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)

The short arm of chromosome 3 is thought to contain multiple tumor suppressor genes, because one copy of this chromosomal arm frequently is missing in carcinomas that have arisen in a variety of tissues. We have isolated a novel gene encoding a 1755-amino acid polypeptide, through large-scale sequencing of genomic DNA at 3p21.3. Mutational analysis of this gene by reverse transcription-PCR revealed the lack of functional transcripts and an increase of nonfunctional RNA transcripts in a significant proportion (33%) of cancer cell lines and primary cancers (4 of 14 esophageal cancer cell lines, 2 of 2 renal cancer cell lines, 11 of 30 primary non-small cell lung cancers, and 3 of 10 primary squamous cell carcinomas of the esophagus). However, no alterations of the gene itself were detected in any of the cancers examined. Introduction of the cDNA significantly suppressed the growth of four different cancer cell lines, two of which produced no normal transcript on their own. No such effect occurred when antisense cDNA, cDNA corresponding to an aberrant transcript, or the vector DNA alone were transfected. These data suggest that aberrant transcription of this gene, designated DLC1 (deleted in lung cancer 1), may be involved in carcinogenesis of the lung, esophagus, and kidney.
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PMID:Molecular cloning of a candidate tumor suppressor gene, DLC1, from chromosome 3p21.3. 1021 8

A gene or genes on chromosome 8p22-23 have been implicated in prostate carcinogenesis by the observation of frequent deletions of this region in prostate cancer cells. More recently, two genetic linkage studies in hereditary prostate cancer (HPC) families suggest that germline variation in a gene in this region may influence prostate cancer susceptibility as well. DLC1 (deleted in liver cancer), a gene in this interval, has been proposed as a candidate tumor suppressor gene because of its homology (86% similarity) with rat p122 RhoGAP, which catalyzes the conversion of active GTP-bound rho complex to the inactive GDP-bound form, and thus suppresses Ras-mediated oncogenic transformation. A missense mutation and three intronic insertions/deletions in 126 primary colorectal tumors have been previously identified. However, there are no reports of DLC1 mutation screening in prostate tumors or in germ line DNA of prostate cancer patients. In this study, we report the results of the first mutation screen and association study of DLC1 in genomic DNA samples from hereditary and sporadic prostate cancer patients. The PCR products in the 5' UTR, all 14 exons, exon-intron junctions, and 3' UTR were directly sequenced in 159 HPC probands. Eight exonic nucleotide polymorphisms (SNPs) were identified, only one of which resulted in an amino acid change. Twenty-three other SNPs were identified in intronic regions. Seven informative SNPs that spanned the complete DLC1 gene were genotyped in an additional 249 sporadic cases and 222 unaffected controls. No significant difference in the allele and genotype frequencies were observed among HPC probands, sporadic cases, and unaffected controls. These results suggest that DLC1 is unlikely to play an important role in prostate cancer susceptibility.
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PMID:Evaluation of DLC1 as a prostate cancer susceptibility gene: mutation screen and association study. 1287 22

Allelic imbalance on chromosome arm 8p is common in head and neck squamous cell carcinoma (HNSCC). DLC1, a tumour suppressor gene inactivated in liver carcinogenesis and encoding a Rho GTPase activating protein (RhoGAP) maps to one of the deleted regions (8p21.3-22). In order to determine whether inactivation of DLC1 is involved in HNSCC, we have screened tumour cell lines for DLC1 mutations and expression. Pathological mutations were not identified in any of the 17 cell lines tested. Seven polymorphisms were identified; 13 of the 17 of cell lines were homozygous for all seven polymorphisms compared to only 2 of 17 controls suggesting a loss of heterozygosity in a majority of the cell lines. DLC1 expression was observed in all 11 HNSCC cell lines tested, thus excluding the possibility of transcriptional silencing of DLC1 by promoter hypermethylation. Overall, our data suggest that hemizygous deletions of the DLC1 locus are frequent in HNSCCs but this gene is unlikely to be primary target for inactivation on this chromosomal arm.
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PMID:DLC1 is unlikely to be a primary target for deletions on chromosome arm 8p22 in head and neck squamous cell carcinoma. 1515 23

ARHGAP family genes encode Rho/Rac/Cdc42-like GTPase activating proteins with RhoGAP domain. Here, we characterized human ARHGAP10 gene by using bioinformatics. Complete coding sequence of ARHGAP10 isoform A was determined by assembling nucleotide position 1-725 of FLJ41791 cDNA (AK123785.1) and 5'-truncated IMAGE4310652 cDNA (BC011920.2). Nucleotide position 240-2600 of ARHGAP10 isoform A was identical to GRAF2 cDNA (AB050785.1). Complete coding sequence of ARHGAP10 isoform B was derived from FLJ41791 cDNA. ARHGAP10 isoform A, consisting of exons 1-23, encoded full-length protein (786 aa). ARHGAP10 isoform B, consisting of exons 1-5 and intron 5, encoded C-terminally truncated protein (163 aa). ARHGAP10 gene was found encoding two isoforms due to alternative splicing. ARHGAP10 mRNA was expressed in chondrosarcoma, breast cancer, kidney tumors, and brain tumors. ARHGAP10 and ARHGAP26 (GRAF), showing 57.9% total amino-acid identity, shared the common-domain structure with BAR, PH, RhoGAP and SH3 domains. ARHGAP10-NR3C2 locus at human chromosome 4q31.23 and ARHGAP26-NR3C1 locus at human chromosome 5q31 were paralogous regions (paralogons) within the human genome. ARHGAP gene family was found consisting of at least 32 members, including ARHGAP1, ARHGAP2 (CHN1), ARHGAP3, (CHN2), ARHGAP4, ARHGAP5, ARHGAP6 (STARD8), ARHGAP7 (STARD12 or DLC1), ARHGAP8, ARHGAP9, ARHGAP10, ARHGAP12, ARHGAP13 (SRGAP1), ARHGAP14 (SRGAP2), ARHGAP15, ARHGAP17 (RICH1), ARHGAP18, ARHGAP19, ARHGAP20, ARHGAP21, ARHGAP22, ARHGAP23, ARHGAP24, ARHGAP25, ARHGAP26, STRAD13 (DLC2), HA-1, GMIP, PARG1, PIK3R1, PIK3R2, RACGAP1, and FNBP2. Genetic alterations of ARHGAP family genes lead to carcinogenesis through the dysregulation of Rho/Rac/Cdc42-like GTPases.
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PMID:Characterization of human ARHGAP10 gene in silico. 1537 73

ARHGAP1, ARHGAP2, ARHGAP3, ARHGAP4, ARHGAP5, ARHGAP6, ARHGAP7 (DLC1), ARHGAP8, ARHGAP9, ARHGAP10, ARHGAP12, ARHGAP13 (SRGAP1), ARHGAP14 (SRGAP2), ARHGAP15, ARHGAP17 (RICH1), ARHGAP18, ARHGAP19, ARHGAP20, ARHGAP21, ARHGAP22, ARHGAP23, ARHGAP24, ARHGAP25, ARHGAP26, STARD13 (DLC2), HA-1, GMIP, PARG1, RACGAP1, PIK3R1, PIK3R2, and FNBP2 genes encode Rho/Rac/Cdc42-like GTPase activating (RhoGAP) proteins. Here, we characterized human ARHGAP27 gene by using bioinformatics. Complete coding sequence of ARHGAP27 isoform 1, encoding a full-length 889-aa protein, was determined by assembling exon 1 (nucleotide position 143440-144096 of AC091132.16) and most part of FLJ43547 cDNA (nucleotide position 69-3628 of AK125535.1). Complete coding sequence of ARHGAP27 isoform 2, encoding an N-terminally truncated 548-aa protein, was derived from FLJ43547 cDNA. ARHGAP27 isoform 1 consists of exons 1-17, while ARHGAP27 isoform 2 consists of exons 1B, and 2-17. ARHGAP27 gene encoded two isoforms due to alternative splicing of alternative promoter type. ARHGAP27 mRNA was expressed in germinal center B cell, spleen, chronic lymphocytic leukemia, pancreatic cancer, and lung cancer. LOC303583 (NM_ 198759.1) was the representative rat Arhgap27 cDNA. Human ARHGAP27 showed 84.3% total-amino-acid identity with rat Arhgap27, and 39.0% total-amino-acid identity with human ARHGAP12. ARHGAP27 and ARHGAP12 shared the common-domain structure, consisting of SH3, WW, PH, and RhoGAP domains. ARHGAP27 gene was located at human chromosome 17q21, while ARHGAP12 gene was located at human chromosome 10p11. ARHGAP family genes are cancer-associated genes, because their genetic alterations lead to carcinogenesis through the dysregulation of Rho/Rac/ Cdc42-like GTPases. This is the first report on identification and characterization of the ARHGAP27 gene.
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PMID:Identification and characterization of ARHGAP27 gene in silico. 1549 70

Molecular characterizations of hepatocellular carcinoma have indicated frequent allelic losses on chromosomes 4q, 8p, 16q and 17p, where the minimal deleted regions have been further defined on 4q12-q23, 4q31-q35, 8p21-p22, 16q12.1-q23.1 and 17p13. Despite these regions are now well-recognized in early liver carcinogenesis, few underlying candidate genes have been identified. In an effort to define affected genes within common deleted loci of hepatocellular carcinoma, we conducted transcriptional mapping by high-resolution cDNA microarray analysis. In 20 hepatocellular carcinoma cell lines and 20 primary tumors studied, consistent downregulations of novel transcripts were highlighted throughout the entire genome and within sites of frequent losses. The array-derived candidates including fibrinogen gamma peptide (FGG, at 4q31.3), vitamin D binding protein (at 4q13.3), fibrinogen-like 1 (FGL1, at 8p22), metallothionein 1G (MT1G, at 16q12.2) and alpha-2-plasmin inhibitor (SERPINF2, at 17p13) were confirmed by quantitative reverse transcription-polymerase chain reaction, which also indicated a more profound downregulation of FGL1, MT1G and SERPINF2 relative to reported tumor-suppressor genes, such as DLC1 (8p22), E-cadherin (16q22.1) and TP53 (17p13.1). In primary hepatocellular carcinoma examined, a significant repression of MT1G by more than 100-fold was indicated in 63% of tumors compared to the adjacent nonmalignant liver (P = 0.0001). Significant downregulations of FGG, FGL1 and SERPINF2 were also suggested in 30, 23 and 33% of cases, respectively, compared to their nonmalignant counterparts (P < 0.016). In summary, transcriptional mapping by microarray indicated a number of previously undescribed downregulated genes in hepatocellular carcinoma, and highlighted potential candidates within common deleted regions.
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PMID:Positional expression profiling indicates candidate genes in deletion hotspots of hepatocellular carcinoma. 1698 Sep 51

Epigenetic mechanisms involving DNA methylation and chromatin remodeling are important in silencing tumor suppressor genes (TSG) in various malignancies, including renal cell carcinoma (RCC). DLC1 (deleted in liver cancer 1)/ARHGAP7 is a recently identified 8p22 candidate TSG. Frequent methylation of the DLC1 promoter with resultant gene silencing has been reported in several tumors, but not in RCC yet. We examined DLC1 promoter methylation in 34 primary RCCs and the corresponding non-malignant tissues, and the correlation of DLC1 methylation with the clinicopathological characteristics of RCC patients. Although DLC1 methylation and downregulation were only detected in one of seven RCC cell lines using methylation-specific PCR (MSP) and semi-quantitative reverse-transcription PCR, we found that the DLC1 promoter was methylated in 35% (12/34) of primary RCC tumors, which was further confirmed by direct sequencing of MSP products and high-resolution bisulfite genomic sequencing. In contrast, only one of the 34 (3%) non-malignant renal tissues had weak methylation. Aberrant DLC1 methylation appeared to be a relatively early event during renal tumorigenesis since 33% of the RCC tumors with pT1 (TNM staging) showed methylation, which is similar to other late stage tumors. Thus, our results demonstrated that DLC1 methylation occurs in a subset of RCC tumors and may play a role in renal carcinogenesis.
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PMID:Aberrant methylation of the 8p22 tumor suppressor gene DLC1 in renal cell carcinoma. 1702 74

Gallbladder carcinoma (GBC) is a highly malignant neoplasm and represents the leading cause of cancer death in Chilean women. In order to determine the potential role of promoter methylation in gallbladder carcinogenesis, we investigated the frequency of this epigenetic mechanism by methylation-specific polymerase chain reaction (MSP) in 35 chronic cholecystitis (CC, separated according to the presence or absence of metaplasia), 19 early cancers (mucosa or muscularis propia invasion) and 48 advanced carcinomas with invasion of the gallbladder subserosa (25 cases) and serosa (23 cases). We examined 14 genes and observed an increase of multigenic methylation during tumoral progression which was not significantly associated with the patient's age. Four genes (DAPK1, DLC1, TIMP3, and RARbeta2) displayed a progressive increase in their methylation status from CC without metaplasia to advanced carcinoma invading the serosa layer (P <or= 0.05). The survival analysis indicated that a methylated condition of DLC1 gene is significantly associated with poor prognosis (P = 0.04), whereas a methylated state of MGMT gene correlated with better patient survival (P = 0.006). Our findings indicate that aberrant hypermethylation of promoter regions is an early, progressive and cumulative event in gallbladder carcinogenesis. Furthermore, the methylation levels seems to accumulate in the progression of CC without metaplasia to CC with metaplasia, a fact that could provide new evidence to consider this morphological adaptation of GB mucosa as a premalignant lesion. Finally, the methylation status of some individual genes could be useful biomarkers with potential clinical application in diagnosis or prognosis of GBC if they are validated in a greater number of clinical samples.
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PMID:Promoter methylation profile in preneoplastic and neoplastic gallbladder lesions. 1854 80

Breast cancer is a group of clinically, histopathologically and molecularly heterogeneous diseases, with different outcomes and responses to treatment. Triple-negative (TN) breast cancers are defined as tumors that lack the expression of estrogen receptor, progesterone receptor and epidermal growth factor receptor 2. This subgroup accounts for 15% of all types of breast cancer and its prevalence is higher among young African, African-American and Latino women. The hypermethylation of CpG islands (CpGI) is a common epigenetic alteration for suppressing gene expression in breast cancer and has been shown to be a key factor in breast carcinogenesis. In this study we analyzed the hypermethylation of 110 CpGI within 69 cancer-related genes in TN tumors. For the methylation analysis, we used the methyl-specific multiplex-ligation probe amplification assay. We found that the number of methylated CpGI is similar between TN and non-TN tumors, but the methylated genes between the groups are different. The methylation profile of TN tumors is defined by the methylation of five genes (that is, CDKN2B, CD44, MGMT, RB and p73) plus the non-methylation of 11 genes (that is, GSTP1, PMS2, MSH2, MLH1, MSH3, MSH6, DLC1, CACNA1A, CACNA1G, TWIST1 and ID4). We conclude that TN tumors have a specific methylation profile. Our findings give new information for better understanding tumor etiology and encourage future studies on potential drug targets for triple-negative breast tumors, which now lack a specific treatment.
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PMID:Methylation profile of triple-negative breast carcinomas. 2355 34

Colorectal cancer (CRC) is characterized by specific patterns of copy number alterations (CNAs), which helped with the identification of driver oncogenes and tumor suppressor genes (TSGs). More recently, the usage of single nucleotide polymorphism arrays provided information of copy number neutral loss of heterozygosity, thus suggesting the occurrence of somatic uniparental disomy (UPD) and uniparental polysomy (UPP) events. The aim of this study is to establish an integrative profiling of recurrent UPDs/UPPs and CNAs in sporadic CRC. Our results indicate that regions showing high frequencies of UPD/UPP mostly coincide with regions typically involved in genomic losses. Among them, chromosome arms 3p, 5q, 9q, 10q, 14q, 17p, 17q, 20p, 21q and 22q preferentially showed UPDs/UPPs over genomic losses suggesting that tumor cells must maintain the disomic state of certain genes to favor cellular fitness. A meta-analysis using over 300 samples from The Cancer Genome Atlas confirmed our findings. Several regions affected by recurrent UPDs/UPPs contain well-known TSGs, as well as novel candidates such as ARID1A, DLC1, TCF7L2 and DMBT1. In addition, VCAN, FLT4, SFRP1 and GAS7 were also frequently involved in regions of UPD/UPP and displayed high levels of methylation. Finally, sequencing and fluorescence in situ hybridization analysis of the gene APC underlined that a somatic UPD event might represent the second hit to achieve biallelic inactivation of this TSG in colorectal tumors. In summary, our data define a profile of somatic UPDs/UPPs in sporadic CRC and highlights the importance of these events as a mechanism to achieve the inactivation of TSGs.
Carcinogenesis 2015 Oct
PMID:Patterns of somatic uniparental disomy identify novel tumor suppressor genes in colorectal cancer. 2624 11


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