UMLS:C0596263 - FACTA Search

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Query: UMLS:C0596263 (carcinogenesis)
64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the gastric remnant has been reported to be at high risk for carcinogenesis, the process of carcinogenesis of gastric remnant cancer (GRC) remains unclear. In this study, genetic alterations in GRC were examined in order to investigate the carcinogenic pathways of GRC. Twenty-one patients with GRC were investigated and were compared to 36 patients with sporadic gastric cancer (GC) as a control group. Microsatellite instability (MSI) was examined using 8 primer marker sets. Immunohistochemical staining for hMLH1 and hMSH2 as the DNA mismatch repair system was performed. The high-level MSI (MSI-H) frequency (43%; 9/21) of GRC was significantly higher (p=0.001) than that of the sporadic GC (6%; 2/36). The MSI-H incidence (67%: 8/12) of GRC after gastrojejunostomy (Billroth II anastomosis) was significantly (p=0.015) higher than that (11%: 1/9) after gastroduodenostomy (Billroth I anastomosis). The MSI-H in GRC was significantly (p<0.0001) associated with lack of expression of both hMLH1 and hMSH2. The inactivation of hMLH1 or hMSH2 was significantly frequent (p=0.035) in GRC after gastrojejunostomy (58%: 7/12), compared with that in gastroduodenostomy (11%: 1/9). GRC was more closely associated with the MSI pathway than sporadic GC. Carcinogenesis in the remnant stomach following distal gastrectomy with gastrojejunostomy was found to be associated with the MSI pathway due to inactivation of the DNA mismatch repair system.
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PMID:Carcinogenesis in the remnant stomach following distal gastrectomy with billroth II reconstruction is associated with high-level microsatellite instability. 1661 51

Somatic mutation of K-ras is known to be a common event in colorectal cancer tumourigenesis however its association with age at onset has not been widely explored. In this study, we have analyzed tumours from a population-based study of colorectal cancer diagnosed before the age of 45 years, in which cases had been previously screened for germ-line mismatch repair gene mutations and for microsatellite instability. We used a micro-dissection and sequencing approach to search for somatic K-ras mutations in codons 12, 13 and 61 in 101 early-onset colorectal cancers. Six (6%) somatic K-ras mutations were detected; five in codon 12 (4 G>T transitions and 1 G>A) and one in codon 13 (G>A transition). All codon 12 mutations were identified in microsatellite stable tumours and the codon 13 mutation was identified in a MSI-high tumour. Four cases with K-ras mutations had no reported family history of colorectal cancer and two had some family history of colorectal cancer. None were known to carry a germ-line mutation in hMSH2, hMLH1, hMSH6 or hPMS2. The role of somatic K-ras mutations in early-onset colorectal cancer carcinogenesis appears to be minor, in contrast to its significant role in colorectal cancer of later age of onset.
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PMID:Low somatic K-ras mutation frequency in colorectal cancer diagnosed under the age of 45 years. 1676 42

The frequency of synchronous or metachronous multiple primary carcinomas in patients with gastrointestinal carcinoma or colorectal carcinoma (CRC) has been reported to be approximately 10%. We determined the role of hMSH2 and hMLH1 in double carcinomas with both GC and CRC. Fifty-six patients with synchronous or metachronous colorectal carcinoma with gastric carcinoma (CRC with GC), and 69 patients with CRC alone was included in our study. We investigated their clinicopathological characteristics, family history and immunohistochemical stains of hMSH2 and hMLH1 were compared between the patients with CRC alone and those with both CRC with GC. The defective protein expression of hMSH1 and/or hMLH1 in colorectal carcinomas was significantly higher in patients with both CRC with GC than in those with CRC alone (p < 0.0001). The survival rate in patients with both CRC with GC was significantly lower than that in those with CRC alone (p < 0.01), in addition, the survival rate in patients with defective protein expression of hMSH2 and/or hMLH1 was higher than in those with a positive protein expression of hMSH2 and/or hMLH1 in CRC with GC (p < 0.05). The incidence of defective protein expression of hMSH2 and/or hMLH1 in CRC with GC patients suggests that abnormalities in the function of hMSH2 and hMLH1 may play an important role in carcinogenesis. Our findings indicate that the CRC patients who demonstrate a defective protein expression of hMSH2 and/or hMLH1 have a higher risk of developing secondary carcinoma in the gastrointestinal tract.
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PMID:Loss of protein expression of hMLH1 and hMSH2 with double primary carcinomas of the stomach and colorectum. 1678 21

Impaired mismatch repair (MMR) is reportedly crucial in the early stages of endometrial carcinogenesis. Although estrogen exposure is considered an important risk factor for endometrial carcinoma, the relationship between estrogen and MMR activity remains undetermined. The present study was undertaken to elucidate the effect of estrogen on MMR activity in normal and malignant endometrial cells. The expression of MMR proteins, hMLH1 and hMSH2, and its correlation with estrogen was examined using immunohistochemical and immunofluorescent techniques. The effect of estradiol (E2) on the expression of hMLH1/hMSH2 protein/mRNA and in vitro MMR activity using two types of heteroduplex (G/T mismatches, 2-base insertion-deletion loops) was examined in cultured normal endometrial glandular cells and estrogen receptor-positive endometrial carcinoma Ishikawa cells. Immunohistochemical expression of hMLH1 and hMSH2 in normal endometrial glands was positively correlated with the serum E2 levels. The expression of hMLH1/hMSH2 protein and mRNA was increased in normal endometrial glandular and Ishikawa cells by E2 treatment. In vitro MMR activity was up-regulated by E2 in both types of cell and heteroduplex. Immunofluorescent analysis demonstrated that E2 enhanced proliferation and hMLH1/hMSH2 expression in both cells; however, proliferating cells without hMLH1/hMSH2 expressions implying high-risk cells were more frequently observed under low E2 concentrations. Collectively, the E2-induced up-regulation of MMR activity in endometrial cells suggests that high estrogen levels act as an intrinsic defense against endometrial carcinogenesis, whereas the imbalance between cell growth and MMR under low E2 environment as seen at postmenopause is vulnerable to carcinogenesis.
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PMID:Estrogen up-regulates mismatch repair activity in normal and malignant endometrial glandular cells. 1682 17

The multistep development of malignant tumors with increasing accumulation of genetic alterations from preneoplastic lesions to invasive carcinoma is an accepted model of carcinogenesis. Urothelial carcinoma of the bladder and upper urinary tract is an interesting model system to study tumor development and progression. There is both clinical and molecular evidence that urothelial carcinoma can be divided in two groups with different characteristics: 1) well differentiated genetic stable and mostly superficial papillary tumors with frequent recurrence and low progression risk and 2) poorly differentiated mostly solid and invasive tumors with a high number of genetic alterations. The aim of the studies summarized in this manuscript were: 1) to identify genetic changes with importance for urothelial carcinogenesis by investigation of preneoplastic and early neoplastic urothelial lesions, 2) to define molecular markers for progression of papillary carcinoma, and 3) to investigate the importance of microsatellite instability and mismatch repair defects for development of tumors of the upper urinary tract which are frequently found within the HNPCC syndrome. The investigation of urothelial hyperplasias, dysplasias and carcinoma in situ by deletion mapping (LOH analysis), FISH, CGH and mutation detection revealed that urothelial hyperplasias are precursors of papillary bladder tumors and flat dysplasias can be regarded as precursors of solid bladder cancers. In bladder cancer patients, there are genetic alterations already detectable in histologically inconspicous urothelium. The investigation of papillary bladder cancers for progression-related genetic alterations showed that mutations in the wnt pathway genes APC and beta-Catenin do not play an important role in urothelial carcinogenesis. Instead, the expression of the antagonistic wnt-related genes WIF-1 and sFRPI is strongly reduced in bladder cancer and associated with poor prognosis in papillary tumors. Loss of sFRP1 expression is not due to gene mutation but to epigenetic inactivation by promoter hypermethylation and is related to deletions at chromosome 8p12. In contrast to bladder cancers, tumors of the ureter and renal pelvis develop through a different genetic pathway in 30% of cases. The loss of mismatch repair proteins (hMSH2, hMLH1 or hMSH6) leads to a mutator phenotype with accumulation of genetic alterations in multiple repetitive sequences (microsatellite instability, MSI). MSI-positive tumors were predominantly located in the ureter and showed a lower tumor stage and grade and papillary and frequently inverted growth pattern. They were more frequent in females and younger patients and had a higher incidence of colorectal carcinomas and other tumors in the family. Chromosome 9 deletions, a hallmark of urothelial carcinomas, and the number of chromosomal alterations as detected by CGH analysis were significantly less frequent in these tumors. These data strongly suggest a distinct molecular pathway in the development of upper urinary tract tumors with mutator phenotype.
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PMID:[Molecular changes in development and progression of urothelial carcinoma]. 1688 10

Early colorectal carcinomas (submucosal invasive adenocarcinomas) can be classified into polypoid growth carcinoma (PG-Ca) and non-polypoid growth carcinoma (NPG-Ca) types, the latter transforming more rapidly to advanced carcinoma. Previously, we indicated that stromal genetic instability might contribute to tumorigenesis of both sporadic and ulcerative colitis-associated colorectal adenocarcinomas. In the present study, we analyzed genetic instability of both epithelial and surrounding stromal components in PG-Ca and NPG-Ca. In 99 colorectal submucosal invasive adenocarcinomas, epithelial and stromal genetic instability was analyzed with National Cancer Institute standard microsatellite markers, chromosome 17 (Chr.17) markers and tumor suppressor gene-related markers, using a combination of the laser-captured microdissection and GeneScan approaches. Immunohistochemical analysis was carried out for hMLH1, hMSH2, MGMT and p53. In addition, we investigated methylation of the hMLH1 and MGMT promoters. The frequencies of epithelial microsatellite instability (MSI) with Chr.17 markers were significantly higher in NPG-Ca (33.3%) compared to PG-Ca (10.4%), particularly with D17S579 and D17S796. For loss of heterozygosity, only D17S786 showed a significant difference. The frequencies of stromal MSI with all markers were 31.7% and 25.9% in NPG-Ca and PG-Ca, respectively, but D17S579 and TP53 showed higher MSI in NPG-Ca than PG-Ca. Immunohistochemically, p53 protein expression in PG-Ca was significantly higher in loss of heterozygosity-positive cases with altered Chr.17 markers overall, especially the D17S796 marker, compared to cases without genetic instability. These results suggest that epithelial and stromal MSI of Chr.17 markers contributes more to carcinogenesis in NPG-Ca, whereas stromal genetic instability might be necessary for the development of both types of colorectal carcinoma.
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PMID:Genetic instability on chromosome 17 in the epithelium of non-polypoid colorectal carcinomas compared to polypoid lesions. 1703 12

The DNA mismatch repair (MMR) system guards against genomic instability, therefore the mutations in the human MMR genes cause the majority of the hereditary nonpolyposis colorectal cancer (HNPCC) and a small percentage of the sporadic colon cancer. hMSH2 is one of MMR genes involved in the correction of mispairing during replication and its mutations are associated with both--microsatellite instability and the hereditary and sporadic colon tumourgenesis. The aim of this study was to analyse the T/G mutation (codon 458) in exon 8 of hMSH2 gene in the sporadic colon cancer cells. We also examined the relationship between the T/G mutation of hMSH2 gene, and the selected prognostic factors such as Dukes' stage, histological grade and lymph node metastasis. We analysed samples of tumour from 75 patients with sporadic colorectal cancers. The mutation in the hMSH2 gene ware determined by the RFLP-PCR. We found T/G mutation in exon 8 of hMSH2 gene in 5 patients (6,7%). There was no statistically significant difference between this mutation and selected clinical parameters. The results of our studies revealed that mutations of hMSH2 gene may lead to development of colorectal cancer. No dependence between the mutation of hMSH2 gene and clinical parameters, suggests that the mutation of hMSH2 gene may have a critical significance for the first steps of carcinogenesis in colon epithelial.
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PMID:The T/G mutation in exon 8 of hMSH2 gene in the sporadic colon cancer patients. 1713 86

Bcl2 has been reported to suppress DNA mismatch repair (MMR) with promotion of mutagenesis, but the mechanism(s) is not fully understood. MutSalpha is the hMSH2-hMSH6 heterodimer that primarily functions to correct mutations that escape the proofreading activity of DNA polymerase. Here we have discovered that Bcl2 potently suppresses MMR in association with decreased MutSalpha activity and increased mutagenesis. Exposure of cells to nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone results in accumulation of Bcl2 in the nucleus, which interacts with hMSH6 but not hMSH2 via its BH4 domain. Deletion of the BH4 domain from Bcl2 abrogates the ability of Bcl2 to interact with hMSH6 and is associated with enhanced MMR efficiency and decreased mutation frequency. Overexpression of Bcl2 reduces formation of the hMSH2-hMSH6 complex in cells, and purified Bcl2 protein directly disrupts the hMSH2-hMSH6 complex and suppresses MMR in vitro. Importantly, depletion of endogenous Bcl2 by RNA interference enhances formation of the hMSH2-hMSH6 complex in association with increased MMR and decreased mutagenesis. Thus, Bcl2 suppression of MMR may occur in a novel mechanism by directly regulating the heterodimeric hMSH2-hMSH6 complex, which potentially contributes to genetic instability and carcinogenesis.
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PMID:Bcl2 impedes DNA mismatch repair by directly regulating the hMSH2-hMSH6 heterodimeric complex. 1725 74

In order to identify representative genetic alterations in esophageal squamous cell carcinomas (ESCC) and useful markers for future early detection, 34 ESCC samples with neighboring normal epithelia and 30 esophageal biopsy samples from Linzhou, P.R. China, were studied. Of the 38 microsatellite markers selected, half were linked with tumor suppressors. More than 40% of the tumor samples showed loss of heterozygosity (LOH) in at least one of the eight markers, D3S1067 and D3S1561 (both linked to hMLH1 locus), FABP2, D4S1613, D9S171 (p14ARF, p15INK4b, p16INK4a loci), Rb1 (intron), p53-2 (intron), and NM23-H1. Most of the 38 microsatellite markers did not display microsatellite instability (MSI) in more than 30% of the tumor samples, except D9S942 (p14ARF, p15INK4b, p16INK4a loci) and Bat26, which showed frequency at 32 and 41%, respectively. Of all the ESCC samples examined, 20 samples exhibited LOH in 25% or more of the informative markers. Three samples displayed MSI in more than 30% of the markers, indicating that MSI might be an important event in these subset ESCC cases. Statistically significant correlations were found between LOH of the hMLH1 locus and the general LOH status of the sample, and between the LOH of the hMLH1 locus and p53 mutations. In addition, correlation was found between MSI in D3S1067/D3S1561 and the general MSI status in the samples. However, MSI in the introns of hMLH1 and hMSH2 were not correlated with the general MSI status of the tumors. LOH analysis was also performed in 30 esophageal biopsy samples containing precancerous lesions with matching blood samples using nine microsatellite markers selected from the above studies. LOH frequence ranged from 0 to 33% in informative cases, mostly in the 9p21 and p53 gene regions, suggesting these regions are possible targets of genomic instability in early stage ESCC carcinogenesis. The results demonstrate the degree of genetic alterations at different loci of the chromosomes. Some of the microsatellite markers may be useful for the early detection of ESCC.
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PMID:Characterization of genetic alteration patterns in human esophageal squamous cell carcinoma using selected microsatellite markers spanning multiple loci. 1739 7

The aim of this investigation was to evaluate clinicopathologic and immunohistochemical characteristics of synchronous primary gastric adenocarcinomas. Immunohistochemistry for p53 (suppressor pathway) and for hMLH1, hMSH2, and hMSH6 (mutator pathway) was performed using ABC-technique amplification by biotinylated tyramide. Synchronous primary gastric adenocarcinomas were detected in 19/553 (3.43%) of the patients. The tumors were localized in distal stomach in 22, body in 14, and proximal in five. There was a predominance of intestinal type in the group of synchronic tumors compared to the solitary lesions, 73.2 vs 37.3%, p = 0.001. Synchronous neoplasias were diagnosed in earlier stage than solitary neoplasias, T1-T2 = 60.9% vs T1-T2 = 28.4%, p = 0.0001; and N0 = 68.4% vs N0 = 26.2%, p = 0.001. p53 was detected in 52.6% of the patients with synchronous tumors. Altered hMLH1 immunoexpression occurred in 26.3% of the patients and hMSH6 in 5.3%. hMSH2 immunoreactivity was positive in all tumors. p53 was solely detected in 17 tumors, while hMLH1 was altered in 10/24 negative p53 tumors, p = 0.01. Synchronous gastric adenocarcinomas presented higher frequency of intestinal type and early gastric cancer in comparison to solitary gastric cancer. Two routes of carcinogenesis, mutator, and suppressor appear to be involved independently in the development of synchronous tumors.
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PMID:Clinicopathologic and immunohistochemistry characterization of synchronous multiple primary gastric adenocarcinoma. 1745 92

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