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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Because most colorectal carcinomas appear to arise from adenomas, studies of different stages of colorectal neoplasia may shed light on the genetic alterations involved in tumor progression. We looked for four genetic alterations (ras-gene mutations and allelic deletions of chromosomes 5, 17, and 18) in 172 colorectal-tumor specimens representing various stages of neoplastic development. The specimens consisted of 40 predominantly early-stage adenomas from 7 patients with familial adenomatous polyposis, 40 adenomas (19 without associated foci of carcinoma and 21 with such foci) from 33 patients without familial polyposis, and 92 carcinomas resected from 89 patients. We found that ras-gene mutations occurred in 58 percent of adenomas larger than 1 cm and in 47 percent of carcinomas. However, ras mutations were found in only 9 percent of adenomas under 1 cm in size. Sequences on chromosome 5 that are linked to the gene for familial adenomatous polyposis were not lost in adenomas from the patients with polyposis but were lost in 29 to 35 percent of adenomas and carcinomas, respectively, from other patients. A specific region of chromosome 18 was deleted frequently in carcinomas (73 percent) and in advanced adenomas (47 percent) but only occasionally in earlier-stage adenomas (11 to 13 percent). Chromosome 17p sequences were usually lost only in carcinomas (75 percent). The four molecular alterations accumulated in a fashion that paralleled the clinical progression of tumors. These results are consistent with a model of colorectal tumorigenesis in which the steps required for the development of cancer often involve the mutational activation of an oncogene coupled with the loss of several genes that normally suppress tumorigenesis.
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PMID:Genetic alterations during colorectal-tumor development. 284 97

Microsatellite instability characterizes a sub-set of sporadic colorectal cancers (CRCs) as well as CRCs from patients with hereditary non-polyposis colorectal cancer (HNPCC). In order to clarify when the cells acquire a replication-error phenotype (RER) during colorectal-tumor progression, we examined the incidence of RER in 80 primary tumors and 36 liver metastases at 8 microsatellite loci; 1 mono-, 5 di-, 1 tetra- and 1 pentanucleotide. RER were detected in 20.1% (17/80) of primary tumors, including 5 tumors showing RER at 2 or more loci (RER2), while the incidence of RER in liver metastases (22.2%, 8/36) was almost the same as that in primary tumors, and there was only one RER2 case in metastases. There were 3 cases in which both primary tumors and liver metastases had the same type of RER at the same locus, and there were 2 cases that showed RER in primary tumors but not in liver metastases. In contrast, there was no case in which RER was detected in a metastasis but not in the corresponding primary tumor. The RER phenotype did not show correlation with any clinicopathological parameters of cancer-cell aggressiveness, such as clinical staging, histological grade and survival. These results indicate that a sub-set of CRCs acquire the RER phenotype in the relatively early stages of colorectal carcinogenesis, and that the RER phenotype is not associated with aggressiveness of CRCs.
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PMID:Microsatellite instability in primary and metastatic colorectal cancers. 762 2

The cytosine DNA methyltransferase (MT) enzyme, which catalyzes DNA methylation at CpG sites, is overexpressed at the mRNA level during the progressive stages of colon cancer. This paper describes the adaption of a sensitive microassay for determining MT enzyme activity during tumor progression in human colon and murine lung. MT activity was progressively elevated in mucosa from familial adenomatosis polyposis patients, mucosa adjacent to cancers, and in colonic adenocarcinomas when compared to colonic mucosa from control patients. In addition, the activity of this enzyme was increased in alveolar type II but not Clara cells isolated from A/J mice following carcinogen exposure and continued to increase during tumor progression. The use of a microassay for measuring MT activity indicates that changes in enzyme activity were in general agreement with previous findings of increased MT mRNA levels during colon cancer progression and also implicates the involvement of this pathway in lung cancer development.
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PMID:A microassay for measuring cytosine DNA methyltransferase activity during tumor progression. 859 74

Mismatch repair genes are the responsible genes for hereditary non-polyposis colon cancer, and mutation of these genes causes replication error (RER). In several RER-positive colon cancer cell lines, mutations of repetitive sequences of transforming growth factor beta (TGF-beta) type II receptor (RII) gene have been reported. Since TGF-beta inhibits cell proliferation, loss of response to TGF-beta is an important tumor progression step. In this study, the relationship between RER status and mutation of the RII gene was analyzed in 112 cases of various types of sporadic gastrointestinal and hepatobiliary cancer (41 with gastric, 49 with colorectal, 5 with gallbladder, and 17 with hepatic cancers). RER was found in 17 cases (4 with gastric, 12 with colorectal, and 1 with gallbladder cancer), and 10 of those (3 with gastric and 7 with colorectal cancer) showed mutations of the RII gene. Of interest was that in all seven cases with colorectal cancer, tumors were located at the cecum. These data indicate that mutation of the RII gene, presumably caused by abnormality of repair gene, play an important role in carcinogenesis of sporadic gastrointestinal cancer, especially at the cecum.
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PMID:A transforming growth factor beta type II receptor gene mutation common in sporadic cecum cancer with microsatellite instability. 897 Nov 66

Genetic instability related to defective DNA mismatch repair genes may be involved in the pathogenesis of carcinoma in Hereditary Non-Polyposis Colorectal Cancer (HNPCC). To test that the targets of genetic instability could include critical transforming genes involved in colon tumor progression, we examined 23 colorectal carcinomas in patients with HNPCC in order to detect somatic mutations in K-ras and p53 genes. Using single strand conformation polymorphism followed by direct DNA sequencing, we detected 4 mutations in K-ras gene (17%) and 3 in p53 gene (13%) which change the amino acid sequence of the protein p53. This is significantly lower than in sporadic cancer. Our data suggest that colon cancer in HNPCC might partly involve a distinct pathogenetic mechanism that involves other genes than those altered in sporadic tumors.
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PMID:K-ras and p53 mutations in hereditary non-polyposis colorectal cancers. 903 76

A cytogenetically visible interstitial deletion of chromosome band 10q23 was found in a 6-year-old boy with mental retardation, dysmorphic features, and juvenile polyposis coli. In order to map this patient's deletion physically, we performed fluorescence in situ hybridization by using yeast artificial chromosomes (YACs) in the vicinity of the deletion. Five YACs that span an 11-15 cM region within the deletion were identified. This patient's deletion contains the putative locus for Cowden syndrome and a recently discovered candidate tumor suppressor gene (MMAC1 or PTEN) that has been implicated in the progression of a variety of human malignancies. Furthermore, the deletion is near and possibly overlaps a locus associated with juvenile polyposis. The findings in this patient with a constitutional 10q23 deletion raise the issue of whether there are separate genes in this region that are involved in Cowden syndrome, Bannayan-Riley-Ruvalcaba syndrome, juvenile polyposis, and tumor progression, or whether all of these entities could be due to a single gene.
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PMID:Deletion 10q23.2-q23.33 in a patient with gastrointestinal juvenile polyposis and other features of a Cowden-like syndrome. 949 22

Peutz-Jeghers syndrome (PJS) is an autosomal dominant condition characterized by intestinal hamartomatous polyps, mucocutaneous melanin deposition, and increased risk of cancer. Families with PJS from the Johns Hopkins Polyposis Registry were studied to identify the molecular basis of this syndrome and to characterize the pathogenesis of gastrointestinal hamartomas and adenocarcinomas in PJS patients. Linkage analysis in the family originally described by Jeghers in 1949 and five other families confirmed linkage to 19p13.3 near a recently identified gene responsible for PJS. Germ-line mutations in this gene, STK11, were identified in all six families by sequencing genomic DNA. Analysis of hamartomas and adenocarcinomas from patients with PJS identified loss of heterozygosity (LOH) of 19p markers near STK11 in 70% of tumors. Haplotype analysis indicated that the retained allele carried a germ-line mutation, confirming that STK11 is a tumor suppressor gene. LOH of 17p and 18q was identified in an adenocarcinoma but not in hamartomas, implying that allelic loss of these two regions corresponds to late molecular events in the pathogenesis of cancer in PJS. The adenocarcinomas showing 17p LOH also demonstrated altered p53 by immunohistochemistry. None of the 18 PJS tumors showed microsatellite instability, LOH on 5q near APC, or mutations in codons 12 or 13 of the K-ras proto-oncogene. These data provide evidence that STK11 is a tumor suppressor gene that acts as an early gatekeeper regulating the development of hamartomas in PJS and suggest that hamartomas may be pathogenetic precursors of adenocarcinoma. Additional somatic mutational events underlie the progression of hamartomas to adenocarcinomas, and some of these somatic mutations are common to the later stages of tumor progression seen in the majority of colorectal carcinomas.
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PMID:Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. 985 45

The interaction of the adenomatous polyposis coli (APC) tumor-suppressor protein and the intracellular cell-adhesion protein beta-catenin is crucial for the development of colorectal tumors. Since functional nuclear complexes of beta-catenin with transcription factors have been identified recently, the knowledge of level and distribution of beta-catenin in sporadic colorectal tumors will give important insights into the intracellular mechanism of sporadic colorectal tumor initiation and progression. In contrast to the familiar adenomatous polyposis syndrome and to the majority of sporadic colorectal tumors, Peutz-Jeghers (PJ) syndrome is not caused by mutations in the APC gene. Since PJ syndrome is an inherited disease with an increased risk for gastrointestinal adenocarcinoma, whether beta-catenin plays a similarly important role for the development of PJ polyps should be further investigated. For these reasons we analyzed the distribution of beta-catenin in a total of 60 sporadic colorectal tumors at different stages of progression and in 6 PJ polyps. In addition to the localization at the cell-to-cell border membranes, fluorescence immunohistochemistry revealed a nuclear accumulation of beta-catenin in single tumor cells of 10/14 small adenomas with mild dysplasia and in 14/16 adenomas with moderate dysplasia. Further tumor progression is accompanied by an expansion of cells with increased level of nuclear and cytoplasmic beta-catenin. These cells were observed in 5/16 adenomas with moderate dysplasia and in 15/15 adenomas with severe dysplasia. In all adenocarcinomas investigated, as well as in the corresponding lymph node metastases, a sub-population of tumor cells exhibited a remarkably increased level of beta-catenin within the entire cytoplasm and the nucleus. In contrast to the situation in sporadic colorectal tumors, nuclear and cytoplasmic beta-catenin was not increased in PJ polyps. These results point to an extensive redistribution of beta-catenin, which starts early in colorectal tumorigenesis. The nuclear accumulation in single cells of small adenomas can be considered as the first visible sign of the loss of APC function. Thus the immunohistochemical detection of beta-catenin distribution could serve as a criterion for estimating the malignant potential in the clinico-pathological evaluation of colon tumors during their early progression.
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PMID:Intracellular distribution of beta-catenin in colorectal adenomas, carcinomas and Peutz-Jeghers polyps. 1035 35

Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomal dominant disease, predisposing to the development of colorectal cancer and other tumor types such as endometrial, small bowel, stomach, ovary and urinary tract carcinoma, while most investigators find no association between HNPCC and cancer of the breast. We have identified hMLH1 mutations in 2 Amsterdam-criteria HNPCC families where both male and female gene carriers were affected with breast cancer. To investigate whether these breast cancers were caused by other genetic factors, we analyzed the 2 breast cancer susceptibility genes BRCA1 and BRCA2. In one family we did not find any mutation in the breast cancer genes, while in the other, a BRCA1 mutation segregated in the breast cancer cases. Hereditary breast cancer, and in particular BRCA1 tumors, display discrete histo-pathological and immunohistological characteristics. The tumor from a woman with both hMLH1 mutations and a BRCA1 mutation exhibited typical BRCA1 histology, e.g., grade 3 invasive ductal carcinoma with dense lymphocytic infiltration, and immunohistology, estrogen receptor (ER) negative, progesterone receptor (PgR) negative, strongly p53 positive, c-erbB-2 negative and highly Ki67 positive (>50% stained cells). The histology of the breast tumor from the man with both one hMLH1 mutation and a BRCA1 mutation was a grade 2 invasive ductal carcinoma without any special BRCA1 features. Immunohistology was also different. This might merely reflect a true difference in male breast tumor progression vs. female. We cannot exclude that the combined effect of BRCA1 and hMLH1 dysfunction has a bearing on tumor progression.
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PMID:Germline BRCA1 and HMLH1 mutations in a family with male and female breast carcinoma. 1070 98

The tumor suppressor SMAD4, also known as DPC4, deleted in pancreatic cancer, is a central mediator of TGF-beta signaling. It was previously shown that mice homozygous for a null mutation of Smad4 (Smad4-/-) died prior to gastrulation displaying impaired extraembryonic membrane formation and endoderm differentiation. Here we show that Smad4+/- mice began to develop polyposis in the fundus and antrum when they were over 6 - 12 months old, and in the duodenum and cecum in older animals at a lower frequency. With increasing age, polyps in the antrum show sequential changes from hyperplasia, to dysplasia, in-situ carcinoma, and finally invasion. These alterations are initiated by a dramatic expansion of the gastric epithelium where Smad4 is expressed. However, loss of the remaining Smad4 wild-type allele was detected only in later stages of tumor progression, suggesting that haploinsufficiency of Smad4 is sufficient for tumor initiation. Our data also showed that overexpression of TGF-beta1 and Cyclin D1 was associated with increased proliferation of gastric polyps and tumors. These studies demonstrate that Smad4 functions as a tumor suppressor in the gastrointestinal tract and also provide a valuable model for screening factors that promote or prevent gastric tumorigenesis.
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PMID:Haploid loss of the tumor suppressor Smad4/Dpc4 initiates gastric polyposis and cancer in mice. 1077 76


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