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

All cancers result from the accumulation of mutations of proto-oncogenes and tumor suppressor genes. Sporadic and familial colorectal cancers result from the accumulation of the following genes, in a relatively stereotyped chronological order: the tumor suppressor gene apc whose mutations are responsible for the familial adenomatous polyposis; the proto-oncogene K-ras which is mutated in 50% of large adenomas (> 1 cm) and adenocarcinomas; the tumor suppressor gene dcc; and the tumor suppressor gene p53 whose inactivation in a factor of bad prognosis. While some of them are induced by mutagens, others result from an instability of the genome. Two types of instability are observed in both sporadic and familial colorectal cancer. The first type, which is found in 25-50% of cases, appears as cytogenetic abnormalities with aneuploidy and allelic losses. The second type of instability is induced by mutations of the hMSH2 or hMLH1 genes which code for proteins involved in the mechanism of DNA repair.
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PMID:[Genes, heredity and colorectal cancer]. 787 58

L-myc is a nuclear oncogene which is sometimes activated late in tumourigenesis. Digestion of DNA with EcoRI reveals a simple restriction fragment length polymorphism (RFLP) located in the second intron of L-myc, with allele sizes 10 kb (L-allele) and 6.6 kb (S-allele). Some studies have suggested that the presence of the S-allele in the constitutional DNA of a patient with cancer is associated with a higher risk of metastasis in lung, breast and renal cell carcinomas. The aims of this study were to determine if the S-allele was significantly associated with metastasis and also with inactivation of tumour suppressor genes in colorectal cancer. One hundred and twenty-four Caucasian colorectal cancer patients were studied for L-myc genotype, and a subgroup of these (108) had their tumours examined for allele loss at multiple loci on nine chromosomal arms (1p, 1q, 5q, 8p, 14q, 17p, 17q, 18q, 22q) and for mutations in the 12th codon of K-ras. The percentage of individuals with the SS genotype was 19% (4/21) Dukes Stage A, 19% (10/54) Dukes B, 25% (8/32) Dukes C and 40% (8/20) Dukes D. The trend observed here is significant (P < 0.05, Wilcoxon Rank Sum Test). Also, the SS genotype was significantly more common in individuals whose tumours showed allelic loss on 18q (P < 0.01, Fishers Exact Test). This work suggests that the S-allele of L-myc, or a gene in linkage disequilibrium with it, may modify the development of colorectal cancer.
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PMID:Association of the SS genotype of the L-myc gene and loss of 18q sequences with a worse clinical prognosis in colorectal cancers. 790 81

Aberrant crypt foci (ACF) are microscopic lesions which have been postulated to precede the development of adenomatous polyps, the precursors to colorectal cancer. APC and ras gene mutations have been shown to be important early molecular events in the development of colorectal neoplasms. The objective of this study was to establish the nature and frequency of these two genetic alterations in ACF harvested from human colorectal resection specimens. One hundred and fifty-four ACF comprised of between 1 and 56 crypts were harvested from the grossly normal mucosa of colorectal resection specimens of 28 patients with varying pathological diagnoses. One hundred and twenty-five ACF from 20 colons were screened for the presence of K-ras codon 12 mutations with a polymerase chain reaction/restriction enzyme-based method. The APC gene mutation cluster region was screened in 65 ACF from 20 colons using a polymerase chain reaction/single strand conformation polymorphism technique. Putative mutations were confirmed by direct sequencing. K-ras codon 12 mutations were identified in 13% (16 of 125) of ACF. We also identified APC mutations in 4.6% (3 of 65) of ACF. The results of this study demonstrate that both APC and K-ras mutations occur in ACF. These observations support the role of the ACF as a colorectal cancer precursor and provide further insight into the early genetic changes which occur during colorectal tumorigenesis.
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PMID:Somatic APC and K-ras codon 12 mutations in aberrant crypt foci from human colons. 792 90

Colorectal carcinogenesis is a complex multistage process and occurs through the accumulation of gene mutations in both oncogenes and tumour suppressor genes. Frequent genetic abnormalities include mutation of the familial adenomatous polyposis (APC) and/or the mutated in colorectal cancer (MCC) genes on chromosome 5q21, activation of K-ras and loss of the tumour suppressor genes p53 and DCC (deleted in colorectal cancer). In our laboratory we have developed human in vitro colonic cell culture model systems, to determine the biological consequences of these well characterised genetic changes, and how such changes can uncouple proliferation from differentiation and ultimately lead to the malignant phenotype.
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PMID:Biological consequences of the genetic changes which occur during human colorectal carcinogenesis. 831 91

Ras mutations are an important early event in a number of carcinogen-induced rodent tumors. Colon carcinogenesis induced in rats by azoxymethane is a useful model as it mimics the adenoma-carcinoma sequence observed in humans. In addition, aberrant crypt foci develop in the rat and these lesions appear to be potentially important precursors to adenomas in colorectal cancer. Recent studies have shown that specific K-ras codon 12 and 13 mutations are present in up to 66% of carcinogen-induced rat colon adenocarcinomas. We studied the frequency of these mutations during the aberrant crypt focus-adenoma-carcinoma sequence in azoxymethane-induced Fisher F344 rats. K-ras codon 12 GAT and codon 13 GAC mutations were detected with a sensitive assay based on the amplification of DNA using the polymerase chain reaction. No mutations were present in normal mucosa. Of 27 aberrant crypt foci, K-ras mutations were identified in 2 lesions containing 5 and 10 aberrant crypts, respectively. Mutations were present in 1 of 23 and 10 of 27 adenomas and adenocarcinomas, respectively. These data suggest that K-ras mutations play a role during the stages of carcinogenesis in azoxymethane-induced rat colon cancer. The demonstration of a genetic mutation in aberrant crypt foci provides further evidence for the significance of these lesions as precursor markers of malignant potential during colorectal tumorigenesis.
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PMID:K-ras mutations in aberrant crypt foci, adenomas and adenocarcinomas during azoxymethane-induced colon carcinogenesis. 840 99

Gene changes in multiple oncogenes, multiple growth factors and multiple tumor-suppressor genes are observed in stomach cancer. Among them, those most commonly implicated in both well-differentiated adenocarcinoma and poorly differentiated adenocarcinoma are inactivation (mutations and allele loss) of the p53 gene, and activation (abnormal expression and amplification) of the c-met gene. Moreover, they occur at an early stage of stomach carcinogenesis. In addition, loss of heterozygosity (LOH) on chromosome 5q (APC locus) is frequently associated with well-differentiated adenocarcinoma. LOH on chromosome 18q (DCC locus) and LOH of the bcl-2 gene also are common events of well-differentiated adenocarcinoma. LOH on chromosomes 1q and 7q may be involved in the progression of well-differentiated adenocarcinoma. Conversely, the development of poorly differentiated adenocarcinoma, in addition to changes in p53 and c-met genes, requires reduction or dysfunction of cadherin. Overexpression of bcl-2 protein is observed in poorly differentiated adenocarcinoma or signet-ring cell carcinoma. Moreover, the K-sam gene is amplified preferentially in poorly differentiated adenocarcinoma of scirrhous carcinoma. K-sam amplification in scirrhous carcinoma often occurs independently of c-met gene amplification. LOH on chromosome 1p also is relatively common in poorly differentiated adenocarcinoma. Exceptionally, signet-ring cell carcinoma shares APC mutations. There are some differences in expression of the growth-factor/receptor system between well-differentiated adenocarcinoma and poorly differentiated adenocarcinoma. Moreover, interaction between cell-adhesion molecules in tumor cells expressing c-met and hepatocyte growth factor (HGF) from stromal cells is linked with morphogenesis of two histological types of stomach cancer. Intestinal metaplasia and adenoma of the stomach also contain p53 mutations and K-ras mutations or tpr-met rearrangement. Taken together, different genetic pathways of stomach carcinogenesis may exist for poorly differentiated and well-differentiated stomach cancers. Some of the latter may develop by a cumulative series of gene alterations similar to those of colorectal cancer.
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PMID:Molecular mechanism of stomach carcinogenesis. 844 Jul 43

The frequency of activating mutations at codons 12 and 13 of the K-ras gene was investigated in 57 sporadic adenomas from 47 patients using the polymerase chain reaction and oligonucleotide hybridisation assay. Sixty eight per cent of the adenomas tested were positive for K-ras mutations. This high frequency, combined with the lack of a correlation between mutations and adenoma size, suggest that K-ras mutations occur earlier in the adenoma-carcinoma sequence than has previously been suggested. The high frequency observed in sporadic adenomas contrasts with the reported low frequency (18%) in adenomas from patients with familial adenomatous polyposis (FAP), suggesting a possible difference in the molecular genesis of FAP and non-FAP adenomas. Finally, it was found that adenomas from patients with a personal history of colorectal cancer were more likely to contain a K-ras mutation than those from patients with no such history. This is a new finding and worthy of further study.
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PMID:High frequency of K-ras mutations in sporadic colorectal adenomas. 847 89

Markers that predict tumor aggressiveness on a case-by-case basis would enable individualization and optimization of oncologic therapy. To achieve this goal, the presence and specific type of K-ras-2 point mutation was determined from formalin-fixed, paraffin-embedded tissue sites in 247 primary and 166 metastatic-recurrent colorectal adenocarcinomas, using a novel approach consisting of topographic tissue selection, DNA amplification, and direct sequencing applicable to large and needle-biopsy-sized specimens. The results provide the basis for a genotypic classification of colorectal cancer capable of predicting individual tumor aggressiveness, including the pattern and extent of metastasis.
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PMID:Determination of tumor aggressiveness in colorectal cancer by K-ras-2 analysis. 848 86

Molecular genetics is a tool that can be learned as a language to assist clinicians in the management of colorectal cancer patients. Following a brief review of the genetic controls of colorectal cancer, the author focuses on the models of the Registry for Familial Adenomatous Polyposis and the Registry for Hereditary Nonpolyposis Colon Cancer to demonstrate most vividly the impact molecular genetics is currently having on the practical management of colon cancer. Recent discoveries of K-ras oncogene mutations in stool cultures and the prognostic implications of mutations of the TP53 and DCC genes are discussed in the context of future applications to the management of patients.
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PMID:Contributions of molecular genetics to the clinical management of colorectal cancer. 855 21

The reasons for the relatively rare occurrence of small bowel adenocarcinomas when compared to the high frequency of colonic adenocarcinomas are unknown. Activating mutations in the K-ras oncogene occur in about 40% of colonic adenocarcinomas, possibly reflecting the consequences of carcinogenic exposure. To study whether the low incidence of small bowel adenocarcinomas might be due to the absence of activation of cellular oncogenes in small bowel adenocarcinomas, we examined the frequency of K-ras mutations in small bowel adenocarcinomas. K-ras mutations were determined using a polymerase chain reaction (PCR)-based method to detect codon 12 mutations by restriction fragment length polymorphism. PCR amplification was successful in six of nine small bowel adenocarcinoma samples, and revealed point mutations of K-ras at codon 12 in five of these six cases. We conclude that the small bowel might be exposed to carcinogens similar to those responsible for colorectal cancer, but may have developed protective mechanisms against cancer formation.
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PMID:Frequent K-ras mutations in small bowel adenocarcinomas. 856 42


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