Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cancer in adenomas are thought to be an excellent model of colorectal carcinogenesis based on the adenoma-carcinoma sequence. We searched for alterations in the APC mutation cluster region, the whole coding regions of TGF-beta type II receptor (RII) and beta-catenin exon 3 in 16 cases of cancer in adenomas of the colon. Overexpression of the p53 protein was also analyzed. Nine of the 16 cases showed APC mutations in both the adenoma and cancer regions. Loss of heterozygosity in APC was found in one cancer in adenoma that had no mutation. p53 overexpression was detected in one adenoma and 10 cancerous regions, most of which also exhibited APC alterations. Two cases showed a missense mutation at codon 191 or loss of heterozygosity in TGF-beta RII in both the adenoma and cancer. Our data support the hypothesis that alterations of APC and p53 are responsible for most of the adenoma-carcinoma pathway, rather than TGF-beta RII alterations.
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PMID:Genetic alterations are frequent in APC but rare in the TGF-beta type II receptor gene in cancer in adenomas of the colon. 956 1

Some mixed hyperplastic adenomatous polyps (MHAPs) contain dysplastic lesions or even carcinomas. These polyps are considered to be different from ordinary hyperplastic polyps and may have a preneoplastic potential. We investigated APC and K-ras mutations in MHAPs of the colon and rectum, and also in colorectal adenomas and hyperplastic polyps to identify molecular differences between MHAPs, adenomas and hyperplastic polyps, using direct sequencing of mutation cluster regions (MCR) in APC and K-ras. No APC mutations were identified in 12 MHAPs and 8 hyperplastic polyps, whereas 10 of 27 (37.0%) adenomas showed somatic mutations. K-ras mutations were identified in one of 12 (8.3%) MHAPs, one of 8 (12.5%) hyperplastic polyps, and 10 of 27 (37.0%) adenomas. p53 mutation was found in a carcinoma arising in an MHAP. Mutations other than APC mutations may play a role in the development of MHAPs.
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PMID:Genetic alterations of mixed hyperplastic adenomatous polyps in the colon and rectum. 960 Jan 24

p53 gene mutation (exon4, 5, 6, 7, 8 and intron6) in gastric cancer and precancerous lesions and p53 gene (exon4 and ontron6), APC gene deletion in gastric carcinomas were studied by PCR/SSCP and PCR/RFLP. Results showed mutation rate of p53 in metaplasia, dysplasia and gastric carcinoma was 37.5% (3/8), 42.17% (8/19), 53.33 (16/30) respectively. There was significant difference among groups of metaplasia, dysplasia, cancer and normal controls. No exon8 mutation was found in metaplasia and dysplasia, but 4 cases were found to have exon8 mutation in cancer group. It is suggested that exon8 mutation occurs at the late stage of gastric cancer, but exon 5, 6, 7 mutation occur in the course of precancerous lesion to cancer. Loss of heterozygosity (LOH) of exon4, intron6, APC was 47, 37% (9/19), 8.73% (2/23), 16.67% (3/18) respectively. LOH of exon4 had something to do with poor differentiation, lymph node metastasis, depth of invasion. LOH of exon4 may be of prognostic marker of gastric cancer. We are led to conclude that p53 gene mutation is an early event and perhaps work together with ras oncogene in gastric carcinogenesis.
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PMID:Abnormal change of p53 gene in gastric and precancerous lesions and APC gene deletion in gastric carcinoma and near tissues. 963 93

We have extended the algebraic models for cancer initiation and progression developed by Nordling, Armitage-Doll and Knudson-Moolgavkar to include the effect of cell turnover rate in normal tissue, stochastic growth of preneoplastic adenomas, and the general case wherein a subfraction of the population is at risk. We have also gathered the mortality data available for the United States from 1900 to 1991 and categorically organized them by birth year cohorts and age specific death rates for ages 0 to 104 in 5-year groupings. Using these data, we first explored the quantitative nature of the biases of underreporting or misdiagnosis as historical age-dependent functions. Then we used the extended algebraic model to calculate the parameters of subpopulation fraction at risk, mutation rates and adenoma growth rates. We observe that death rates for all cancers are low in childhood and early adulthood, rise in middle age in an approximately linear manner, reach a maximum in old age, and even after correction for reporting bias, decrease markedly in extreme old age. We represent this behavior as the natural result of a continuous process of cell division, death and mutation within a subpopulation at risk. This population at risk within any birth cohort is defined by the product of a constant inherited risk factor multiplied by a historically valuable environmental risk factor. Our formulation permits explicit calculation of the fraction at risk of death from any cancer as a historical function. With regard to the algebraic description of the process of carcinogenesis, we use Nordling's concept that n genetic events in a cell population of constant cell number are required to initiate a colony capable of net cell growth or 'adenoma.' We adopt and extend Moolgavkar's use of the 'Gambler's Ruin' stochastic process to describe the probability of adenoma survival and the canonical expectation that a surviving adenoma will soon contain many initiated cells by virtue of stochastic distribution of surviving cells. We consider that within the growing adenoma, it is necessary for a cell to acquire m additional mutations in order to attain the carcinoma phenotype of cell growth rapid enough to kill in a short time. This would be irrespective of the need for any additional genetic events that may define the subsequent phenotypes of large lethal tumors, as these would be automatically acquired and be physiologically selected in any rapidly growing cell mass. It is evident that the steps of initiation and progression are dependent on both the rates of genetic change per cell division and the cell kinetic rates of division and death. We have chosen to first examine colon cancer because the rates of cell division in normal colonic epithelium, dysplastic adenomas and small carcinomas have been directly observed as reported herein. For colon cancer, we calculate that about 65% of the US population is at risk for both males and females, and that this fraction has been constant for the earliest recorded birth cohorts of the mid-19th century to the beginning of the 20th century. The changes that have been observed in colon cancer mortality rates appear to arise from historical changes in death rates by unknown 'other causes of death', which share both genetic and environmental risk factors with colon cancer and explicitly include undiagnosed deaths by colon cancer. Considering all possible values of n and m, we find the case of n=2 and m=1 to give the best concordance with present knowledge of mutations in the colon by the loss of two alleles of the APC gene and the observation that for m=1, a rate of genetic change approximately equal to that calculated for initiation mutation rates is obtained. Our estimates for the rate of initiation and progression mutation rates show no significant historical shifts and are approximately 1-2x10-7 events per cell division. (ABSTRACT TRUNCATED)
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PMID:Mutation, cell kinetics, and subpopulations at risk for colon cancer in the United States. 968 10

Germline mutations of the PTEN/MMAC1/TEP and LKB1 genes cause hamartomas to develop in the gastrointestinal tracts of patients with Cowden syndrome and Peutz-Jeghers syndrome, respectively. PTEN mutations may also be responsible for some cases of juvenile polyposis. Histologically, hamartomas appear benign, but there is good evidence that in these syndromes, the hamartomas can progress to colorectal carcinoma. It remains unknown whether or not cancers that develop from hamartomas acquire a spectrum of mutations similar to those in sporadic colon cancers. PTEN and LKB1 are candidate genes for mutations in sporadic colon cancers, either as initiating events in tumorigenesis or providing a selective advantage during tumor growth. Using single-strand conformational polymorphism analysis, we have screened a set of sporadic colon cancers for somatic mutations in PTEN and LKB1. No variants predicted to alter protein function were detected in LKB1, but 1 of 72 cancers showed a somatic mutation in PTEN, together with allele loss. This cancer did not have a detectable APC mutation or allele loss at APC. It remains possible that PTEN and LKB1 are inactivated in other sporadic colon cancers by means such as deletion or promoter methylation. Like BRCA1 and BRCA2, however, it appears that PTEN and LKB1 mutations can cause cancers when present in the germline, but occur rarely in the soma.
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PMID:Genetic pathways of colorectal carcinogenesis rarely involve the PTEN and LKB1 genes outside the inherited hamartoma syndromes. 970 96

Classical familial adenomatous polyposis (FAP) is a high-penetrance autosomal dominant disease that predisposes to hundreds or thousands of colorectal adenomas and carcinoma and that results from truncating mutations in the APC gene. A variant of FAP is attenuated adenomatous polyposis coli, which results from germ-line mutations in the 5' and 3' regions of the APC gene. Attenuated adenomatous polyposis coli patients have "multiple" colorectal adenomas (typically fewer than 100) without the florid phenotype of classical FAP. Another group of patients with multiple adenomas has no mutations in the APC gene, and their phenotype probably results from variation at a locus, or loci, elsewhere in the genome. Recently, however, a missense variant of APC (I1307K) was described that confers an increased risk of colorectal tumors, including multiple adenomas, in Ashkenazim. We have studied a set of 164 patients with multiple colorectal adenomas and/or carcinoma and analyzed codons 1263-1377 (exon 15G) of the APC gene for germ-line variants. Three patients with the I1307K allele were detected, each of Ashkenazi descent. Four patients had a germ-line E1317Q missense variant of APC that was not present in controls; one of these individuals had an unusually large number of metaplastic polyps of the colorectum. There is increasing evidence that there exist germ-line variants of the APC gene that predispose to the development of multiple colorectal adenomas and carcinoma, but without the florid phenotype of classical FAP, and possibly with importance for colorectal cancer risk in the general population.
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PMID:The APC variants I1307K and E1317Q are associated with colorectal tumors, but not always with a family history. 972 71

There is vast evidence in support of the idea that accumulated genetic changes (mutations) are the underlying cause of neoplasia development. This multi-step process is aptly illustrated by colorectal carcinoma (CRC), usually developing in the course of decades, and presumably requiring at least seven genetic events to complete its development. In CRC the oncogenes most frequently undergoing mutation are c-k-ras and c-myc, and among tumor suppressant genes--APC, MCC, DCC, p53. An updated model of the molecular bases for adenoma occurrence and its evolution into carcinoma is presented. Inheritance of a single gene only which has undergone mutation augments substantially the predisposition to CRC. This is noted in a clearcut manner in the hereditary syndromes familial adenomatous polyposis (FAP) and hereditary non-polypous colorectal carcinoma (HNPCC). Recent studies along these lines suggest that the genetic defect in FAP increases the incidence of tumor initiation through functional impairment of the APC gene which is a gene regulator of the enhanced colorectal mucosa proliferation. Contrarily, the defect in HNPCC involves mainly the tumor progression through mutation of the DNA repair genes (MMRs), which are regulators of the genome stability. The study of hereditary syndromes give rise to a new concept for the occurrence and development of sporadic and inherited cancer in humans.
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PMID:[The molecular biology and genetics of colorectal carcinoma]. 973 86

Carcinoma in ulcerative colitis (UC) develops from dysplastic precursor lesions, which include flat dysplasia (FD) and polypoid dysplasias (PD). PD may present as single or multiple polypoid structures or as plaque-like lesions that, independent of histological grade, are an indication for colectomy. PDs are histologically similar to adenomas and may not be readily distinguished by light microscopy. It is not known whether FD and PD are different entities, or whether they represent etiologically similar lesions with different morphological expression. We microdissected 25 cases of UC with PD and 19 samples of FD with surrounding chronic colitis (CC) in UC. Loss of heterozygosity (LOH) at the von Hippel Lindau (vHL) gene locus and the putative tumor suppressor genes APC, INK4A (9p16), and p53 was studied. LOH of the vHL gene, INK4A (9p16), and APC was also studied in 11 sporadic adenomas of the colon. LOH at the vHL locus was present in 50% of the samples of PD and in 12% of the samples of FD. LOH was seen in CC close to PD and FD in 26% and 12% of cases, respectively. No adenoma showed LOH of the vHL gene markers studied. LOH in p53 was seen in PD in 16% cases and in FD in 42% cases and in CC close to PD and FD in 0% and 14% cases, respectively. LOH patterns between PD and FD of the markers for APC and 9p16 were not different. LOH in APC was seen in two of five cases of adenoma. We conclude that PD and FD share genetic alterations in APC and 9p16 genes. More frequent involvement of the VHL gene in PD and surrounding CC and involvement of p53 in HGD and CC in FD may represent genetic differences between the development of PD and FD and may be the cause of the different morphology. The infrequency of LOH at the vHL locus in adenomas versus PD may serve as a discriminator between adenomas and PD in diagnostically problematic cases.
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PMID:Loss of heterozygosity of the von Hippel Lindau gene locus in polypoid dysplasia but not flat dysplasia in ulcerative colitis or sporadic adenomas. 974 12

The different proteins of the E-cadherin/catenin cell-cell adhesion complex are believed to play a predominant role in carcinogenesis. Aberrant expression of these proteins has been found in many different human carcinomas, indicating abnormal regulation. In general, inactivating mutations of the human E-cadherin gene are rare; they are, however, highly frequent in infiltrating lobular breast carcinomas and in diffuse gastric carcinomas. These mutations mostly occur in combination with loss of heterozygosity (LOH) of the wild-type allele. Mutations were found at very early non-invasive stages, thus associating E-cadherin mutations with loss of growth control and defining E-cadherin as a real tumour suppressor for these particular tumour types. Defects affecting both alleles of the alpha E-catenin gene have been found in different human carcinoma cell lines, resulting in the loss of E-cadherin-mediated cell-cell adhesion. Mutations of the beta-catenin gene in colon tumours and melanomas were found to result in an accumulation of the protein in the cytosol. Upon translocation to the nucleus, this beta-catenin enhances TCF/LEF-dependent transcriptional activity. This suggests that mutated beta-catenin can act as an oncogene in these particular tumour types. The multiple interaction partners of beta-catenin are known to be involved in signal transduction, actin organization, protein phosphorylation or transcriptional regulation. This makes this protein an intriguing alternative target for either activation or inactivation in human cancer types characterized by frequent E-cadherin or APC deficiencies.
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PMID:Dysregulation of the E-cadherin/catenin complex by irreversible mutations in human carcinomas. 982 69

Germ-line mutations of the adenomatous polyposis (APC) gene, responsible for familial adenomatous polyposis (FAP) were analyzed in 15 patients with FAP-associated papillary thyroid carcinomas: 13 had the mutation between codons 778 and 1309 (exon 15), 1 at codon 593 (exon 14), and 1 at codon 140 (exon 3). Therefore APC gene mutations clustered in the genomic area associated with congenital hypertrophy of the retinal pigment epithelium (CHRPE) (codons 463-1387). Ocular patches were documented in 12 patients. In particular, 4 of the 15 patients, all women with a mean age of 23.5 (range 20-32), were found during the study of 15 consecutive kindreds who had undergone systematic screening for extra-colonic manifestations. Three of them belonged to the same kindred and were asymptomatic. These four patients were also screened for loss of heterozygosity of APC in the thyroid tumoral tissue. No biallelic inactivation of the APC gene was found. In contrast, three of these four patients had activation of the ret-PTC oncogene. In particular, there was activation of the ret-PTC1 isoform, a chimeric gene resulting from fusion of a gene named H4 with the RET gene. On histologic examination, three of the four patients showed Hashimoto-like lymphocytic infiltration. Present data suggest that: (1) the incidence of FAP-associated thyroid cancer probably has been underestimated in the past; (2) intensive screening could detect a larger than expected number of thyroid carcinomas; (3) systematic screening is recommended in patients with ocular patches and genetic mutation in exon 15; (4) Hashimoto-like findings do not exclude carcinoma but are a frequent accompanying finding; (5) despite frequent multicentricity and early lymph node involvement, FAP-associated thyroid tumors seem to have an excellent prognosis, in particular those showing ret-PTC activation.
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PMID:Genetic alterations in thyroid carcinoma associated with familial adenomatous polyposis: clinical implications and suggestions for early detection. 984 49


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