated in the establishment and progression of colorectal cancer disease and that soluble interleukin (IL)-2Receptor (sIL-2R) serum level is involved in this. On this basis we investigated the immunological implications of p53 and c.Ki-ras gene alterations, evaluating the relationhips in the immune network between sIL-2R levels in the serum and immunological parameters (IL-2, IL-4 serum levels; CD3, CD16 and CD19 expression on the surface of peripheral blood mononuclear cells--PBMC). Our results suggest that, in the stepwise progression of colorectal cancer, the c-Ki-ras gene alteration is involved in a switch of the host immune response to a suppressive type which, as we have previously reported, may be a determining or concurrent cause of malignant transformation. Alteration in the p53 gene does not appear to ulteriorly impair the patients' immunological response. Our data supports the role of c-Ki-ras gene mutations and p53 deletions as prognostic markers in the passage of normal tissue to adenoma and adenoma to carcinoma respectively. Moreover, the evaluation of the mechanisms involved in the alterations of c-Ki-ras gene seems to be more important than that of p53 suppressor gene for the improvement of prevention, biotherapy treatment and tumor biology understanding.
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PMID:Immunological implications of alterations in the c-Ki-ras and p53 genes in the stepwise progression of colorectal cancer: indications for the improvement of prognosis, biotherapy treatment and tumor biology understanding 1085 92

Our previous data on colorectal cancer suggest that there are faults at the level of mechanisms of the proliferative responses of patients peripheral blood mononuclear cells (PBMC) to the interleukin (IL)-2 and IL-2 PBMC production, which increase with the stage advancement. The damages in the proliferative response seem to be eliminated by the costimulator effects of the signals produced by the anti-CD3 monoclonal antibody (antiCD3), and the disregulation in TH subsets of CD4+ T cells with a malfunction of TH1 cells and an expansion of TH2, might contribute to this situation. So, by using biotherapeutic treatments to allow the generation of productive immune response in these patients it is essential to identify the defect in their immune system to discover how these mechanisms should be appropriately manipulated in vivo to switch their immune response from a non-productive to a productive one. We have studied this in a group of patients and healthy subjects as the control group, performing their immunological evaluation by determining these parameters: serum levels of IL-2, interferon (IFN) gamma, IL-4, IL-6, IL-7, IL-8, tumour necrosis factor (TNF) alpha, soluble IL-2 receptor (sIL-2R), intercellular adhesion molecule 1 (sICAM-1) and CD30 (sCD30) molecules; PBMC phenotypic antigens expression (CD3, CD4, CD8, CD19, CD16, CD56, CD57, CD25) on peripheral blood mononuclear cells (PBMC); proliferative response of PBMC to IL-2, IL-4 and anti-CD3 monoclonal antibody (antiCD3). Moreover, since mutant c-Ki-ras oncogene is a very frequent finding in colorectal cancers and there are indications which suggest its involvement in tumour progression, the analysis of c-ki-ras codon 12 and 13 were determined and the statistical evaluation of the above immunological parameters were performed by comparing the patient groups with (M+) and without (M-) these mutations with each other, and with the healthy group. The results underline the necessity of biotherapeutic treatments inducing TH1 cell functions in these patients. Moreover in M+ it seems also important to solve the problem of the switch from B to macrophage cells as immune cells which present antigens, and the possible involvement of c-Ki-ras gene mutations in the impairment of T cell receptor activation (TCR).
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PMID:Necessity of biotherapeutic treatments inducing TH1 cell functions in colorectal cancer. 1085 98

Mutations of the TP53 and Ki-ras genes have been reported to be of prognostic importance in colorectal carcinomas. An increased intracellular concentration of the p53 protein, although not identical to, is sometimes seen in tumours with TP53 mutation and has been correlated with poor prognosis in some tumour types. Previous colorectal cancer studies, addressing the prognostic importance of Ki-ras mutation and TP53 aberrations, yielded contradictory results. The aim of this study was to determine in a clinically and therapeutically homogeneous group of 122 sporadic Dukes' B colorectal carcinomas with a median follow-up of 67 months (3-144 months) whether or not p53 protein expression, TP53 mutation and K-ras mutation correlated with prognosis. p53 staining was performed by immunohistochemistry, using the monoclonal antibody DO7 on paraffin-embedded tissue. Mutations in exons 5-8 of the TP53 gene and in codons 12 and 13 of the K-ras gene were assayed in paraffin-embedded tissue by the single-strand conformation polymorphism (SSCP) assay. Nuclear p53 staining was found in 57 (47%) tumours. Aberrant migration patterns indicating mutation of the TP53 gene were found in 39 (32%) tumours. Forty-six carcinomas (38%) showed a mutation of the Ki-ras codons 12 or 13. In a univariate analysis, patients with wild-type TP53 status showed a trend towards better survival, compared with those with mutated TP53 (log-rank test, P = 0.051). Likewise, tumours immunohistochemically positive for p53 showed a worse prognosis than p53-negative tumours (P = 0.010). The presence or absence of mutations in Ki-ras did not correlate with prognosis (P = 0.703). In multivariate analysis, only p53 immunoreactivity emerged as an independent marker for prognosis hazard ratio (HR) = 2.16, 95% confidence interval (CI) 1.12-4.11, P = 0.02). Assessment of p53 protein expression is more discriminative than TP53 mutation to predict the outcome of Dukes' stage B tumours and could be a useful tool to identify patients who might benefit from adjuvant therapy.
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PMID:p53 and Ki-ras as prognostic factors for Dukes' stage B colorectal cancer. 1088 5

Colorectal cancer has provided an excellent model for studying the genetic basis of cancer and is one of the better-understood malignancies in this regard. The orderly progression of the disease, with distinct genetic alterations at each step, is a useful framework for deciphering the molecular basis of neoplasia. Epigenetics, the study of clonal changes in gene expression without associated genetic lesions, has raised increased interest recently, in part because of the identification of DNA methylation as a potential molecular mediator of the process. Several tumor-suppressor genes are silenced in various neoplasms in association with aberrant promoter methylation, and in the absence of coding region mutations. The study of DNA methylation changes in colorectal cancer has now provided additional clues into the pathogenesis of the disease. This review presents evidence for a model whereby DNA methylation changes play two distinct roles in the molecular evolution of colorectal cancer. Initially, progressive methylation and silencing of a subset of genes takes place in normal tissues as a function of age or time-dependent events and predisposes these normal cells to neoplastic transformation. At a later stage of disease progression, DNA methylation plays an important role in a subset of tumors affected by the CpG island methylator phenotype (CIMP), a recently identified pathway that results in a form of epigenetic instability through the simultaneous silencing of multiple genes. DNA methylation changes have important interactions with genetic lesions in this cancer type. CIMP+ cancers include the majority of tumors with sporadic mismatch repair deficiency through hypermethylation of the hMLH1 promoter, and also account for the majority of tumors with Ki-ras mutations through an unknown mechanism. By contrast, CIMP- cases evolve along a more classic genetic instability pathway, with a high rate of p53 mutations and chromosomal changes. Thus, the integration of epigenetic and genetic information provides a more complete molecular understanding of colorectal cancer and may have implications for the diagnosis, prognosis, and treatment of patients affected by this disease.
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PMID:The epigenetics of colorectal cancer. 1091 11

The predictive and prognostic value of the c-K-ras mutation is still unequivocal despite extensive and intensive studies. Investigation of the occurrence of mutations in 88 colorectal cancer patients' specimens using the polymerase chain reaction (PCR) is reported: age: 61.9 years (27-80), gender: 48 male, 42 female, Dukes' stages: 43 at B, 35 at C, 10 at D, primary of tumour: 52 colon, 36 rectal adenocarcinoma. Mutation of one of the three ras-codons was detectable in the 54 cases, more frequently at the Dukes' stage C (p < 0.05). The ras-mutation correlated to a more elevated death-rate in the Dukes' B and C stages (p < 0.01). Mean survival time and time to progression were significantly longer at the Dukes' stage B if mutation was not detected (p < 0.01). The genetic alteration occurred significantly more frequently at tumours of the right-side colon, than the left side (p < 0.02) or rectum (p < 0.05). However, in the age group of 41-50 years, it was more significantly identified in the cases of rectal cancer (p < 0.01). At the age of 51-60 years mutations were detected in men at a higher rate (p < 0.05). The mutation of the codon 13 appeared more frequently in the cases of local recurrences (p < 0.05). The occurrence of the ras-oncogene is a sign of an extremely malignant potential of tumour. This fact manifested itself in the time to progression and mean survival time of patients at the same clinical or pathological stage. The higher frequency of genetic alterations at the proximal colon may be the reason for more unfavourable prognosis of the disease localised to this site. Reconstructing the molecular events, the presence of the ras mutation proved to be an important element for prognosis of the disease and should be a basis of potentially individualised therapeutic intervention.
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PMID:The prognostic value of the presence of mutations at the codons 12, 13, 61 of K-ras oncogene in colorectal cancer. 1092 94

Chromosomal instability and microsatellite instability represent the major pathways for colorectal cancer (CRC) progression. However, a significant percentage of CRC shows neither pattern of instability, and thus represents a potentially distinctive form of the disease. Flow cytometry was used to determine the degree of DNA aneuploidy in 46 consecutive sporadic colorectal cancers. Microsatellite status was determined by PCR amplification using standard markers, while immunostaining was used to examine the expression of p53. K- ras status was determined by restriction-mediated PCR assay. Twenty-five (54%) tumours were aneuploid, 14 (30%) were diploid and microsatellite-stable and seven (15%) were diploid and microsatellite-unstable. Tumours with microsatellite instability were more likely to be right sided, to occur in women and to be associated with an improved survival. Aneuploid tumours were significantly more common in men and were likely to be left sided. The diploid microsatellite-stable (MSS) tumours did not show a sex or site predilection, but were strongly associated with the presence of metastatic disease at the time of diagnosis. Our data suggests that diploid, MSS tumours represent a biologically and phenotypically distinct subset of colorectal carcinoma, and one that is associated with the early development of metastases. We suggest that the genetic stability that characterizes these tumours may favour the maintenance of an invasive phenotype, and thus facilitate disease progression. These findings may have important implications for treatment options in this disease subset.
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PMID:Microsatellite-stable diploid carcinoma: a biologically distinct and aggressive subset of sporadic colorectal cancer. 1116 82


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