Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of heterozygosity of chromosome 3p21 is one of the most frequent alterations in solid tumors, including thyroid carcinomas. Recently, we have characterized the novel tumor suppressor gene RASSF1 located in this locus. The RASSF1A isoform is epigenetically inactivated in a variety of human primary tumors. In this study, we investigated the expression and methylation status of the RASSF1 gene in thyroid carcinoma. In nine thyroid cancer cell lines, the RASSF1A promoter CpG island was methylated completely, and expression was absent. Treatment of these cell lines with the DNA methylation inhibitor 5-aza-2'-deoxycytidine reactivated the transcription of RASSF1A. The methylation status of the RASSF1A promoter was analyzed in 38 primary thyroid tumors, including 1 poorly differentiated thyroid carcinoma, 5 medullary thyroid carcinoma (MTC), 10 follicular thyroid carcinoma (FTC), 9 undifferentiated thyroid carcinoma (UTC), and 13 papillary thyroid carcinoma (PTC). In 71% of thyroid carcinomas, the RASSF1A CpG island was hypermethylated. Methylation frequency was higher in the aggressive forms of thyroid carcinoma and was found in 80% of MTC, in 78% of UTC, and in 70% of FTC, compared with 62% in the more benign PTC. RASSF1A inactivation was detected in all stages of thyroid carcinoma scored by Tumor-Node-Metastasis classification. Additionally, we analyzed the methylation frequency of the CpG island of cell cycle inhibitor p16(INK4a) in the same thyroid tumors. The p16 gene was inactivated in 56 and 25% of cell lines and primary tumors, respectively. p16 methylation was detected in 56% of UTC, 10% of FTC, and 25% of PTC but not in MTC. In UTC, which belongs to the most aggressive carcinomas in humans, the most common combined inactivation of RASSF1A and p16 was detected. In general, 90% of tumors with p16 inactivation were also silenced for RASSF1A expression. However, RASSF1A hypermethylation was detected three times more frequently in thyroid cancers. Thus, RASSF1A inactivation may play a crucial role in the malignancy of thyroid carcinoma.
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PMID:Frequent epigenetic silencing of the CpG island promoter of RASSF1A in thyroid carcinoma. 1209 77

Ras signaling is important for the intracellular transduction of mitogenic stimuli from activated growth factor receptors. We have investigated 37 sporadic malignant melanomas (15 primary cutaneous melanomas and 22 melanoma metastases) and 6 melanoma cell lines for mutations in the 3 Ras genes NRAS, KRAS and HRAS. All tumors and cell lines were additionally analyzed for mutation and expression of BRAF, which encodes a Ras-regulated serine/threonine kinase with oncogenic properties, as well as for expression of RASSF1A, which encodes a Ras-binding protein with tumor suppressor properties. Mutational analyses identified somatic NRAS mutations in 2 primary melanomas, 4 melanoma metastases and 2 cell lines. One melanoma metastasis showed a somatic KRAS mutation whereas HRAS mutations were not detected. Eight primary melanomas, 6 melanoma metastases and 4 melanoma cell lines carried BRAF mutations affecting the known hot-spot codon 599. None of the tumors or cell lines with BRAF mutation demonstrated NRAS or KRAS mutations. Real-time reverse transcription-PCR showed that 8 melanomas (3 primary tumors, 5 melanoma metastases) had reduced RASSF1A transcript levels of < or =50% relative to benign melanocytic nevi and normal skin. Three melanoma cell lines lacked detectable RASSF1A transcripts. The RASSF1A gene promoter was hypermethylated in these 3 cell lines as well as in 6 of 8 melanomas with reduced RASSF1A mRNA levels. Treatment of the cell lines with 5-aza-2'-deoxycytidine and trichostatin A resulted in demethylation of the RASSF1A promoter and re-expression of RASSF1A transcripts. Most tumors and all cell lines with RASSF1A promoter methylation additionally carried BRAF or NRAS mutations, suggesting a synergistic effect of these aberrations on melanoma growth. Taken together, 57% of the investigated melanomas and 100% of the melanoma cell lines carried mutations in either NRAS, KRAS or BRAF. In addition, 22% of the melanomas and 50% of the cell lines showed reduced RASSF1A transcript levels. Thus, alterations of Ras pathway genes are of paramount importance in the pathogenesis of sporadic melanomas.
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PMID:Frequent alterations of Ras signaling pathway genes in sporadic malignant melanomas. 1496 76

Methylation of the promoter CpG-islands of the candidate tumor suppressor gene RASSF1A (3p21.31) was studied in primary tumors of kidney, breast and ovary (172 cases). Methylation-specific PCR (MSP) and methyl-sensitive restriction endonuclease digestion followed by PCR (MSRA) were applied. Statistically significant correlation (P << 10(-6)) was shown for the results of the MSP and MSRA, and the data of bisulfite sequencing reported earlier. The frequency of RASSF1A methylation according to MSP and MSRA was 86% (25/29) and 94% (50/53) in renal cell carcinoma (RCC) and 64% (18/28) and 78% (32/41)--in breast carcinoma (BC) samples, and 59% (17/29) and 73% (33/45) in ovarian epithelial tumors (OET), respectively. The use of several methyl-sensitive restriction enzymes (HpaII, HhaI, Bsh12361, AciI) enhanced the sensitivity of MSRA and allowed to analyze methylation status of 18 CpG-pairs in the RASSF1A CpG-island. Density of methylation of the RASSF1A CpG-island was 72% (644/900) in RCC, 63% (361/576) in BC, and 58% (346/594) in OET samples (18 CpG-pairs multiplied to the number of samples shown methylation were assumed as 100%). The RASSF1A gene methylation was also observed in samples of morphologically normal tissues adjacent to corresponding tumors (11-35%), but it was not detected in blood DNAs of healthy donors (0/15). The RASSF1A methylation frequency did not show significant correlation to tumor stage, grade and metastases (P = 0.3-1.0). The RASSF1A gene methylation was observed more frequently than other investigated aberrations--hemi- and homozygous deletions inside or around this gene. These observations are consistent with the hypothesis that the RASSF1A gene methylation is an early event in the carcinogenesis and one of the dominant ways of its inactivation.
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PMID:[Methylation of the promoter region of the RASSF1A gene, a candidate tumor suppressor, in primary epithelial tumors]. 1545 37

The methylation level of 13 CpG-dinucleotides in the promoter region of the putative tumor suppressor gene RASSF1A (3p21.31) was analyzed in HPV-positive squamous cell carcinomas of cervix using methyl-sensitive restriction endonuclease analysis followed by PCR. The methylation from 3 to 13 CpG-dinucleotides was observed in 64% (25/39) tumors, 22% (2/9) morphologically normal tissues adjacent to tumors (P = 0.0306) and in 2 from 3 leucocytes of peripheral blood of patients. The methylation of these CpG-dinucleotides was absent in DNA of healthy donor leucocytes (0/10). Methylation level of the examined fragment of the RASSF1A promoter region was significantly higher in tumors of patients with lymph node metastases in comparison to tumors of patients without metastases (P = 8.5 x 10(-12)). The methylation frequency of RASSF1A gene was in two times higher than hemi- and homozygous deletion frequency at the region of location of this gene (chromosome 3p21.31), determined earlier. These data suggest that methylation of the RASSF1A gene is one of the main ways of this gene inactivation in HPV-positive cervical squamous cell carcinomas. The methylation of the RASSF1A gene is an early event in genesis of tumor and the level of methylation increased with tumor progression.
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PMID:[Methylation of the putative tumor suppressor gene, RASSF1A, in primary cervical tumors]. 1561 86

Adjuvant systemic therapy (a strategy that targets potential disseminated tumor cells after complete removal of the tumor) has clearly improved survival of patients with cancer. To date, no tool is available to monitor efficacy of these therapies, unless distant metastases arise, a situation that unavoidably leads to death. We analyzed RASSF1A DNA methylation in pretherapeutic sera and serum samples collected 1 year after surgery from 148 patients with breast cancer who were receiving adjuvant tamoxifen; 19.6% and 22.3% of patients with breast cancer showed RASSF1A DNA methylation in their pretherapeutic and 1-year-after serum samples, respectively. RASSF1A methylation 1 year after primary surgery (and during adjuvant tamoxifen therapy) was an independent predictor of poor outcome, with a relative risk (95% confidence interval) for relapse of 5.1 (1.3-19.8) and for death of 6.9 (1.9-25.9). Measurement of serum DNA methylation allows adjuvant systemic treatment to be monitored for efficacy: disappearance of RASSF1A DNA methylation in serum throughout treatment with tamoxifen indicates a response, whereas persistence or new appearance means resistance to adjuvant tamoxifen treatment. It remains to be seen whether modifications made in adjuvant therapeutic strategies based on detection of circulating nucleic acids will improve survival as well as quality of life.
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PMID:Circulating tumor-specific DNA: a marker for monitoring efficacy of adjuvant therapy in cancer patients. 1573 95

To investigate intra-tumoural coexistence and heterogeneity of aberrant promoter hypermethylation of different tumour suppressor genes in melanoma, we analyzed the intra-tumoural distribution of promoter methylation of RASSF1A, p16, DAPK, MGMT, and Rb in 339 assays of 34 tumours (15 melanoma primaries, 19 metastases) by methylation-specific PCR, correlation to histopathology and RASSF1A expression. We detected promoter hypermethylation of at least one gene in 74% of tumours (30%, 52%, 33%, 20%, and 40% for RASSF1A, p16, DAPK, MGMT and Rb, respectively). 70% of the cases exhibited an inhomogeneous methylation pattern (17%, 45%, 33%, 20%, and 40% for RASSF1A, p16, DAPK, MGMT and Rb, respectively). Samples from the core of the tumours represented the methylation state of the whole tumours more accurately than the periphery. Local intra-tumoural correlation was found between the promoter hypermethylation state of p16 and Rb or p16 and DAPK, or epitheloid tumour cell type and RASSF1A or p16 methylation. Mitosis rate and sex was correlated with methylation of RASSF1A. Histological results confirmed that promoter hypermethylation of RASSF1A led to aberrant expression patterns. We conclude that intra-tumoural inhomogeneity of promoter hypermethylation is frequent in melanoma and this supports the hypothesis of clonal instability during progression of melanomas. In prognosis studies, missing the intra-tumoural sample representativeness may result in a reduction of the sensitivities or specificities.
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PMID:Frequent intra-tumoural heterogeneity of promoter hypermethylation in malignant melanoma. 1752 78

The novel tumor suppressor RASSF1A is frequently inactivated during human tumorigenesis by promoter methylation. In this study, we detected the RASSF1A promoter methylation by methylated-specific PCR and investigated RASSF1A gene expression by semi-quantitative RT-PCR and immunohistochemical staining in 36 cases of breast cancer and their adjacent normal tissues in Chinese women. The promoter methylation of the RASSF1A gene was found to be a frequent event in the breast cancers (61.1%). RASSF1A methylation was not found in the matched adjacent normal tissues. The loss frequency of RASSF1A mRNA was 33.3% and that of the RASSF1A protein was 44.4% in breast cancers. RASSF1A mRNA and protein were all expressed in adjacent normal tissues. The mRNA and protein expression level of RASSF1A was significantly lower in breast cancer than in adjacent normal tissue. However, the promoter methylation of the RASSF1A gene in breast cancers were not correlated with clinical parameters, such as ages, histological types, TNM stages and lymph node metastases. Thus, the promoter methylation of RASSF1A was one reason for the low level of RASSF1A mRNA and protein expression and was a frequent event in primary sporadic breast tumorigenesis in Chinese women.
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PMID:Expression and promoter methylation of the RASSF1A gene in sporadic breast cancers in Chinese women. 1842 70

Chromosomal and genome abnormalities of 3p are frequent events in many epithelial tumours, including lung cancer. Several critical regions with high frequency of hemi--and homozygous deletions in tumours were detected on 3p and more then 20 different cancer-related genes were identified in 3p21.3 locus. Real-time PCR was used to measure mRNA level of tumour-suppressor genes and candidates in 3p21.3 (RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 in basic types of non-small cell lung cancer (NSCLC)--squamous cell lung cancer (SCC) and lung adenocarcinoma (AC). Significant (from 2 to 100 times) and frequent (from 44 to 100%) mRNA level decrease was shown in NSCLC. Level and frequency of mRNA decrease for all genes depended on histological type of NSCLC. Down-regulation of RASSF1A and ITGA9 was associated significantly with AC progression, the same tendency was found for genes RBSP3/CTDSPL, NPRL2/G21, HYAL1 and HYAL2. On the contrary, down-regulation of all genes in SCC was not associated with clinical stages, tumor cells differentiation and metastases in lymph nodes. Significant decrease of RBSP3/CTDSPL, NPRL2/G21, ITGA9, HYAL1 and HYAL2 mRNA levels (on average, 5-13 times) with high frequency (83-100%) was already shown at the first stage of SCC. Simultaneous decrease of all six genes mRNA level was found in the same tumor samples and was not depended on their localization on 3p21.3 and functions of the proteins. Spearman's correlation coefficient r(s) was from 0.63 to 0.91, P < 0.001. Co-regulation of gene pairs ITGA9 and HYAL2, HYAL1 and HYAL2, which mediate cell-cell adhesion and cell-matrix interaction, was suggested based on the obtained data. It was shown that genetic and epigenetic mechanisms were important for down-regulation of RBSP3/CTDSPL and ITGA9 genes. These results supported the hypothesis on simultaneous inactivation of cluster cancer-related genes in extended 3p21.3 locus during development and progression of lung cancer and other epithelial tumors. Significant and frequent decrease of mRNA level of six genes in SCC could be important for development of specific biomarker sets for early SCC diagnosis and new therapeutic approaches/strategies for NSCLC.
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PMID:[Down-regulation of RBSP3/CTDSPL, NPRL2/G21, RASSF1A, ITGA9, HYAL1 and HYAL2 genes in non-small cell lung cancer]. 1914 Mar 16

Breast cancer diversity is histologically evident as various proliferative benign lesions, in situ carcinomas, and invasive carcinomas that may develop into distant metastases. Breast tumor molecular subtypes have been defined by genome-wide expression microarray technology and reveal associations between genetic alterations and the malignant phenotype. Early work has been conducted to use subtype-specific biomarkers to elucidate targeted treatment options early in the course of breast cancer progression. Additionally, DNA methylation is an epigenetic modification that contributes to breast cancer progression by transcriptionally silencing certain tumor suppressor genes. Among the genes characterized as targets for silencing are well-established tumor suppressors such as RASSF1A, RARB, SFN, and TGM2. Measuring elevated gene copy number and aberrant gene promoter methylation can further facilitate characterization of breast tumor molecular subtype; however, profiling of breast tumors based on epigenetic criteria has yet to be established. Epigenomic analysis has been investigated for clinical applicability, and it has great promise when used in combination with minimally invasive techniques for both diagnostic and prognostic purposes.
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PMID:Unraveling breast cancer heterogeneity through transcriptomic and epigenomic analysis. 1945 29

Several studies have reported Oral Squamous Cell Carcinoma (OSCC) association with etiological factors, such as smoking and alcohol. The aim of the present study was to establish whether the methylenetetrahydrofolate reductase (MTHFR) C677T genotype and a high alcohol intake, solely or in interaction, have an impact on the oral cancer risk, DNA methylation, or multiple methylation of tumor-related genes. MTHFR C677T genetic polymorphism was determined by the PCR/RFLP method, and DNA methylation was assessed by nested methylation-specific PCR. The risk for multiple methylation was significantly increased in heavy-drinking patients with the TT genotype, compared with CC and CT patients (OR = 10.873; 95% CI, 1.134-104.24). Multiple methylation was significantly associated with tumor stage (p = 0.018), and showed a trend of association with the presence of nodal metastases (p = 0.058). A significant association was found between TT genotype and methylation status of the RASSF1A gene in OSCC patients (p = 0.012). Heavy-drinking individuals with the TT genotype showed increased oral cancer risk compared with the CC genotype (OR = 3.601; 95% CI, 1.036-12.513), and compared with the CC and CT genotypes (OR = 4.288; 95% CI, 1.325-13.877). Our study suggested gene-environment interactions between high alcohol intake and the MTHFR 677TT genotype for elevated oral cancer risk, with a significant impact on multiple methylation of cancer-related genes.
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PMID:Interaction between the MTHFR C677T polymorphism and alcohol--impact on oral cancer risk and multiple DNA methylation of tumor-related genes. 2094 Mar 65


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