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

Colon carcinomas appear to arise from the cumulative effect of mutations to several genes (APC, DCC, p53, ras, hMLH1, and hMSH2). By using novel colonic epithelial cell lines derived from the Immorto mouse, named the YAMC (young adult mouse colon) cell line, and an Immorto-Min mouse hybrid, named the IMCE (Immorto-Min colonic epithelial) cell line, carrying the Apc min mutation, we investigated the effect of an activated v-Ha-ras gene on tumor progression. The YAMC and IMCE cell lines are normal colonic epithelial cell lines which are conditionally immortalized by virtue of expression of a temperature-sensitive simian virus 40 (SV40) large T antigen. Under conditions which permit expression of a functional SV40 large T antigen (33 degrees C plus gamma interferon), neither the YAMC nor the IMCE cell line grows in soft agar or is tumorigenic in nude mice. In vitro, when the SV40 large T antigen is inactivated (39 degrees C without gamma interferon), the cells stop proliferating and die. By infecting the YAMC and IMCE cell lines with a replication-defective psi2-v-Ha-ras virus, we derived cell lines which overexpress the v-Ha-ras gene (YAMC-Ras and IMCE-Ras). In contrast to the parental cell lines, under conditions in which the SV40 large T antigen is inactive, both the YAMC-Ras and IMCE-Ras cell lines continue to proliferate. Initally YAMC-Ras cells do not form tumors; however, tumors are visible after 90 days of incubation. IMCE-Ras cells form colonies in soft agar under both permissive and nonpermissive culture conditions. Furthermore, IMCE-Ras cells form tumors in nude mice within 3 weeks. The phenotype of the IMCE-Ras cell line thus clearly demonstrates that a defective Apc allele and an activated ras gene are sufficient to transform normal colonic epithelial cells and render them tumorigenic.
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PMID:Synergy between Apc min and an activated ras mutation is sufficient to induce colon carcinomas. 862 90

Overexpression of cyclooxygenase-2 (COX-2) has been reported in gastric cancers. However, the relationship between expression of COX-2 and clinico-pathological or genotypic features has not been elucidated. To address the issue, expression of COX-2 protein was analyzed in 100 gastric cancers as well as 7 gastric cancer cell lines by using immunoblot analysis. Overexpression of COX-2 in cancer tissues compared with matched non-cancerous tissues was found in 70% of cases and was significantly associated with lymphatic involvement, lymph node metastasis and advanced tumor stage. Interestingly, overexpression of COX-2 was less frequent in gastric cancers with microsatellite instability (MSI) than in those without MSI (8/20 vs. 62/80, p < 0.01). Expression of COX-2 protein was detected in some gastric cancer cell lines without MSI at various levels, but not in those with MSI. Our results suggest that overexpression of COX-2 may play an important role in tumor progression of gastric cancer and also support the notion that gastric cancers with and without MSI represent distinctive pathways of carcinogenesis. We also observed a reduction of MSI phenotype after aspirin or sulindac treatment in a hMLH1-defective gastric cancer cell line SNU-1, which lacks COX-2 expression. Int. J. Cancer (Pred. Oncol.) 84:400-403, 1999.
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PMID:Overexpression of cyclooxygenase-2 protein is less frequent in gastric cancers with microsatellite instability. 1040 93

CpG islands are short stretches of CpG rich regions that are frequently associated with the promoter region of genes. Aberrant methylation of CpG islands is one mechanism of inactivating tumor suppressor genes (TSGs) in neoplasia, and there is growing evidence that altered cytosine methylation play important roles in cancer development. However, the differences in global CpG island methylation patterns between normal and cancer cells remain poorly understood. By examining a large number of loci in a series of cancers, global methylation profiles can be constructed. Such studies revealed that in colorectal cancer, there appears to be two types of methylation that are associated with cancer progression: type A (for age-related) methylation, and type C (for cancer-specific) methylation. Initially, type A methylation arises as a function of age in normal colorectal epithelial cells. By affecting genes that regulate the growth and/or differentiation of these cells, such methylation may result in a predisposition state that precedes tumor formation in the colon. Type C methylation, by contrast, was found exclusively in a subset of cancers, which display a CpG island methylator phenotype (CIMP). CIMP is a novel molecular instability pathway that appears to be responsible for most cases of aberrant TSG methylation in colorectal cancer, and which has important interactions with genetic pathways as well. In fact, CIMP+ tumors account for the majority of sporadic colorectal cancers with microsatellite instability, through methylation of the mismatch repair gene hMLH1. This model whereby age-related methylation increases cell-susceptibility to transformation and cancer-specific methylation results in neoplastic progression in a subset of cases may be applicable to many human neoplasms.
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PMID:CpG island methylator phenotypes in aging and cancer. 1054 43

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

Infection with specific genotypes of human papillomavirus (HPV) has been strongly implicated in cervical carcinogenesis. However, HPV infection alone is insufficient for malignant transformation of the cervical epithelium. An alteration of microsatellite repeats is the result of slippage owing to strand misalignment during DNA replication and is referred to as microsatellite instability (MSI). These defects in DNA repair pathways have been related to human carcinogenesis; however, the role of MSI in the tumorigenesis of cervical cancer remains unclear. The clinical and pathological features of cervical cancers which are MSI-positive have also not been fully characterized. This study investigated the prevalence of MSI in cervical cancer and its relationship to clinico-pathological characteristics and HPV infection. Polymerase chain reaction-based microsatellite assay combined with tissue microdissection was used to examine for MSI in 50 cervical squamous cell carcinomas in Hong Kong women. In addition, the immunohistochemical staining was performed to determine the expression of major DNA mismatch repair genes, hMSH2 and hMLH1. Six cases (12%) displayed a low frequency of MSI (MSL-L) showing MSI at one locus only in 5 loci examined. Seven cases (14%) showed a high frequency of MSI (MSI-H) having MSI at 2 or more loci. Grouping MSI-L and MSI-H cases together as MSI-positive, statistical analysis of HPV infection, tumor grade, clinical stage and clinical status failed to disclose differences between MSI-positive and MSI-negative cases (p > 0.05). However, MSI-H correlated with advanced stage of disease (p < 0.05). Individuals with MSI-H tumors appeared to have reduced overall survival compared to individuals with MSI-L and MSI-negative tumors, but the difference was not statistically significant (p = 0.059). An absence of either MSH2 or MLH1 expression was observed in 2 MSI-L and 4 MSI-H cases, respectively. The results suggest that MSI is present in a subgroup of cervical squamous cell carcinomas, and defects resulting in MSI may be related to tumor progression and possibly poor prognosis in cervical cancer.
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PMID:Microsatellite instability, expression of hMSH2 and hMLH1 and HPV infection in cervical cancer and their clinico-pathological association. 1158 36

Genetic or epigenetic inactivation of one of the DNA mismatch repair (MMR) genes in tumor precursor cells causes a profound mutator phenotype, known as the microsatellite mutator phenotype (MMP). This mutator phenotype induces mutations not only in cancer genes that drive tumorigenesis but also in other DNA repair genes. The functional significance of these successive DNA repair gene mutations, however, has not been substantiated. Here we show that the concomitant inactivation of two DNA MMR genes (hMLH1 and hMSH6) increases the mutator phenotype. We isolated cell clones of the SW48 MMP-positive cell line with either active or inactive hMSH6. All of these clones lacked expression of hMLH1 because of promoter hypermethylation. Compared with inactivation of hMLH1 alone, the additional inactivation of hMSH6 produced a higher mutation rate and a different spectrum of mutations in the endogenous hprt gene. These results confirm our model that the mutator phenotype can increase during tumorigenesis by the consecutive inactivation of different members of the DNA MMR system. Thus, a stronger mutator phenotype accelerates the accumulation of mutations in target cancer genes, which, in turn, speeds up tumor progression. The results of this study also have significant impact on our understanding of the mechanism of DNA MMR.
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PMID:Functional significance of concomitant inactivation of hMLH1 and hMSH6 in tumor cells of the microsatellite mutator phenotype. 1174 74

Gliomas are characterized by highly variable biological behavior. After surgical resection and postoperative therapy they frequently recur with the same or higher-grade histology. Although a number of genetic aberrations have been described in gliomas of different histological types, the molecular mechanisms of the histological and clinical progression are poorly understood. In this study, we performed longitudinal microsatellite and mismatch repair gene analysis in paired samples of primary and recurrent gliomas in order to reveal whether genetic instability is associated with tumor progression. The 7 microsatellite loci of the 7 patients displayed a total of 18 (54.5%) alterations in the primary and 15 (45.5%) alterations in the recurrent gliomas as compared with the corresponding non-neoplastic cells, but no alterations were found in the hMLH1 and hMSH2 genes. These results suggest that microsatellite instability is associated with the development of the primary gliomas rather than with the recurrence or progression, and it is not associated with structural alterations in the hMLH1 or hMSH2 genes. Comparison of the microsatellite patterns in primary and secondary gliomas revealed 4 different modalities of clonal evolution, involving clonal identity, clonal deletion, clonal progression, and different clonality, suggesting that intensive clonal selection may play a central part in the recurrence of gliomas.
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PMID:Microsatellite analysis of primary and recurrent glial tumors suggests different modalities of clonal evolution of tumor cells. 1202 42

To understand the role of gene promoter methylation in neoplastic evolution and progression, the methylation changes associated with 15 candidate tumor suppressor genes were studied throughout stages of tumor progression involving intraductal papillary mucinous neoplasms (IPMN) of the pancreas. Genomic DNA from 28 pancreatic IPMN tissue samples, categorized histologically as non-invasive intraductal IPMN (n = 3), IPMN with carcinoma in situ (n = 7), IPMN with microinvasion <1 mm (n = 4), and infiltrative IPMN with associated adenocarcinoma (n = 14), was modified by bisulfite treatment and analyzed with methylation-specific PCR (MSP). Promoter methylation of at least one tumor suppressor gene was present in 26/28 (92%) of the IPMNs. The cell cycle control genes, p16 and p73, were methylated frequently (>50%) in both non-invasive and invasive tumors. APC methylation was discovered in <10% of the non-invasive IPMNs versus 45% of the IPMNs associated with infiltrative adenocarcinoma, P = 0.040. Mismatch repair genes, hMLH1 and MGMT, were frequently methylated in the invasive IPMNs compared with the non-invasive tumors (38 versus 10% and 45 versus 20%, respectively) as was E-cadherin (38 versus 10%), P = 0.11. Multiple gene methylation at greater than three loci was present in 55% of the invasive tumors compared with 20% of the non-invasive tumors, P = 0.075. Lymph node status did not predict multi-gene methylation among tumors associated with invasive cancer. Compared with non-invasive IPMNs of the pancreas, IPMNs associated with adenocarcinoma demonstrate higher rates of aberrant tumor suppressor gene methylation. The sequential acquisition of hypermethylation at multiple gene promoter sites may explain tumor progression in IPMNs and other malignancies. Detection of methylation within selected genes may afford an accurate diagnostic molecular marker and predictor of neoplastic behavior.
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PMID:Molecular progression of promoter methylation in intraductal papillary mucinous neoplasms (IPMN) of the pancreas. 1258 67

Chronic lymphocytic leukemia (CLL) is an indolent B cell non-Hodgkin lymphoma (NHL) that may transform into diffuse large B cell lymphoma (DLBL). This transformation is referred to as Richter's syndrome or transformation. To analyze whether microsatellite instability (MSI) and DNA mismatch repair defects are associated with Richter's transformation, we have performed microsatellite analysis, mutational analysis of hMLH1 and hMSH2 genes and methylation status analysis of CpG island of the hMLH1 promoter on serial biopsy specimens from 19 patients with CLL. Ten cases of CLL showed no histologic alteration in the second biopsy, and nine cases of CLL underwent morphologic transformation to DLBL in the second biopsy. Using eight microsatellite loci, high level of MSI was associated with Richter's transformation in four cases of CLL, but none of the CLLs displayed this level of MSI without transformation. Mutations of the hMLH1 or hMSH2 genes were not detected in any of the lymphoma samples. In five cases of Richter's transformation the hMLH1 promoter was hypermethylated in both CLL and DLBL samples. Hypermethylation of the hMLH1 promoter associated with high-level of MSI in four cases, and low-level of MSI in one case. These results suggest that in certain cases of Richter's transformation the DNA mismatch-repair defect-initiated genetic instability may play a role in tumor progression.
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PMID:Microsatellite instability and hMLH1 promoter hypermethylation in Richter's transformation of chronic lymphocytic leukemia. 1259 41

Overall DNA methylation status was studied in a group of 28 sporadic human endometrial carcinomas (ECs) using the [32P]-postlabeling technique. Moreover, expression of the DNA mismatch repair proteins (hMLH1 and hMSH2) was investigated in ECs using immunohistochemistry. Mean 5-methyldeoxycytosine (m5dC) content in the studied group was 3.48+/-0.37% (range, 2.89-4.12%). The mean m5dC scores were significantly different between early (3.35+/-0.33%) and advanced (3.66+/-0.36%) endometrial neoplasms (chi2-test; p=0.03). There was a markedly increased overall DNA methylation with the degree of histological differentiation and with the infiltration of the myometrium (p<0.05). Loss of hMLH1 and hMSH2 expression was reported in 7 (25%) and 5 (18%) tumors, respectively, but the immunoreactivity did not correlate with the known clinicopathological variables of cancer. In addition, no obvious correlation was found between global m5dC content and the lack of hMLH1 and hMSH2 protein expression in human uterine tumors (p=0.97 and p=0.19 for hMLH1 and hMSH2, respectively; Spearman's rank correlation test). Our results clearly show that alterations in global DNA methylation may influence tumor progression, but they are not directly associated with the inactivation of the mismatch-repair machinery in sporadic human ECs.
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PMID:Global DNA methylation in relation to hMLH1 and hMSH2 protein immunoreactivity in sporadic human endometrial carcinomas. 1268 91


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