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) is a hallmark of the DNA mismatch repair deficiency that is one of the pathways of gastric carcinogenesis. Clinicopathologic characteristics of MSI+ gastric cancers remain unclear. To determine the correlation between MSI status and clinical features, we analyzed 327 consecutive gastric cancers for the occurrence of MSI in the BAT-26 marker. Because it has been proven that MSI at BAT-26 reflects the MSI+ phenotype, cancers with alteration at BAT-26 were categorized as having the MSI+ phenotype. The expressions of hMLH1, hMSH2, p53, MUC1, MUC2, and CEA were evaluated immunohistochemically using the tissue array method. The MSI+ phenotype was found in 9.5% (31/327) of gastric cancers examined. MSI+ gastric cancers were significantly associated with older age, antral location, Borrmann's gross Type II, intestinal subtype, lower prevalence of lymph node metastasis, and lower pTNM stage (P <.05). By multivariate logistic regression, MSI+ gastric cancers had a lower prevalence of lymph node metastasis independent of tumor invasion (P <.001). MSI+ gastric cancers displayed frequent frameshift mutations of transforming growth factor-beta type II receptor (90.3%), BAX (61.3%), hMSH3 (38.7%), and E2F4 (61.3%) genes and diminished hMLH1 (24/31) or hMSH2 (4/31) expressions. The MSI+ phenotype correlated with patient survival in advanced gastric carcinoma (P =.046). In conclusion, MSI+ phenotype in gastric cancers was found to have distinct clinicopathologic characteristics and to be predictive of a favorable outcome in advanced carcinoma.
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PMID:Distinct clinical features and outcomes of gastric cancers with microsatellite instability. 1206 77

Mechanisms for bladder carcinogenesis and the development of recurrentbladder cancer remain unclear. Aberrant methylation of the 5' CpG island is thought to play an important role in the inactivation of the tumor suppressor genes in cancer. To study whether specific or bulk hypermethylation predicts intrabladder recurrence, we determined the frequency of aberrant promoter hypermethylation of seven genes, hMLH1, O(6)-methylguanine-DNA-methyltransferase (MGMT), p16, Von Hippel-Lindau (VHL), death-associated protein kinase (DAP-kinase), glutathione S-transferase P1 (GST-P1) and E-cadherin in 55 superficial bladder cancers and 5 normal urothelial epithelia by methylation-specific PCR (MSP). These patients of superficial bladder cancer had been followed prospectively by cystoscopy. Simultaneous hypermethylation of three genes or more among the seven genes was observed in 2 (7%) of 30 patients in the nonrecurrence group and 7 (28%) of 25 patients in the recurrence group. There was a significant concordance between the number of methylated genes and the development of recurrence (P = 0.012). In particular, the recurrence rate for 24 months was 88% for hypermethylation of DAP-kinase and 28% for nonmethylation of DAP-kinase. Hypermethylation of DAP-kinase is, therefore, a strong indicator of the superficial bladder cancer associated with a high recurrence rate (P < 0.001; hazards ratio, 7.01). Our results suggest that hypermethylation of DAP-kinase might be a useful prognostic marker for disease recurrence in superficial bladder cancers.
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PMID:The association of death-associated protein kinase hypermethylation with early recurrence in superficial bladder cancers. 1212 40

The pattern of hMLHI and hMSH2 mutations was assessed to identify the genetic correlation between hereditary gastric and colorectal cancers. Four disease groups and their healthy family members were assembled according to the presentation of gastric cancer: FG, familial clustering of gastric cancer (n = 32); CG, family with one or more colorectal and gastric cancers in first-degree relatives (n = 22); HS, seven HNPCC families corresponding to the Amsterdam criteria (AMS+) and 12 suspected HNPCC families which did not satisfy one of the criteria (AMS-), but no gastric cancer among first- and second-degree relatives (n = 19); and SG, sporadic gastric cancer (n = 33). In the CG group, three were included in AMS + and six in AMS- criteria. Peripheral blood was obtained from them to detect hMLHI and hMLH2 mutations using PCR-SSCP analysis and direct sequencing. The incidence of mutations was 9.4% in the FG group, 54.5% in the CG group, 31.6% in the HS group, and none in the SG group. The incidence, type, and number of the mutation were not different between the CG and HS groups. Thirty-four different mutations included 19 in hMLH1 and 15 in hMSH2. Gastric cancer was the most common extracolonic malignancy in HNPCC and suspected HNPCC families (9/28, 32.1%). The hMLH1 or hMSH2 mutation occurred in seven of 10 families with AMS+, whereas it occurred in four of 18 with AMS- (70% vs. 22.2%, P = .013). Five mutations in the hMLH1 and six mutations in the hMSH2 were exclusively found in families with gastric cancer. All three mutations in the FG group were in hMLHI and there was no mutation in their healthy family members. This study demonstrates that some familial clustering type of gastric cancer appears to be associated with hMLHI mutations thereby indicating a difference from the hereditary gastric cancer studies previously reported. In addition, hMLHI and hMSH2 mutations may impact the gastric cancer carcinogenesis in HNPCC or suspected HNPCC.
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PMID:hMLH1 and hMSH2 mutations in families with familial clustering of gastric cancer and hereditary non-polyposis colorectal cancer. 1213 70

Microsatellite instability has been proposed as an alternative pathway of colorectal carcinogenesis. The aim of this study was to evaluate the interest of immunohistochemistry as a new tool for highlighting mismatch repair deficiency and to compare the results with a PCR-based microsatellite assay. A total of 100 sporadic proximal colon adenocarcinomas were analysed. The expression of hMLH1, hMSH2 and hMSH6 proteins evaluated by immunohistochemistry was altered in 39% of the cancers, whereas microsatellite instability assessed by PCR was detected in 43%. There was discordance between the two methods in eight cases. After further analyses performed on other tumoural areas for these eight cases, total concordance between the two techniques was observed (Kappa=100%). Our results demonstrate that immunohistochemistry may be as efficient as microsatellite amplification in the detection of unstable phenotype provided that at least two samples of each carcinoma are screened, because of intratumoural heterogeneity.
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PMID:Microsatellite instability and intratumoural heterogeneity in 100 right-sided sporadic colon carcinomas. 1217 76

Abnormal hypermethylation of CpG islands associated with tumor suppressor genes can lead to repression of gene expression and contribute significantly to tumorigenesis. Esophageal squamous cell carcinoma (ESCC) is thought to be developed through a multi-stage process, which involves basal cell hyperplasia (BCH), dysplasia (DYS), carcinoma in situ (CIS) and carcinoma. In the present study, we studied the hypermethylation of 10 selected genes in biopsies from normal individuals and resected tissues from ESCC patients. Tumor and neighboring normal and precancerous tissues including BCH, DYS and CIS were microdissected from the resected tissues by laser capture microdissection. Hypermethylation of CpG islands was examined in these samples for 10 genes: p16(INK4a), p15(INK4b), p14(ARF), human leukocyte antigen (HLA)-A, -B, -C, hMLH1, E-cadherin (E-cad), fragile histidine triad and von Hippel-Lindau (VHL). Methylation of two Alu sequences, which neighbor E-cad and VHL, respectively, was used as control to verify the procedure of DNA extraction and chemical modification. In 48 biopsy samples with BCH or DYS, the most frequent hypermethylated genes were p16(INK4a) (18.8%) and p14(ARF) (14.6%). Seventeen out of these 48 samples (35.4%) contained hypermethylation of at least one gene. In the resected tissues, 52% of the BCH and 81% of the tumors showed hypermethylation of at least one gene. Genes hypermethylated in earlier stage lesions were always found hypermethylated at the later stage lesions in the same patient. All of the genes were methylated at some stages and they were clustered into four groups according to their frequencies. The first group of genes, which consisted of p16(INK4a) and p14(ARF), was most frequently hypermethylated in all stages, and the frequencies increased from normal epithelial (0%) to BCH, to displasia/carcinoma in situ and ESCC. Other genes were hypermethylated less frequently. Our results suggest that hypermethylation of key genes, such as p16(INK4a), p14(ARF) and hMLH1, may be used in combination with other molecular changes, such as p53 mutation, in the development of biomarkers for predicting the risk for ESCC.
Carcinogenesis 2002 Oct
PMID:Detection of multiple gene hypermethylation in the development of esophageal squamous cell carcinoma. 1237 81

High-frequency microsatellite instability (MSI-H) results from deficiency in nucleotide mismatch repair. It contributes significantly to carcinogenesis in the human colorectal mucosa. Here we study 41 colorectal and three other HNPCC-related cancers with MSI-H to provide comprehensive information on the mechanisms of inactivation of the two major proteins involved, hMLH1 and hMSH2. Seventeen of the patients had family histories meeting the criteria for Bethesda grades 1, 2 or 3. Of these familial cases, 14 (83%) had early-onset disease, defined on the basis of diagnosis prior to the age of 50, but in three the disease was of late onset (>50 years). A second subset of 20 patients had early onset disease without family history. The remaining seven patients were selected to allow comparisons with sporadic, late-onset disease, the molecular basis of which has been extensively reported elsewhere. We stratified the tumours initially on the basis of hMLH1 or hMSH2 protein deficiency, detected by immunohistochemistry, and then by analysis of germline and somatic mutation, mRNA transcription, loss of heterozygosity (LOH) at the hMLH1 and hMSH2 loci, and methylation status in two regions of the hMLH1 promoter. The functional significance of several of these changes in the MSI-H tumours was confirmed by comparisons with 16 tumours with low-frequency microsatellite instability and 56 tumours with stable microsatellites. As anticipated, patients with family histories usually showed germline mutation of hMSH2 or hMLH1. In many cases the residual normal allele was silenced in their tumours by loss of heterozygosity (LOH). The small subset of late-onset, sporadic cases confirmed the preponderance in this group of biallelic hMLH1 promoter methylation. In the early-onset, apparently sporadic subset there were 11 tumours with hMLH1 deficiency, five with hMSH2 deficiency and four with no detectable abnormality in expression of either protein. These showed a complex mixture of lesions, including germline and somatic mutations, promoter methylation, LOH, suppression of wild-type RNA by as yet undiscovered mechanisms, or no detectable abnormality in any of these parameters. Evidence is presented to indicate that methylation in proximal region of the hMLH1 promoter is a more reliable correlate of transcriptional silencing in colorectal cancers than methylation in upstream region. These observations have significant implications for management of patients with MSI-H tumours.
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PMID:Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers. 1238 21

Promoter hypermethylation is an alternative mechanism of gene silencing in human cancers including gastric cancer. While intestinal metaplasia (IM) is generally regarded as a precancerous lesion of the stomach, our study examines the presence of gene promoter hypermethylation in IM of patients with and without gastric cancer. We examined 31 samples of gastric cancer, 36 gastric IM (21 associated with gastric cancer and 15 from noncancer patients) and 10 normal gastric biopsies. Tissues containing foci of IM were carefully microdissected from paraffin-embedded section. Bisulfite-modified DNA was examined for gene promoter hypermethylation in DAP-kinase, E-cadherin, GSTP1, p14, p15, p16, RASSF1A and hMLH1 by methylation-specific-PCR. None of the control gastric tissues had hypermethylation detected, but gene promoter hypermethylation was frequently detected in gastric cancer and IM. The mean number of methylated genes in cancer and IM was 3.0 and 1.4, respectively (p < 0.0001). Methylation in IM from cancer patients was all associated with concurrent methylation in the corresponding tumor samples. The numbers of methylated genes were similar in IM obtained from cancer and noncancer patients. By examining the methylation patterns of these genes, 3 differential methylation patterns were recognized: hypermethylation was more frequent in cancer than in IM (DAP-kinase, p14, p15 and p16); comparable frequencies of methylation in cancer and IM (E-cadherin and hMLH1); and no methylation (GSTP1). Aberrant methylation in tumor-related genes is frequently detected in gastric IM of both cancer and noncancer patients, suggesting their early involvement in the multistep progression of gastric carcinogenesis.
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PMID:Promoter hypermethylation of tumor-related genes in gastric intestinal metaplasia of patients with and without gastric cancer. 1244 5

DNA methylation is essential for embryonic development and important for transcriptional repression, as observed in several biological phenomena. These include genomic imprinting, X-inactivation and carcinogenesis. The basic mechanism by which DNA methylation silences transcription is generally understood, but there is still much to be learned about how DNA methyltransferase is targeted to a specific region of the gene. Silencing by DNA methylation occurs at an early stage of carcinogenesis, when the DNA repair genes, MGMT and hMLH1, are frequently inactivated, resulting in mutations in key cancer-related genes in cells. Mice defective in Mgmt and/or Mlh1 gave clear evidence of the significant roles of these proteins in carcinogenesis. Recently, it has been demonstrated that DNA methylation is linked to histone methylation in fungi and plants, although it remains unknown whether this mechanism occurs in mammalian systems.
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PMID:Gene silencing in phenomena related to DNA repair. 1248 18

We investigated the spectrum and genetic basis for mismatch repair (MMR) deficiency in renal cell carcinoma (RCC) by examining expression of four MMR genes important for hereditary and sporadic carcinogenesis. MMR deficiency was assessed using microsatellite instability (MSI) and genetic analyses of 25 cell lines derived from renal tumors. MMR gene alterations were detected using reverse transcription of RNA coupled with polymerase chain reaction (RT-PCR) and DNA sequencing. Three RCC lines with undetectable MLH1 were identified and investigated for MSI and inactivating mutations in the hMLH1 MMR gene. Genetic instability and hMLH1 mutations were identified in two RCC lines and their corresponding tumors. Genetic alterations affecting expression were limited to MLH1 since other MMR proteins (MSH2, MSH6 and PMS2) were detectable in our RCC lines. Complete inactivation of MMR is apparently uncommon in RCC and occurs predominantly through inactivating mutations in the hMLH1 gene.
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PMID:Mismatch repair gene mutations in renal cell carcinoma. 1249 84

The "hyperplastic polyp" is considered a benign lesion with no malignant potential, whereas "serrated adenoma" is a precursor of adenocarcinoma. The morphologic complexity of the serrated adenoma varies from being clearly adenomatous to being difficult to distinguish from hyperplastic polyp, which creates a need for more detailed morphologic analysis of all serrated polyps. We evaluated 24 morphologic variables in 289 serrated polyps from the colon and rectum. Cluster analysis and discriminant analysis were performed. A subset of polyps was immunostained for hMLH1 and hMSH2. Major differences were found between right-sided and left-sided polyps. A distinct group of serrated polyps with abnormal proliferation was identified throughout the colon and rectum. These polyps demonstrated decreased expression of hMHL1 and hMSH2 compared with polyps with normal proliferation. Left-sided serrated polyps with normal proliferation further clustered into three groups: vesicular cell-type, goblet cell-type, and mucin-poor-type. We recommend evaluation of the localization, size, and morphologic features when serrated polyps are included in colorectal carcinogenesis research. Polyps with abnormal proliferation are similar to the polyps in "hyperplastic polyposis" and, because of their decreased expression of hMLH1 and hMSH2, may be the subset of polyps associated with the development of colorectal carcinoma via the microsatellite instability pathway.
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PMID:Morphologic reappraisal of serrated colorectal polyps. 1250 29


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