Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We are in an era where the potential exists for deriving comprehensive profiles of DNA alterations characterizing each form of human cancer. Such profiles would provide invaluable insight into mechanisms underlying the evolution of each tumor type and will provide molecular markers, which could radically improve cancer detection. To date, no one type of DNA change has been defined which accomplishes this purpose. Herein, by using a candidate gene approach, we show that one category of DNA alteration, aberrant methylation of gene promoter regions, can enormously contribute to the above goals. We have now analyzed a series of promoter hypermethylation changes in 12 genes (p16(INK4a), p15(INK4b), p14(ARF), p73, APC,(5) BRCA1, hMLH1, GSTP1, MGMT, CDH1, TIMP3, and DAPK), each rigorously characterized for association with abnormal gene silencing in cancer, in DNA from over 600 primary tumor samples representing 15 major tumor types. The genes play known important roles in processes encompassing tumor suppression, cell cycle regulation, apoptosis, DNA repair, and metastastic potential. A unique profile of promoter hypermethylation exists for each human cancer in which some gene changes are shared and others are cancer-type specific. The hypermethylation of the genes occurs independently to the extent that a panel of three to four markers defines an abnormality in 70-90% of each cancer type. Our results provide an unusual view of the pervasiveness of DNA alterations, in this case an epigenetic change, in human cancer and a powerful set of markers to outline the disruption of critical pathways in tumorigenesis and for derivation of sensitive molecular detection strategies for virtually every human tumor type.
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PMID:A gene hypermethylation profile of human cancer. 1130 70

Recent studies from our laboratory suggest that gene-specific methylation changes in sputum could be good intermediate markers for the early detection of lung cancer and defining the efficacy of chemopreventive interventions. The purpose of our study was to determine the prevalence for aberrant promoter methylation of the p16, O(6)-methylguanine-DNA methyltransferase (MGMT), death-associated protein (DAP) kinase, and Ras effector homologue (RASSFIA) genes in nonmalignant bronchial epithelial cells from current and former smokers in a hospital-based, case control study of lung cancer. The relationship between loss of heterozygosity, at 9p and p16 methylation in bronchial epithelium and the prevalence for methylation of these four genes in sputum from cancer-free, current and former smokers were also determined. Aberrant promoter methylation of p16 was seen in at least one bronchial epithelial site from 44% of cases and controls. Methylation of the DAP kinase gene was seen in only 1 site from 5 cases and 4 controls, whereas methylation of the RASSFIA was not detected in the bronchial epithelium. Promoter methylation for p16 and DAP kinase was seen as frequently in bronchial epithelium from current smokers as from former smokers. No promoter methylation of these genes was detected in bronchial epithelium from never-smokers. Methylation of the p16 gene was detected in sputum from 23 of 66 controls. DAP kinase gene promoter methylation was also seen in sputum from 16 controls, and 8 of these subjects were positive for p16 methylation. Methylation of the MGMT gene was seen in sputum from 9 controls, whereas RASSFIA promoter methylation was only seen in 2 controls. The correlation between p16 status in the bronchial epithelium obtained from lung lobes that did not contain the primary tumor and the tumor itself was examined. Seventeen of 18 tumors (94%) showed an absolute concordance, being either methylated in the tumor and at least 1 bronchial epithelial site, or unmethylated in both tumor and bronchial epithelium. These results indicate that aberrant promoter hypermethylation of the p16 gene, and to a lesser extent, DAP kinase, occurs frequently in the bronchial epithelium of lung cancer cases and cancer-free controls and persists after smoking cessation. The strong association seen between p16 methylation in the bronchial epithelium and corresponding primary tumor substantiates that inactivation of this gene, although not transforming by itself, is likely permissive for the acquisition of additional genetic and epigenetic changes leading to lung cancer.
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PMID:Aberrant promoter methylation in bronchial epithelium and sputum from current and former smokers. 1195 99

Differential gene methylation is observed in a variety of human malignancies. The study of the pattern of methylated genes helps to understand carcinogenesis and to identify potential marker tumor genes for clinical use. The differential methylated genes in undifferentiated nasopharyngeal carcinoma (NPC) of Chinese were studied by methylation-specific polymerase chain reaction (MSP). Methylation status of 11 tumor-associated genes (ARF, caspase-8, CDH1, CDKN2A, CDKN2B, MGMT, MLH1, RASSF1A, THBS1, TP73 and VHL) was studied in 30 primary undifferentiated NPC and paired peripheral blood of 12 patients. The methylation profile of NPC in order of frequency was CDH1 (50%), CDKN2B (50%), THBS1 (50%), RASSF1A (46%), MLH1 (40%), MGMT (28%), CDKN2A (23%), TP73 (20%), caspase-8 (7%), ARF (3%) and VHL (0%). Methylation of at least 1 gene was observed in 93% of primary NPC. Of the 12 patients with at least 1 methylated gene in the primary tumor, all 12 (100%) patients had at least 1 of the methylated gene promoter detectable in their peripheral blood. The results show high frequency of methylation in NPC and the potential of using methylation as peripheral blood tumor marker in screening NPC.
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PMID:Differential gene methylation in undifferentiated nasopharyngeal carcinoma. 1263 81

Methylation profile was analyzed in eleven cases of therapy-related leukemia (t-leukemia) for p14, p15, p16, Rb, hMLH1, hMSH2, MGMT, APC, RAR beta, DAPK, RIZ1, FHIT, and SOCS-1 genes by using methylation specific polymerase chain reaction (MSP) analysis. Six (55%) of eleven cases showed methylation of at least one gene. The average time to the development of t-leukemia after the treatment of the primary tumor was significantly shorter in patients with methylation than those without methylation (49.3 months vs. 133.2 months, P=0.044). These results suggest that hypermethylation might be involved in the development of t-leukemia.
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PMID:Aberrant methylation in promoter-associated CpG islands of multiple genes in therapy-related leukemia. 1288 5

The methylation pattern in the promoter region of p16, DAPK, MGMT and GSTP1 genes was investigated in oral cancer tissues and tumor associated adjacent tissues, using methylation specific PCR assay. The samples constituted 60 primary oral tumors and corresponding adjacent clinically and histopathologically normal mucosa, and buccal epithelial scrapings from 20 normal healthy individuals without any tobacco habits. The incidence of hypermethylation in oral tumor and adjacent mucosa for p16 gene was 66.7 and 50%, for DAPK was 68.3 and 60%, and MGMT gene was 51.7 and 26.7%, respectively. The overall hypermethylation in the three genes in the primary tumor was 86.7%, and corresponding adjacent normal mucosa tissues 76.7%. Hypermethylation was not observed in the promoter region of GSTP1 gene in either the primary tumors or the corresponding adjacent normal mucosa. Absence of aberrant methylation in the four genes was noted in buccal scrapings from normal healthy individuals with no tobacco habits. Thus, a high frequency of promoter region hypermethylation was observed in p16, DAPK and MGMT genes in oral cancer tissues as well as in corresponding adjacent normal mucosa. Our results indicate that epigenetic alteration of these genes is a frequent event in oral cancer, and is an early event observed in normal oral mucosa of the patients, indicating the critical importance of the epigenetic alteration in chewing tobacco associated oral carcinogenesis.
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PMID:Concurrent hypermethylation of multiple regulatory genes in chewing tobacco associated oral squamous cell carcinomas and adjacent normal tissues. 1469 37

Methylation of promoter regions of CpG-rich sites is an important mechanism for silencing of tumor suppressor genes (TSG). To evaluate the role of tumor suppressor genes caspase-8 (CASP8), TIMP-3, E-cadherin (CDH1), p16INK4A, and MGMT in medulloblastoma tumorigenesis, 51 medulloblastomas (46 primary tumor specimens, 5 cell lines) were screened for methylation of promoter linked CpG-islands. For CASP8, we examined the 5' UTR region that has been shown to be associated with expression of CASP8. As detected by methylation specific PCR, methylation rate was low for TIMP-3 (3% of tumor samples; 1/5 cell lines), for MGMT (0% of tumor samples; 1/5 cell lines), for p16INK4A (2% of tumor samples; 2/5 cell lines) and for CDH1 (8% of tumor samples; 1/4 cell lines). CASP8, however, was methylated in 90% of tumor samples and 4/5 cell lines examined. Screening other tumor entities for CASP8 methylation, we found a similarly high level in 6 neuroblastoma cell lines in contrast to 5 osteosarcoma-, 4 Ewing's sarcoma- and 6 non-embryonic tumor cell lines without any increased promoter methylation. From our results we conclude that methylation of the CASP8 5' UTR region may play a role in inactivation of CASP8 in neural crest tumors.
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PMID:Promoter methylation pattern of caspase-8, P16INK4A, MGMT, TIMP-3, and E-cadherin in medulloblastoma. 1502 56

Breast cancer recurrence is a result of undetected metastasis present at the time of primary patient treatment. More sensitive methods are needed to identify subclinical disease progression to better accompany those increasing advances in early breast cancer screening. Aberrant hypermethylation of tumor-suppressor genes is found frequently in primary breast tumors and has been implicated in disease initiation and progression. Epigenetic characterization of tumor cells may provide highly specific and sensitive molecular surrogates for surveillance. We evaluated whether tumor-associated methylated DNA markers could be identified circulating in bone marrow (BM) aspirates and paired serum samples from 33 early-stage patients undergoing surgery for breast cancer. Quantitative methylation-specific PCR (qMSP) was performed using a selected tumor-related gene panel for RAR-ss2, MGMT, RASSF1A, and APC. Tumor-associated hypermethylated DNA was identified in 7 (21%) of 33 BM aspirates and 9 (27%) serum samples. In three patients both BM and serum were positive for hypermethylation. The most frequently detected hypermethylation marker was RASSF1A occurring in 7 (21%) patients. Concordance was present between gene hypermethylation detected in BM or serum samples, and matched-pair primary tumors. Advanced AJCC stage was associated with an increased incidence of circulating gene hypermethylation. In addition, methylation patterns in the sentinel lymph node (SLN) metastasis corresponded with that of the primary tumor, confirming epigenetic clonality is associated with early tumor dissemination. This study demonstrates the novel finding of tumor-associated epigenetic markers in BM aspirates/blood and their potential role as targets for molecular detection.
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PMID:Epigenetic analysis of body fluids and tumor tissues: application of a comprehensive molecular assessment for early-stage breast cancer patients. 1710 14

Glioma, and in particular high-grade astrocytoma termed glioblastoma multiforme (GBM), is the most common primary tumor of the brain. Epigenetic silencing of the MGMT (O(6)-methylguanine-DNA Methyl transferase) DNA repair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with GBM who receive alkylating agents. The methylation status of the MGMT promoter is determined by methylation-specific polymerase chain reaction analysis (MSP). This protocol is often challenging with GBM specimens, because of extensive necrosis and scarcity of malignant cells. The objective of this study was to develop a reliable, clinically validated assay for detection of epigenetic silencing of the MGMT gene using formalin-fixed, paraffin-embedded brain tumor resections and methylation-specific PCR.
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PMID:A simplified laboratory validated assay for MGMT promoter hypermethylation analysis of glioma specimens from formalin-fixed paraffin-embedded tissue. 1726

The DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) plays a pivotal role in alkylating drug resistance. Here, we determined MGMT activity in primary and recurrent glioblastomas (GBM, WHO grade IV) of patients who received radiation therapy (RT) or RT plus chemotherapy with alkylating agents (temozolomide, chloroethylnitrosoureas). The mean MGMT activity of untreated GBM was 37 +/- 45 (range 0-205) fmol/mg proteins. In the 1st, 2nd and 3rd recurrences, MGMT activity increased from 66 +/- 50 (13-194) to 68 +/- 44 (14-143) and 182 +/- 163 (64-423) fmol/mg protein, respectively. Comparing patients who received RT only with RT plus chemotherapy, a significant increase of MGMT in 1st recurrences was only found after treatment with RT plus chemotherapy, indicating either selection of MGMT expressing cells or induction of the MGMT gene by alkylating agents. The p53 status was not significantly related to the MGMT expression level, although a trend for lower MGMT activity in p53 positively stained tumors was observed. Patients expressing MGMT activity of <or=30 fmol/mg protein in the pretreatment tumor had a significant better therapeutic response than patients expressing MGMT above this level, which was shown by Kaplan-Meyer curves and the recurrence free interval after primary tumor resection. In patients who received RT only, this correlation was not found. The data revealed a threshold of MGMT expression (30 fmol/mg protein) below which patients respond better to alkylating agents. Therefore, determination of MGMT activity in the primary tumor appears to be useful in predicting the outcome of GBM therapy.
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PMID:MGMT in primary and recurrent human glioblastomas after radiation and chemotherapy and comparison with p53 status and clinical outcome. 1800 Aug 22

Epigenetic silencing of the O(6) -methylguanine-DNA methyltransferase (MGMT) gene promoter is associated with prolonged survival in glioblastoma patients treated with temozolomide (TMZ). We investigated whether glioblastoma recurrence is associated with changes in the promoter methylation status and the expression of MGMT and the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2 in pairs of primary and recurrent glioblastomas of 80 patients, including 64 patients treated with radiotherapy and TMZ after the first operation. Among the primary tumors, the MGMT promoter was methylated in 31 patients and unmethylated in 49 patients. In 71 patients (89%), the MGMT promoter methylation status of the primary tumor was retained at recurrence. MGMT promoter methylation, but not MGMT protein expression, was associated with longer progression-free survival, overall survival and postrecurrence survival (PRS). Moreover, PRS was increased under salvage chemotherapy. Investigation of primary and recurrent glioblastomas of 43 patients did not identify promoter methylation in any of the four MMR genes. However, recurrent glioblastomas demonstrated significantly lower MSH2, MSH6 and PMS2 protein expression as detected by immunohistochemistry. In conclusion, reduced expression of MMR proteins, but not changes in MGMT promoter methylation, is characteristic of glioblastomas recurring after the current standards of care.
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PMID:Promoter methylation and expression of MGMT and the DNA mismatch repair genes MLH1, MSH2, MSH6 and PMS2 in paired primary and recurrent glioblastomas. 2142 58


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