Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0596263 (carcinogenesis)
 64,820 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Microsatellite instability (MSI) of short repetitive sequences in human chromosomal DNA can result from defective DNA mismatch repair function in tumor cells. We hypothesize that DNA mismatch repair (MMR) activity is down-regulated during prostatic carcinogenesis. To test this hypothesis, MMR activities and mismatch repair-related genes were analyzed in five different prostate cancer cell lines. Our results demonstrate that MMR activities were decreased as compared to MMR proficient HeLa cells. Interestingly, LNCaP, PC-3 and DU145 had much lower MMR activities as compared to DUPro and TSUPr1. The MMR-related genes (hMLH1, hPMS1, hPMS2, hMSH2, hMSH3, hMSH6) showed mRNA transcripts in all prostate cancer cell lines. However, Western blotting showed decreased or absent hMLH1 protein expression in PC-3, DU145, DUPro and TSUPr1 cells. Similarly, the hMSH2 protein expression was low or absent in DU145 and LNCaP cells. This is the first report that demonstrates decreased MMR activities is associated with low expression of hMLH1, hMSH2 and other MMR-related proteins in prostate cancer.
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PMID:DNA mismatch repair enzyme activity and gene expression in prostate cancer. 1144 57

Current evidence suggests that epigenetic changes play an important role in the evolution of human cancers. In this study, we evaluated whether hypermethylation of CpG islands at the gene promotor regions of several tumor-related genes is involved in the carcinogenesis of oligodendroglial tumors. We examined the methylation status of 11 genes in a series of 43 oligodendroglial tumors (19 oligodendrogliomas, 13 anaplastic oligodendrogliomas, 9 oligoastrocytomas, and 2 anaplastic oligoastrocytomas) by methylation-specific polymerase chain reaction. Our results showed that hypermethylation of CpG islands was detectable in 8 of 11 genes studied and 74% of tumors were hypermethylated in at least 1 gene. Promotor hypermethylations were detected in O6-methylguanine-DNA methyltransferase (MGMT), RB1, estrogen receptor, p73, p16INK4a, death-associated protein kinase, p15INK4b, and p14ARF at 60%, 34%, 30%, 16%, 12%, 10%, 7%, and 2%, respectively. No hypermethylation was detected in the promotors of glutathione-S-transferase P1, von Hippel-Lindau or the DNA mismatch repair (hMLH1) genes. Statistical analysis revealed that concordant hypermethylation of at least 2 genes, p16INK4a and p15INK4b were significantly associated with anaplastic oligodendroglial tumors, and hypermethylation of MGMT was significantly associated with loss of chromosome 19q and with combined loss of chromosomes 1p and 19q. More importantly, several candidate tumor suppressor genes such as p16INK4a, p15INK4b, and p73 that were previously reported as unmutated in oligodendroglial tumors were found to be hypermethylated in their CpG islands. Taken together, we conclude that hypermethylation of CpG islands is a common epigenetic event that is associated with the development of oligodendroglial tumors.
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PMID:Concurrent hypermethylation of multiple genes is associated with grade of oligodendroglial tumors. 1148 55

The role of microsatellite instability (MSI) in the pathogenesis of hepatocellular carcinoma (HCC) is incompletely defined. Although high-frequency MSI (MSI-H) is infrequently seen in HCC, some studies have suggested a role for MSI in HCC development. While MSI has been clearly defined for a subset of tumors, in particular colorectal, gastric and endometrial cancers, generally accepted criteria have not been developed for other tumors. Colorectal cancers (CRC) are classified as MSI-H if >30-40% of >5 microsatellite loci analyzed show instability. The MSI-H phenotype is associated with defective DNA mismatch repair (MMR) and is observed in the majority of tumors from patients with hereditary non-polyposis colon cancer (HNPCC) and also in 15% of sporadic CRCs. Inactivating mutations of the hMLH1 or hMSH2 genes lead to defects in MMR in HNPCC. In sporadic CRCs, MMR is usually due to hypermethylation of the hMLH-1 promoter. The role of defective MMR in hepatocellular carcinogenesis is controversial. Immunohistochemistry for hMLH1 and hMSH2 reliably indicates hMLH1 or hMSH2 loss in MSI-H CRC tumors. To investigate the role of defective MMR in HCC carcinogenesis, we performed immunohistochemistry for hMLH1 and hMSH2 on 36 HCCs. BAT26, a microsatellite marker that reliably predicts MSI-H was also examined. All 36 of the tumors stained positively for both hMLH1 and hMSH2, strongly suggesting an absence of either inactivating mutations of hMLH1 and hMSH2 or promoter hypermethylation of hMLH1. None of the tumors showed MSI at the BAT26 locus. These findings suggest that defective MMR does not contribute significantly to hepatocellular carcinogenesis.
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PMID:hMLH1 and hMSH2 expression in human hepatocellular carcinoma. 1149 37

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

DNA methylation is the main epigenetic modification in humans. The methylation of promoter inhibits the transcription in most genes. In normal tissues, isolated CpG dinucleotides in bulk chromatin are often methylated, whereas cytosines in CpG islands are unmethylated. In neoplasms including gastrointestinal cancer, this pattern of methylation is commonly reversed. The alteration of DNA methylation plays a key role in the process of carcinogenesis. The gastrointestinal carcinogenesis is suggested to be associated with the decrease of total genomic DNA methylation; hypomethylation of certain specific oncogenes such as c-myc, c-Ha-ras, c-fos and alpha-fetoprotein; and hypermethylation of the promoter of some tumor suppressor genes containing p16(INK4A), E-cadherin and hMLH1 genes. This review focuses on the analysis methods for methylation, studies for aberrant DNA methylation in gastrointestinal carcinogenesis, and the intervention changing methylation, including the treatment of 5-azacytidine, supplement of folate and gene therapy.
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PMID:Alteration of DNA methylation in gastrointestinal carcinogenesis. 1159 58

To determine whether methylation of the hMLH1 promoter is related to increasing age and gastric carcinogenesis, we examined hMLH1 methylation and expression in 100 gastric cancers. hMLH1 methylation and aberrant protein expression were observed in 9 and 13 cancers, respectively. Normal and intestinal metaplastic tissues adjacent to cancers with hypermethylation did not exhibit any hMLH1 methylation, indicating that it may be specific to gastric cancers. The frequency of hMLH1 methylation significantly increased with age. These results suggest that hMLH1 methylation plays an important role in gastric carcinogenesis in old people.
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PMID:Age-related hypermethylation of the hMLH1 promoter in gastric cancers. 1166 99

The CpG island methylator phenotype (CIMP) is a newly described mechanism for carcinogenesis in colorectal carcinomas and adenomas characterized by methylation of multiple CpG islands. The causes of CIMP are unknown. We studied CIMP in hyperplastic polyps (HPs), with emphasis on patients with multiple HPs (5 to 10 HPs), large HPs (one HP >1 cm) or hyperplastic polyposis (>20 HPs). Methylation of p16, MINT1, MINT2, MINT31, and hMLH1 was analyzed by methylation-specific polymerase chain reaction in 102 HPs, 8 serrated adenomas, 19 tubular adenomas, and 9 adenocarcinomas from 17 patients, with multiple/large HPs or hyperplastic polyposis and in 16 sporadic HPs from 14 additional patients. Sporadic HPs were CIMP-negative (not methylated at any locus), but 43% of HPs from multiple/large HPs, or hyperplastic polyposis were CIMP-high (two or more methylated loci, P = 0.00001). Methylation among the four loci was correlated within HPs (odds ratio, 3.41; P = 0.002), and the methylation status of HPs within the same patient was also correlated (odds ratio, 5.92; P = 0.0001). CIMP-high HPs were present primarily in patients with a predominance of HPs in the right colon and/or serrated adenomas (P = 0.0009) and were associated with the absence of K-ras proto-oncogene mutations (odds ratio, 5.08; P = 0.03). Our findings of concordant CpG island methylation of HPs in multiple/large HPs or hyperplastic polyposis supports the concept that some patients have a hypermethylator phenotype characterized by methylation of multiple HPs and other colorectal lesions. The hypermethylator phenotype is related to patient-specific factors, such as carcinogenic exposure or genetic predisposition.
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PMID:Concordant CpG island methylation in hyperplastic polyposis. 1183 73

The inactivation of the DNA mismah repair (MMR) system, which is associated with the predisposition to the hereditary non-polyposis colorectal cancer (HNPCC), has also been documented in nearly 20% of the sporadic colorectal cancers. These tumors are characterized by a high frequency of microsatellite instability (MSI(+) phenotype), resulting from the accumulation of small insertions or deletions that frequently arise during replication of these short repeated sequences. A germline mutation of one of the two major MMR genes (hMSH2 or hMLH1) is found in half to two-thirds of the patients with HNPCC, whereas in sporadic cases hypermethylation of the hMLH1 promoter is the major cause of the MMR defect. Germline mutations in hMSH6 are rare and rather confer predisposition to late-onset familial colorectal cancer, and frequent extracolonic tumors. Yet, the genetic background of a number of HNPCC patients remains unexplained, indicating that other genes participate in MMR and play important roles in cancer susceptibility. The tumor-suppressor genes that are potential targets for the MSI-driven mutations because they contain hypermutable repeated sequences are likely to contribute to the etiology and tissue specificity of the MSI-associated carcinogenesis. Because the prognosis and the chemosensitivity of the MSI(+) colorectal tumors differ from those without instability, the determination of the MSI phenotype is expected to improve the clinical management of patients. This review gives an overview of various aspects of the biochemistry and genetics of the DNA mismah repair system, with particular emphasis in its role in colorectal carcinogenesis.
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PMID:DNA mismatch repair defects: role in colorectal carcinogenesis. 1190 Aug 75

Aberrant crypt foci (ACF) are postulated to be the earliest precursor lesion in colorectal carcinogenesis, and CpG island methylation has been described as an important molecular pathway. We therefore studied methylation in ACF from patients with familial adenomatous polyposis (FAP) or sporadic colorectal cancer. We assessed methylation status of the p16 tumor suppressor gene, MINT1 (methylated in tumor 1), MINT2, MINT31, O(6)-methylguanine-DNA methyltransferase gene, and hMLH1 mismatch repair gene. We compared methylation to ACF histopathology, K-ras proto-oncogene mutation, loss of heterozygosity at chromosome 1p, and microsatellite instability. Methylation was present in 34% (21 of 61) of ACF, including both FAP and sporadic types, but was more frequent in sporadic ACF [53% (18 of 34) versus 11% (3 of 27), P = 0.002], especially dysplastic sporadic ACF [75% (3 of 4) versus 8% (2 of 24), P = 0.004]. MINT31 was more frequently methylated in heteroplastic ACF than dysplastic ACF [35% (11 of 31) versus 7% (2 of 30), P = 0.01]. Strong associations of ACF methylation with K-ras mutation (P = 0.007) and with loss of chromosome 1p (P = 0.04) were observed, but methylation was the only molecular abnormality identified in 16% (10 of 61) of ACF. Our findings suggest that methylation in ACF is an early event in the pathogenesis of a subset of colorectal carcinomas, and that ACF from FAP patients and patients with sporadic colorectal cancer have distinct epigenetic changes that reflect differences in molecular pathogenesis.
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PMID:CpG island methylation in aberrant crypt foci of the colorectum. 1200 Jul 33

We characterized four pancreatic carcinoma cell lines (designated SNU-213, SNU-324, SNU-410, and SNU-494) established from histopathologically varied primary or liver metastatic tumor samples of Korean patients. Three cell lines grew as adherent monolayers and one as adherent and floating cell clumps. All lines had: (1) relatively high viability; (2) an absence of mycoplasma or bacterial contamination; (3) genetic heterogeneity as assessed by DNA-fingerprinting analysis; (4) an absence of MADH4 mutation. Among the lines, three lines had mutations in codon 12 in K- ras, two lines harbored p53 mutations within the DNA-binding domain; two lines had homozygous deletions in both p16 and p15 genes; and one line had a missense mutation. Two lines (SNU-324 and SNU-410) had genetic alterations in the TGFBR2 gene: the SNU-324 line had a -1-bp or +1-bp mutation in 10-bp polydeoxyadenine repeat tracts; the SNU-410 line had a genomic deletion in this gene. Mutation analysis of mismatch repair genes demonstrated that SNU-324 has two heterozygous missense mutations in different exons of the hMLH1 gene. In addition, this line showed microsatellite instability and harbored frameshift mutations in simple repeated sequences of the coding regions of the TGFBR2, BAX, and hMSH3 genes. These defects of microsatellite instability and mismatch repair genes suggest the possibility of a new mutator phenotype for pancreatic carcinogenesis. These cell lines should be very useful for studying the biology of pancreatic carcinoma, particularly those related to mutator phenotype and genetic alterations in the TGFBR2 gene.
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PMID:Establishment and characterization of four human pancreatic carcinoma cell lines. Genetic alterations in the TGFBR2 gene but not in the MADH4 gene. 1203 78


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