Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0009402 (colorectal cancer)
 53,228 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This study investigated the frequency and importance of Ki-ras codon 12 mutations in 99 Hong Kong Chinese colorectal carcinoma specimens by allele-specific oligonucleotide hybridization. The frequency of mutations detected was 30% and the most common mutation observed resulted in aspartic acid substitutions. Previous studies showed that specific Ki-ras mutations have been significantly associated with prognosis. Ki-ras codon 12 point mutational activation in CRC was significantly associated with the differentiation status of tumors in this study. Ethnic differences in the patterns of Ki-ras codon 12 point mutations were observed.
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PMID:Ki-ras codon 12 point mutational activation in Hong Kong colorectal carcinoma patients. 1002 77

To clarify the genetic background of cancer patients, microsatellite instability (MSI) and mutations of transforming growth factor-beta type II receptor (RII), p53 and k-ras gene were investigated. MSI were detected in 33.3% of esophageal, 15.8% of gastric, 21.4% of colorectal, 4.5% of bile duct, 0% of gallbladder, 13.3% of pancreatic, 11.6% of breast and 10.5% of thyroid cancers. Mutations of RII gene were detected in only 2 of 9 MSI-positive colorectal cancers. k-ras gene mutations were investigated in colorectal, bile duct, gallbladder, breast and thyroid cancer and were detected in 11.9%, 36.4%, 64.3%, 0%, 0% of each. p53 gene mutations were investigated in colorectal and breast cancer and were detected in 9.5% and 9.3%, respectively. In addition, 4 colorectal cancer cases exhibited more than two kinds of genetic alteration, while breast cancer cases showed only single kind. From these findings, it is suggested that 1) the incidence of each genetic alteration differed among the cancers investigated and organ specificity may exist; 2) the genetic alterations investigated here contributed to a minor part of cancer development, which requires the identification of more unknown genes related to carcinogenesis; 3) to clarify the molecular mechanism of cancer development, the genetic alterations including genomic instability and mutations of several kinds of genes related to cancer development in each case should also be determined along with their genetic molecular profile.
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PMID:[Genetic alterations in human malignant tumor]. 1006 61

Epidemiological and experimental data suggest that dietary fiber and fat are major determinants of colorectal cancer. However, the mechanisms by which these dietary constituents alter the incidence of colon cancer have not been elucidated. Evidence indicates that dominant gain-of-function mutations short-circuit protooncogenes and contribute to the pathogenesis of cancer. Therefore, we began to dissect the mechanisms whereby dietary fat and fiber, fed during the initiation, promotion and progression stages of colon tumorigenesis, regulate ras p21 localization, expression and mutation frequency. Male Sprague-Dawley rats (140) were provided with corn oil or fish oil and pectin or cellulose plus or minus the carcinogen azoxymethane (AOM) in a 2 x 2 x 2 factorial design and killed after 34 weeks. We have previously shown adenocarcinoma incidence in these animals to be 70.3% (52/74) for corn oil + AOM and 56.1% (37/66) for fish oil + AOM (P < 0.05). Total ras expression as well as ras membrane:cytosol ratio was 4- to 6-fold higher in colon tumors than in mucosa from AOM- or saline-injected rats. Expression of ras in the mucosal membrane fraction was 13% higher for animals fed corn oil compared with fish oil feeding (P < 0.05), which is noteworthy since ras must be localized at the plasma membrane to function. The elevated ras membrane:cytosol ratio in tumors was not due to increased farnesyl protein transferase activity or prenylation state, as nearly all detectable ras was in the prenylated form. Phosphorylated p42 and p44 mitogen activated protein kinase (ERK) expression was two-fold higher in tumor extracts compared with uninvolved mucosa from AOM- and saline-injected rats (P < 0.05). The frequency of K-ras mutations was not significantly different between the various groups, but there was a trend toward a greater incidence of mutations in tumors from corn oil fed rats (85%) compared with fish oil fed rats (58%). Our results indicate that the carcinogen-induced changes in ras expression and membrane localization are associated with the in vivo activation of the ERK pathway. In addition, suppression of tumor development by dietary n-3 polyunsaturated fatty acids may be partly due to a combined effect on colonic ras expression, membrane localization, and mutation frequency.
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PMID:Carcinogen and dietary lipid regulate ras expression and localization in rat colon without affecting farnesylation kinetics. 1033 94

The incidence of melanoma, the most aggressive tumor of the skin, is increasing worldwide. The genetic mechanisms responsible for the initiation and progression of melanoma are poorly understood. Mutations of p16 (CDKN2), p53, ras, neurofibromatosis type I gene (NF-1), bcl2 and the retinoblastoma gene have been described, but none are common. Suggesting heterogeneous mechanisms of carcinogenesis. Both familial inheritance of potential tumor suppressor genes, e.g. p16, and differences in DNA-repair capacity contribute to the individual risk for melanoma. The most important carcinogen for melanoma seems to be u.v. exposition whose mutagenic effects can be demonstrated by molecular analysis of detected point mutations in relevant genes. The u.v.-induced DNA damage generates mutations which are capable of activating proto-oncogenes or inactivating tumor suppressor genes, demonstrating the molecular link between u.v. exposition, DNA damage, mutations and tumor initiation and/or progression. A stage-dependent model of melanoma carcinogenesis analogous to colorectal cancer remains to be established, despite the existence of morphologically and histopathologically well defined melanoma precursor lesions in the skin.
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PMID:[Pathogenesis of malignant melanoma. Molecular biology aspect]. 1042 7

The identification of predefined mutations expected to be present in a minor fraction of a cell population is important for a variety of basic research and clinical applications. Here, we describe an approach for transforming the exponential, analog nature of the PCR into a linear, digital signal suitable for this purpose. Single molecules are isolated by dilution and individually amplified by PCR; each product is then analyzed separately for the presence of mutations by using fluorescent probes. The feasibility of the approach is demonstrated through the detection of a mutant ras oncogene in the stool of patients with colorectal cancer. The process provides a reliable and quantitative measure of the proportion of variant sequences within a DNA sample.
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PMID:Digital PCR. 1043 Sep 26

Despite of extensive and intensive investigations, the predictive and prognostic value of c-K-ras mutation is not unequivocal. There has been reported about investigation the occurrence of mutations in the 88 colorectal cancer patient's specimen using polymerase chain reaction. Age: 61.9 years (27-80), gender 8 male, 42 female. Dukes' stages: 43 at the B, 35 at C, 10 at D. Primary of tumour: 52 colon, 36 rectal adenocarcinoma. Mutation out of one of the three ras-codons was detectable in the 54 cases, more frequently at the stage Dukes' C (p < 0.05). The ras-mutation concerned to more elevated death-rate in the stages Dukes' B and C (p < 0.01). Mean survival time to progression was significantly longer at the stage Dukes' B if mutation had not been detected (p < 0.01). The occurrence of the rate of genetic alteration was significantly more frequent at tumours of right-side colon, than left side (p < 0.02) or rectum (p < 0.05) one's. However, at the age of 41-50 years it was significantly more presented at the cases of rectal cancer (p < 0.01). At the age of 51-60 years mutations were detected among men at higher rate (p < 0.05). The cases of local recurrences concerned by mutation at the codon of 13 (p < 0.05). Occurrence of ras-oncogene is the sign of extremely malignant potential of tumour. This fact manifested itself in the time to progression and mean survival time of patients at same clinical or pathological stage. The higher frequency of genetic alterations at the proximal colon may be the reason of more unfavourable prognosis of the disease localised to this site. Reconstructing the molecular events, the presence of ras mutation can serve as a basis for prognosis of the disease and permit of potentially individualised therapeutic intervention.
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PMID:[Prognostic value of the presence of the mutation of the codons 12, 13 and 61 in K-ras oncogene in colorectal cancer]. 1046 47

We have examined the incidence of mutation of the c-Ki-ras proto-oncogene in colorectal adenocarcinomas from two different time periods, namely 1962-1966 and 1994-1996. The first cohort of samples consisted of formalin-fixed, archival paraffin block and represent the oldest colorectal cancer samples for which ras mutation has been examined, while the second cohort of tumours were fresh, flash-frozen samples representative of genetic events occurring in contemporary times. Analysis of mutation status was undertaken by a mismatch-specific oligonucleotide hybridization analysis of exon 1 of the c-Ki-ras proto-oncogene after amplification by the polymerase chain reaction. Mutations in codon 12 or 13 of c-Ki-ras were detected in 28% (14/50) of contemporary samples, a figure consistent with locally established mutation rates. In contrast no mutation was detected in any of the 18 samples from the earlier period, a result that is statistically significant (P = 0.007). Age-standardized rates of colorectal cancer in Singapore have seen a marked increase over the last 30 years, and for the first time we have shown that such an increase in colorectal cancer is associated, at least in part with an increase in incidence of a specific mutagenic change.
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PMID:c-Ki-ras mutations in colorectal adenocarcinomas from a country with a rapidly changing colorectal cancer incidence. 1049 48

The Ki-ras protooncogene frequently is mutated in colorectal adenocarcinomas, but the etiology of this molecular event is uncertain. We investigated the association between variables known or suspected to be related to risk for colorectal cancer and the occurrence of Ki-ras mutations in colorectal adenomas. This study was conducted among 678 male and female participants, 40-80 years of age, enrolled in a phase III trial testing the effects of a wheat bran fiber supplement on adenoma recurrence. Exposure information on the risk factors of interest was assessed through self-administered questionnaires. Mutations in codons 12 and 13 of the Ki-ras protooncogene were analyzed in baseline adenomas 0.5 cm or larger by PCR amplification followed by direct sequencing. Eighteen percent (120 of 678) of the participants had one or more adenoma(s) with Ki-ras mutations. A higher risk of Ki-ras mutations was associated with increasing age and a lower intake of total folate. The odds ratio (OR) for Ki-ras mutations for individuals >72 years of age was 1.98 [95% confidence interval (CI) = 1.19-3.27; P for trend = 0.008] compared with those less than 65 years of age. Compared with individuals in the lower tertile of total folate, those in the upper tertile had an approximately 50% lower risk of having Ki-ras mutation-positive adenomas (OR = 0.52; 95% CI = 0.30-0.88; P for trend = 0.02). There was a suggestion of a stronger inverse association of total folate with G-->T transversions (OR = 0.41; 95% CI = 0.20-0.87) than G-->A transitions (OR = 0.61; 95% CI = 0.31-1.21), although the CIs for the associations overlap. The results of these analyses suggest that the protective effect of folate in colon cancer observed in published studies may be mediated through folate's effect on Ki-ras mutations.
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PMID:Risk factors for Ki-ras protooncogene mutation in sporadic colorectal adenomas. 1053 95

The interpretation of cancer as a somatic evolutionary process involving genetic mutation followed by selection, traces its origins to the early years this century. The dramatic developments in molecular genetics have substantiated these early ideas. Through the application of positional cloning and genomic analysis, many mutations in particular genes, both dominant oncogenes and tumour suppressor genes have now been found in a wide variety of tumours. Other genetic events such as non-disjunction leading to haploid expression of a gene and so reduced gene dosage, or epigenetic changes following, for example, changes in methylation patterns leading to reduced or increased gene expression, may also play critical roles in the progression of a cancer. The analysis of mutations at different stages of colorectal cancer provides a good model for following the initiation and progression of a cancer. Mutations in the APC gene, which explain familial adenomatous polyposis, occur in a high proportion of sporadic colorectal carcinomas and appear to be the earliest known changes. Patterns of mutation in the gene suggest dominant negative or gain of function effects, and also reveal important low penetrance subpolymorphic missense mutations that nevertheless may have a very significant impact on the genetic contribution to colorectal cancer susceptibility. Mutations are also found in related genes in the APC pathway, such as beta-catenin and E-cadherin. Mutations in mismatch repair genes (hMLH1 and hMSH2) have also been shown to occur, as well as reduced expression due to methylation changes, in 10% to 20% of sporadic colorectal carcinomas. In addition, mutations in the well known oncogenes p53 and ras are commonly found. The growth of a cancer is a balance between the rate of cell division and the rate of cell death or apoptosis. Thus, genetic changes which reduce the probability of apoptosis, such as p53 and probably hMLH1, are as important a feature of the evolution of a cancer as those which enhance the independence (APC) and rate of cell division (growth factors). Simple models for the evolution of a cancer that take into account these two processes, show that cancers evolve initially by a series of finite increases in cell population size, following which there may be long periods of cell turnover during which there is an opportunity for further mutation and selection. This explains the long lag periods between the initiation and subsequent progression of most cancers. Our rapidly developing understanding of cancers at the fundamental genetic level provides new opportunities for developing targeted treatments, as well as novel approaches to prevention and early detection.
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PMID:1998 Runme Shaw Memorial Lecture: somatic evolution of cancer. 1057 14

We report a rare case of Crohn disease accompanied by a small-bowel carcinoma that developed in a 54-year-old Japanese man. The ulcerating tumor, which histologically proved to be a poorly differentiated adenocarcinoma and dysplasia surrounding the carcinoma, was located in the diseased ileum. The Ki-67 immunoreactive epithelial cells were increased in regenerative mucosa as compared with values for normal mucosa. The Ki-67- and p53-positive cells were increased in dysplasia and carcinoma as compared with values for regenerative or normal mucosa. In contrast, the p21(WAF1/CIP1) immunoreactive cells were decreased in this order. Intense DCC (deleted in colorectal cancer) expression was constantly shown among normal, regenerative, dysplastic and cancerous tissues. No bcl-2 expression and c-Ki-ras mutations were apparent. In conclusion, enhanced epithelial cell proliferation, p53 overexpression, and decrease of p21(WAF1/CIP1) expression may predispose the small-bowel mucosa to dysplasia and carcinoma development in Crohn disease.
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PMID:A case of adenocarcinoma of the small intestine in a Japanese patient with Crohn disease: a report with immunohistochemical and oncogenic analyses. 1058 70


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