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Query: UMLS:C0001430 (adenoma)
 21,222 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Most adenocarcinomas of the colorectum arise in a visible benign precursor lesion, the adenoma, which is a monoclonal proliferation of dysplastic nonmalignant epithelial cells. The resultant adenoma-adenocarcinoma sequence represents the predominant pathogenetic pathway, in contrast to de novo carcinoma. Therefore, the adenoma is a tempting endpoint for chemoprevention trials. The adenoma-adenocarcinoma sequence occurs in diverse clinical settings. In familial adenomatous polyposis (FAP) syndrome, autosomal dominant inheritance of the mutated APC (adenomatous polyposis coli) gene on chromosome 5q21 typically results in thousands of adenomas in the colorectum and in lesser numbers in the proximal small bowel. Adenocarcinoma usually develops in only a few of these adenomas, typically in the left colon and duodenum. In hereditary nonpolyposis colorectal cancer (HNPCC) syndrome, autosomal dominant inheritance of an unidentified gene appears to result in small numbers of adenomas which progress frequently to adenocarcinoma, predominantly in the right or transverse colon. In familial aggregation of colorectal cancer without a recognizable syndrome, cancer and/or adenomas occur in pedigree members. In "sporadic" cancers and adenomas, family history is absent and the tumors are mainly in the left colon. Colorectal adenomas have variable characteristics including size, shape (polypoid vs. flat), villous architecture, and dysplasia. A variety of oncogenes and tumor suppressor genes are altered during progression. Epigenetic factors are important as evidenced by the disappearance of adenomas in FAP patients after ileorectal anastomosis or treatment with the nonsteroidal antiinflammatory drug sulindac. Several variations on the theme of the adenoma-carcinoma sequence are evident. Identification of the inherited and acquired genetic alterations as well as the interacting environmental factors will provide a rational basis for chemoprevention.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:The adenoma-adenocarcinoma sequence in the large bowel: variations on a theme. 133 99

To examine whether the dosage effect of germ-line mutations in patients with familial adenomatous polyposis (FAP) is sufficient to cause colorectal adenomas, or an additional somatic mutation of the normal allele is required as well, we have investigated somatic mutations of the APC gene in multiple adenomas developed in one FAP patient. In addition to a 5-bp deletion of one allele present constitutionally in this patient, the normal APC allele had been lost in five of seven DNA samples extracted from small adenomas (< 3 mm in diameter) with mild or moderate atypia. This result indicates that the inactivation of both alleles of the APC gene is probably essential for the development of an early-stage adenoma, in agreement with the two-hit mutational model underlying the concept of tumor suppressor genes.
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PMID:Inactivation of both APC alleles in an early stage of colon adenomas in a patient with familial adenomatous polyposis (FAP). 133 60

The molecular genetic alterations in colorectal carcinoma are among the best understood of any common human cancer. Identified abnormalities include both dominant-acting oncogenes (ras, myc, src) and suppressor genes which undergo inactivation or deletion (deleted in colorectal carcinoma gene [DCC], p53, adenomatous polyposis coli gene [APC], and probably loci on chromosomes 1p and 22q). Accumulation of multiple abnormalities is evident in the adenoma-carcinoma sequence with a preferential order, and alteration of DNA methylation is an especially early event. Identification of molecular genetic markers useful for classification and staging of colorectal carcinoma is in its infancy. Deletion of the p53 gene on chromosome 17p, deletion of the DCC gene on 18q, and high fractional allelic loss (fraction of evaluable nonacrocentric autosomal arms with deletion) have been associated with distant metastases and with poorer prognosis in patients without initial evidence of disseminated disease. Additional studies are needed to determine the possible role of these alterations in clinical management.
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PMID:Molecular genetic alterations as potential prognostic indicators in colorectal carcinoma. 154 Sep

Loss of heterozygosity (LOH) and K-ras mutation were analyzed in 111 colorectal polyps and 26 invasive carcinomas from 40 patients with familial adenomatous polyposis of distinct histopathological types. LOH, being less than 2% in moderate adenomas, was detected on chromosome 5q (20%) in severe adenomas, on 5q (26%) and 17p (38%) in intramucosal carcinomas, and on 5q (52%), 17p (56%), 18 (46%), and 22q (33%) in invasive carcinomas. LOH on chromosome 5q occurred most frequently in the region close to the APC gene both in adenomas and carcinomas, and a loss of the normal allele of the APC gene was demonstrated in 3 cases. K-ras mutation markedly increased in the step of development from moderate (11%) to severe (36%) adenomas. These results suggest the following mechanisms for the development of colon tumors in patients with familial adenomatous polyposis: (a) the heterozygous mutant/wild-type condition at the APC gene causes formation of mild or moderate adenoma; (b) the loss of the normal allele in the APC gene leads to a change from moderate to severe adenoma; (c) LOH on chromosome 17p contributes to the conversion of adenoma to intramucosal carcinoma; (d) LOH on other chromosomes, such as 18 and 22q, are involved in the progression of intramucosal carcinoma to invasive carcinoma; and (e) K-ras mutation may also affect the development of moderate to severe adenoma.
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PMID:Genetic changes and histopathological types in colorectal tumors from patients with familial adenomatous polyposis. 197 14

Murine strains which bear constitutive inactivating mutations of either the APC or the p53 tumor suppressor genes are characterised by spontaneous tumors. APC mutated (Min) mice develop large and small bowel adenomas, a small proportion of which, in time, become malignant. p53 deficient mice develop predominantly lymphoma and sarcoma. By interbreeding these strains we have shown that there is co-operativity between these mutations, leading to a shift in phenotype. Most notably, this was characterised by a range of abnormalities of the exocrine pancreas in 83% of animals heterozygous for the APC mutation and constitutively null for functional p53. Dysplasia and preneoplastic foci were seen in 61% of these animals and pancreatic acinar cell adenocarcinoma in 22%. Analysis of these tumors showed them to have lost the remaining wild-type copy of APC. Similar loss of APC was not associated with the development of other extra-intestinal tumors. Surprisingly, given the proposed role for loss of function mutations of the p53 gene in the development of human colorectal cancer, we have found no evidence for either an increase in the rate of adenoma formation in APC +/-, p53 -/- animals, or an increased rate of progression to malignancy compared with APC +/- p53 +/+ mice. These findings highlight striking tissue-specific differences in the tumor suppressor effects of p53.
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PMID:Interaction between murine germline mutations in p53 and APC predisposes to pancreatic neoplasia but not to increased intestinal malignancy. 747 22

Neoplastic progression of colorectal epithelial cells from benign adenomas to malignant carcinomas appears to result from a series of genetic alterations involving both oncogenes and tumor suppressor genes. This progression was recently found to be associated with expression of splice variant isoforms of CD44, a cell surface hyaluronate receptor implicated in carcinogenesis. In this study we examined the relationship of CD44 expression to somatic genetic events in the adenoma-carcinoma sequence: point mutation of K-ras in codons 12 and 13 and overexpression of p53 protein as a marker of gene mutation. Among 22 small adenomas, CD44 was present in 9 (41%), of which only 1 contained a K-ras mutation. CD44 was absent in the other 2 small adenomas positive for K-ras mutation or p53 overexpression. In contrast to the early expression of CD44 in small adenomas, mutations of K-ras and p53 were detected preferentially in large adenomas and late-stage adenomas containing carcinoma. The frequent expression of CD44 prior to K-ras and p53 gene alterations in colorectal neoplasia suggests that activation of CD44 gene expression is related to earlier events in the adenoma-carcinoma sequence, possibly cell activation and proliferation following APC gene mutation or alteration of DNA methylation.
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PMID:CD44 expression in colorectal adenomas is an early event occurring prior to K-ras and p53 gene mutation. 751 84

Focal neoplastic change occurs frequently within the colorectum. Yet, of the several hundreds of microadenomas that are likely to be present within an individual colorectum, only one or two will develop into a clinically diagnosable adenoma. In turn, only a fraction of adenomas will progress to malignancy. The risk that a particular microadenoma will end its natural history as a carcinoma varies according to clinical context. The risk is very low in familial adenomatous polyposis (FAP), but relatively high in hereditary non-polyposis colorectal cancer (HNPCC). This variation is governed by the timing and ordering of the underlying mutational events. In FAP, inactivation of the wild-type APC gene occurs early, whereas K-ras mutations are late events. The converse appears to apply in the case of sporadic adenomas. In flat adenomas, which are known to be relatively aggressive, K-ras mutations may not occur at all. In HNPCC, mutational events are accelerated as a result of defective DNA mismatch repair. The evolution of colorectal adenoma occurs through a variety of quite distinct genetic pathways.
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PMID:Colorectal adenoma progression and genetic change: is there a link? 754 18

Colorectal cancer affect the 15% of general population in developed countries. Cancer is a multistep process in which multiple genetic alterations must usually occur in several years. The premalignant step consists of one or multiple aberrant crypts due to hyperproliferation of cells and its shift from the deep third of the crypt to its surface. It has been suggested that abnormality in the APC gene is responsible for this. Furthermore, there exists DNA hypometilation, activation of the gene K-ras and ornithine decarboxylase activity. There is also a loss of MCC gene, that seems to interact with the APC gene. Entire alterations described make possible the Class I adenoma formation. This adenoma, needs the loss of the DCC gene (late stage in the carcinogenesis process), to become a Class II adenoma. The following alteration is deleted and mutation of the p53 gene. There is also an activation of the c-myc oncogene. These two genes are important mechanisms for the conversion of a benign adenoma to a malignant one, adenoma with in situ carcinoma or Class III adenoma. This type of adenoma becomes carcinoma and metastatic stage, throughout inactivation of several tumor suppressor genes. Besides the hereditary APC alteration and other acquired genetic changes as described above there are other associated genetics, antigenics, and enzymes that have an important role in the adenoma-carcinoma sequence. Several carcinogenic factors have been described which also contribute in the adenoma and carcinoma formation: ulcerative colitis, acromegaly, familial history of colonic neoplasia, certain professions, smoking and drinking, consumption of red or processed meat, etc.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Etiology of colorectal cancer]. 755 83

The APC (adenomatous polyposis coli) gene was isolated as a gene responsible for familial polyposis coli, an autosomal-dominant disease, characterized by development of hundreds to thousands of adenomatous polyps in the colon and rectum. However, recent studies revealed that inactivation of the APC gene also plays a significant role in development of sporadic forms of colorectal adenoma and carcinoma. Furthermore, somatic mutations have also been detected in pancreatic carcinomas as well as some type of gastric carcinomas, suggesting that APC has a critical function in regulation of cell growth in digestive tissues.
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PMID:The adenomatous polyposis coli gene and human cancers. 755 32

Min (multiple intestinal neoplasia) is a mutant allele of the murine Apc (adenomatous polyposis coli) locus, encoding a nonsense mutation at codon 850. Like humans with germline mutations in APC, Min/+ mice are predisposed to intestinal adenoma formation. The number of adenomas is influenced by modifier loci carried by different inbred strains. One modifier locus, Mom-1 (modifier of Min-1), maps to distal chromosome 4. Intestinal tumours from both B6 (C57BL/6J) and hybrid Min/+ mice show extensive loss of the wild-type allele at Apc. B6 Min/+ female mice are predisposed to spontaneous mammary tumours. The incidence of both intestinal and mammary tumours can be increased in an age-specific manner by treatment with ethylnitrosourea (ENU). Min mice provide a good animal model for studying the role of Apc and interacting genes in the initiation and progression of intestinal and mammary tumorigenesis.
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PMID:ApcMin: a mouse model for intestinal and mammary tumorigenesis. 757 92


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