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

In this study, structural changes of the p53 gene in primary specimens of human colorectal carcinomas were analyzed by polymerase chain reaction mediated-DNA sequencing method. Point mutations of p53 gene, including an intronic mutation case, were detected in 8 of 14 carcinomas (57%). Point mutations of the gene were also observed in 2 of 2 adenomas, suggesting that mutations occur prior to the carcinoma stage. These results support that p53 gene plays an important role in the development of colorectal cancer. The frequency of Ki-ras oncogene mutations was also studied by polymerase chain reaction-single strand conformation polymorphism analysis (PCR-SSCP). This resulted in the rate of 42% (10/24), a quite similar value obtained by other methods. As PCR-SSCP analysis is a convenient method to detect point mutation, we have now examined 24 colorectal cancers for the p53 gene by this method, and detected the mutations. Furthermore, expression of the DCC gene, a candidate of tumor suppressor gene involved in colorectal carcinogenesis, was examined by reverse transcriptase-mediated PCR (RT-PCR) assay, resulting in significant reduction on the DCC expression in 8 of 14 carcinoma cases (57%).
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PMID:Mutations of the p53 gene and other genes involving in human colorectal carcinogenesis. 130 99

Retinoblastoma (RB) and the familial adenomatous polyposis/colorectal cancer (FAP/CRC) complex provide well-characterised examples of multistage carcinogenesis and inheritance of a predisposition to cancer. Retinoblastoma appears to conform to the simple two-step model first proposed by Knudson. The gene responsible for RB, now called Rb1, has been located in chromosome region 13q14. The Rb1 gene has been cloned and subjected to extensive analysis. It is probable that the Rb1 gene product has a role in the regulation of transcription. The familial form of RB occurs as the result of a germline mutation of one of the copies of the Rb1 gene. Colorectal cancer, in contrast, appears to be the result of four or five steps involving both activation of oncogenes and inactivation of antioncogenes. The FAP gene has been located in chromosome region 5q21 by genetic linkage, and a candidate gene, MCC (mutated in colon cancer), has been cloned. Other mutations in previously-identified genes that have been identified as important in the genesis of CRC include the activation of p53 and of Ki-ras. A gene lying in chromosome region 18q which is deleted in colorectal cancer, and hence named DCC has been cloned. Its protein product has sequence homology to neural cell adhesion molecules and other related cell-surface glycoproteins. Delineation of the genes involved in the development of tumours such as RB and CRC provides insight into the mechanisms by which sequential mutations result in carcinogenesis.
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PMID:Multistage carcinogenesis in paediatric and adult cancers. 131 30

Kirsten-ras-revertant-1 (Krev-1/Rap1A) is a recently identified tumor suppressor gene which induces flat revertants when introduced into a variety of ras-transformed cell lines in vitro. Since 47% of colorectal carcinomas have transforming mutations in ras protooncogenes, and since Krev-1 is expressed at high levels in normal colonic mucosa, we hypothesized that inactivation at the Krev-1 locus may be necessary for transformation of colonic cells. Loss of heterozygosity is a common method of inactivation of tumor suppressor genes in colorectal tumors. Therefore, we analyzed loss of heterozygosity in 52 patients with sporadic colorectal cancer. Because Krev-1 had no previously described polymorphisms, we first identified a BclI restriction fragment length polymorphism which showed 40% heterozygosity in 50 unrelated individuals. However, only one tumor from 18 informative patients showed allelic loss at the Krev-1 locus. This suggests that loss of heterozygosity is not a common mechanism of inactivation at the Krev-1 locus in colorectal cancer. However, the results do not exclude a role for Krev-1 in the etiology of this neoplasm because inactivation may occur by other mechanisms.
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PMID:Loss of heterozygosity at the human RAP1A/Krev-1 locus is a rare event in colorectal tumors. 134 9

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.
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PMID: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. 134 43

Mutational activation of ras oncogenes is frequently encountered in human tumors. For unexplained reasons, K-ras mutations are predominantly found in pancreatic cancer, colorectal cancer and adeno-carcinoma of the lung, N-ras is predominantly found in a subset of acute leukemias and in myelodysplastic syndromes, while H-ras mutations are rare. In most tumors, ras mutations are not clearly associated with specific clinical or biological features, but in lung cancer, childhood lymphoblastic leukemia and possibly in myelodysplastic syndromes ras mutations may predict a poor prognosis. Accumulating evidence suggests that exposure to chemical carcinogens is responsible for many ras mutations in humans.
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PMID:ras and human tumors. 142 Nov 68

Although several biomarkers have been tested, Dukes' (or TNM) stage at diagnosis is still considered the only prognostic factor of clinical relevance in colorectal cancer. Among the various biomarkers, the fraction of cells engaged in DNA synthesis has been extensively investigated as an indicator of tumor aggressiveness. Bromodeoxyuridine (BUdR) is a non-radioactive thymidine analogue which is incorporated into DNA during the S-phase of cycling cells. In order to evaluate the relationships between cell kinetics and morphologic variables, 500 mg of BUdR were given i.v. to 46 patients with colorectal cancer prior to surgery. After operation, a large tumor sample was taken and processed for immunohistochemical detection of BUdR-labeled cells in various regions of the neoplasm and in normal colorectal mucosa. Smaller superficial tumor specimens were also incubated with 3H-thymidine (3H-TdR) for the autoradiographic identification of labeled cells. In the 43 evaluable tumors, the overall BUdR labeling index (BLI, percent of labeled cells) was significantly higher in carcinoma (20.30 +/- 0.86%, SEM) than in normal colonic mucosa (6.51 +/- 0.49%). BLIs in central and peripheral regions of carcinoma were closely correlated (r = 0.48, p = 0.003). In 21 neoplasms a high correlation between overall BUdR and 3H-TdR labeling index in the same tumor was observed (r = 0.57, p = 0.007). No evident association between overall BLI and clinical or morphologic parameters of the tumor was seen, including number of capillaries and ras-p21 protein expression. We conclude that BUdR immunostaining after in vivo administration of BUdR is a simple method for studying cell kinetics in various regions of colorectal cancer. BUdR labeling data are comparable to those obtained with in vitro incorporation of 3H-TdR.
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PMID:Cell kinetics evaluation of colorectal tumors after in vivo administration of bromodeoxyuridine. 145 24

The molecular genetics of colorectal carcinoma are among the best understood of any common human cancer. Reported molecular genetic abnormalities involve tumor-suppressor genes that undergo inactivation (e.g., apc, mcc, dcc, p53, and possibly genes on chromosomes 8p, 1p, and 22q) and dominant-acting oncogenes (e.g., ras, src, and myc). Multiple clonal genetic abnormalities accumulate during the development of colorectal carcinoma in adenomas. Altered DNA methylation is an early event, and the specific genetic alterations occur in a preferential order. However, the clinical application of molecular genetics in patients who are at risk for or have colorectal carcinoma is in its infancy. Patients with a predisposition to colorectal carcinoma caused by inheritance of familial adenomatous polyposis can be identified by genetic analysis of the apc gene on chromosome 5q21. In patients who undergo curative resection of colorectal cancer, deletion of the p53 gene on chromosome 17p, deletion of the dcc gene on 18q, and high fractional allelic loss (fraction of nonacrocentric autosomal arms with deletion) in the primary tumor appear to indicate an increased likelihood of occult disseminated disease and thus a poor prognosis. Additional studies are needed to establish the role of the molecular genetics of colorectal carcinoma in the management of patients who are at risk for or already have neoplasia of the large bowel.
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PMID:Molecular genetics of colorectal carcinoma. 151 69

To set the basis for a precise assessment of new therapeutic approaches, the prognosis of patients with colorectal cancer should be evaluated with the highest precision. The recent discovery, in tumor cells, of somatically acquired genetic alterations believed to be instrumental in tumor behavior may provide new independent prognostic factors. In the present study, the usual prognostic factors and a set of genetic alterations, i.e., Ki-ras mutations, DNA content, and allelic losses on chromosome 17p, 18q, 5q, and 1p, were investigated in 109 colorectal carcinomas. Univariate analysis for correlation with 5-year survival showed the following significant associations: histological staging (P less than 0.00001), preoperative serum carcinoembryonic antigen concentration (P less than 0.002), DNA content (P less than 0.009), and allelic loss on the short arm of chromosome 17 (P less than 0.002) and 1 (P less than 0.03). In multivariate analysis, only histological staging and allelic loss on the short arm of chromosome 17 were found to be independently associated with shorter survival (P less than 0.0001 and P less than 0.004, respectively). Loss of 17p alleles in colorectal carcinoma thus appears to be a marker of tumor aggressiveness. Its monitoring may lead to an improved classification of patients when adjuvant chemotherapy is considered.
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PMID:Survival and acquired genetic alterations in colorectal cancer. 155 51

This study was performed to determine the correlation of tumor ras and c-myc oncogene expression with clinical and prognostic variables in patients prone to develop colorectal cancer. One hundred eighteen patients with colorectal cancer were studied; mean age was 40 years. Fifty-three were young patients (age 40 or less), 49 had ulcerative colitis, and 16 had multiple polyposis coli. Immunoperoxidase stains of paraffin-embedded cancer sections were performed for the c-myc and ras proteins. ras staining was found to correlate with Dukes stage and prognosis. Patients with tumors negative for ras protein stain had an actuarial five-year survival of 61 percent versus 44 percent for those tumors with a positive stain (P less than 0.05). This correlation was not seen with the c-myc stain. Positive ras oncogene stain appears to be a useful indicator of advanced stage and poor prognosis in colorectal cancer occurring in cancer-prone patients.
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PMID:ras and c-myc protein expression in colorectal carcinoma. Study of cancer-prone patients. 156 93

We have used a rapid, non-radioactive and sensitive method based on allele-specific amplification using the polymerase chain reaction for the identification of K-ras mutations in archival tissues of colorectal carcinomas. Our purpose was to determine whether or not K-ras mutation provides, when present, a tumour marker throughout the natural history of the disease. We have studied 35 patients who developed recurrent cancer. In 71% of these patients a ras mutation in codons 12 or 13 was observed in the primary tumour. For each of these cases an identical ras mutation was found in the DNA from the local or distant recurrence. In the 29% of cases where no ras mutation was observed in the primary tumour, no newly acquired ras mutation appeared in the recurrent tumour. The time interval between primary tumours and recurrences varied from 3 to 60 months. Our results indicate that K-ras mutation provides a stable tumour marker throughout the natural history of colorectal cancer.
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PMID:Stability of K-ras mutations throughout the natural history of human colorectal cancer. 162 81


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