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Results for “Cancer genomics”

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At least 145 records · Page 8Linked to original sources
PubMed1999

Detection of genomically-tagged cancer cells in different tissues at different stages of tumor development: lack of correlation with the formation of metastasis.

Genetic detection of tumor cells in blood, lymphatic nodes or bone marrow using reverse transcription and polymerase chain reaction (PCR) is quite attractive because it allows the early diagnosis of cancer dissemination. Unfortunately, this type of detection strategy cannot be applied to solid parenchymas, because they usually share with tumor cells the mRNA markers. To avoid this impediment, we have developed an experimental model of cancer using cells with a genome-associated tag. DHD/K12-PROb cancer cells were stably transfected with pcDNA3.1CAT. Approximately 10(6) transfected cells (DHD-CAT cells) were injected subcutaneously into the chest of BD-IX rats. Animals were divided into 11 groups according to the time between injection of tumor cells and euthanasia. An additional 'untagged group' was injected with untransfected cells (DHD-Wild). Blood and tissues samples were collected after euthanasia. Macroscopic and microscopic analysis was done. To detect circulating tumor cells or their presence in peripheral organs, we performed PCR with nested primers to amplify chloramphenicol acetyl transferase-encoding (CAT-encoding) DNA sequences. The minimum number of cells that yielded detectable cells routinely was 2 in 10(6). No modification of cancer aggressiveness was observed in DHD-CAT cells. DHD-CAT cells were detected by PCR in lung from the 1st week after inoculation, in liver, spleen and kidney from the 3rd week and in the blood from the 5th week. All animals analyzed 12 weeks after injection showed lung metastases. Metastases in liver, spleen or kidney, either microscopic or macroscopic, were never detected. We have developed an experimental model of cancer based on genomic tagging of tumor cells that allows the detection of small numbers of cells in all organs and the blood. The presence of cancer cells in parenchymas detected with molecular technology does not correlate with the development of clinically relevant metastases.

Adenocarcinoma↗
PubMed2004

Molecular features of the transition from prostatic intraepithelial neoplasia (PIN) to prostate cancer: genome-wide gene-expression profiles of prostate cancers and PINs.

To characterize the molecular feature in prostate carcinogenesis and the putative transition from prostatic intraepithelial neoplasia (PIN) to invasive prostate cancer (PC), we analyzed gene-expression profiles of 20 PCs and 10 high-grade PINs with a cDNA microarray representing 23,040 genes. Considering the histological heterogeneity of PCs and the minimal nature of PIN lesions, we applied laser microbeam microdissection to purify populations of PC and PIN cells, and then compared their expression profiles with those of corresponding normal prostatic epithelium also purified by laser microbeam microdissection. A hierarchical clustering analysis separated the PC group from the PIN group, except for three tumors that were morphologically defined as one very-high-grade PIN and two low-grade PCs, suggesting that PINs and PCs share some molecular features and supporting the hypothesis of PIN-to-PC transition. On the basis of this hypothesis, we identified 21 up-regulated genes and 63 down-regulated genes commonly in PINs and PCs compared with normal epithelium, which were considered to be involved in the presumably early stage of prostatic carcinogenesis. They included AMACR, OR51E2, RODH, and SMS. Furthermore, we identified 41 up-regulated genes and 98 down-regulated genes in the transition from PINs to PCs; those altered genes, such as POV1, CDKN2C, EPHA4, APOD, FASN, ITGB2, LAMB2, PLAU, and TIMP1, included elements that are likely to be involved in cell adhesion or the motility of invasive PC cells. The down-regulation of EPHA4 by small interfering RNA in PC cells lead to attenuation of PC cell viability. These data provide clues to the molecular mechanisms underlying prostatic carcinogenesis, and suggest candidate genes the products of which might serve as molecular targets for the prevention and treatment of PC.

Cell Division↗
PubMedDate not supplied

Genomic profiling in clinical oncology. The predictive value of genomic information in cancer management.

Genomic profiling is a significant addition to the clinician's armamentarium, enabling more specific diagnosis and targeted treatment of a wide range of diseases, including cancer. Although not yet widely used in a clinical setting, the new technology is providing detailed information about the particular genes expressed in malignant tissues. The predictive value of this information has been demonstrated in small clinical trials. The results of these and other groundbreaking studies are briefly reviewed.

Adult↗
PubMed1991

The modification and expression of 21-hydroxylase gene in normal human adrenal gland and adrenal cancer.

Genomic DNA and total RNA from three adrenal cancer tissues were analyzed by hybridization with human 21-hydroxylase gene. Southern blot analysis with restriction enzyme Eco RI revealed major fragments at 18, 13 and 9 kilobase (kb) in normal adrenal glands. In two of three adrenal cancers, however, the band at 18 kb was either absent or decreased and the 9 kb fragment showed an increase in its intensity. Normal liver, kidney and leucocytes has only 18 and 13 kb while lacking the 9 kb fragment. Using Taq I, Bam HI or Bgl II, we found no difference in restriction fragment patterns between adrenal cancer and normal tissues. Cleavage with Hpa II after digestion with Bgl II showed that significantly more DNA was digested into low-molecular weight fragments in adrenal cancer and the normal adrenal gland than those in other normal tissues. By Northern blot analysis, there was difference of signal intensity of hybridizing mRNA between the adrenal cancers and normal adrenal glands. These results suggest that the Eco RI site in the flanking region of the 21-hydroxylase gene may be modified in adrenal cancer tissue, and that inadequate 21-hydroxylase is present in some forms of adrenal cancers.

Adrenal Cortex Hormones↗
PubMed2005

Microarray comparative genomic hybridization profile of a murine model for epithelial ovarian cancer reveals genomic imbalances resembling human ovarian carcinomas.

Microarray comparative genomic hybridization (mCGH) is emerging as a high-resolution technology to detect gene dosage alterations in numerous pathologies, including cancer. We optimized cDNA microarrays to identify genome-wide imbalances in spontaneously transformed mouse ovarian surface epithelial cell lines, an in vitro murine model for ovarian cancer. Amplification of chromosome 19 and a more variable gain pattern of chromosomes 15 and 5 were detected and independently validated using conventional metaphase CGH. In addition, cryptic aberrations in segments of chromosomes 4, 7, 8, 9, 11, 17, and X, allowed identification of 2 related genomic variants among six cell lines studied. Mouse-human synteny revealed an overall early transformation stage with approximately 80% conservation relative to human ovarian malignancies of epithelial origin including low malignant potential tumors, serous carcinoma, and carcinoma cell lines. Importantly, three of the cells bear gained segments 13 and 41 Mbp length of chromosomes 5 and 15, respectively, which are syntenic to human 22q11-13, 8q24 and 12p11-q24, the two latter chromosomal regions thought to define one pathway of karyotypic changes in the development of human ovarian tumors. Our findings support the utility of mouse ovarian surface epithelial (MOSE) cells in studying initiation and progression of human ovarian cancer and as a suitable model to evaluate therapeutic approaches.

Animals↗
PubMed2002

Genomics and cancer.

Genetic and environmental factors are responsible for the genomic lesions that cause cancer, a complex genetic disease associated with genomic instability. Studies aimed at deciphering the lesions in cancer have focused mainly on one or a few genes, despite the genomic scope of the disease. The recently decoded human DNA sequence is anticipated to foster understanding of human evolution and disease and the role of environment and heredity in the human condition. This review addresses the opportunities and challenges that the availability of the human genome sequence holds for cancer research.

Genetic Therapy↗
PubMed1995

Microsatellite instability and pathological aspects of breast cancer.

Genomic instability plays a key role in hereditary nonpolyposis colorectal cancer and in a significant sub-set of non-hereditary colorectal tumors. Recent evidence suggests that microsatellite instability also occurs in various sub-sets of common, non-hereditary forms of extra-colorectal carcinoma. To investigate the role of microsatellite instability in breast cancer, and to correlate this type of alteration with clinico-pathological characteristics, including tumor proliferative activity, we analyzed the status of 8 different microsatellite loci in 28 cases of primary mammary carcinoma. For this purpose, microsatellite banding patterns were compared in paired breast-cancer/peripheral-blood DNA samples. Microsatellite instability was observed in 6/28 (21%) of the cases. Four of the 6 tumors had low proliferative activity, one had high proliferative activity, and in one case proliferative activity values were not available. All chromosomal loci investigated demonstrated microsatellite instability in one or more representative tumors of the series. Shifts in length larger than 2 bp were the most frequent change. Microsatellite instability significantly correlated with the lobular histotype, and with lymph-node involvement. A trend was also observed associating microsatellite instability and large tumor size.

Adult↗
PubMed2004

CDC91L1 (PIG-U) is a newly discovered oncogene in human bladder cancer.

Genomic amplification at 20q11-13 is a common event in human cancers. We isolated a germline translocation breakpoint at 20q11 from a bladder cancer patient. We identified CDC91L1, the gene encoding CDC91L1 (also called phosphatidylinositol glycan class U (PIG-U), a transamidase complex unit in the glycosylphosphatidylinositol (GPI) anchoring pathway), as the only gene whose expression was affected by the translocation. CDC91L1 was amplified and overexpressed in about one-third of bladder cancer cell lines and primary tumors, as well as in oncogenic uroepithelial cells transformed with human papillomavirus (HPV) E7. Forced overexpression of CDC91L1 malignantly transformed NIH3T3 cells in vitro and in vivo. Overexpression of CDC91L1 also resulted in upregulation of the urokinase receptor (uPAR), a GPI-anchored protein, and in turn increased STAT-3 phosphorylation in bladder cancer cells. Our findings suggest that CDC91L1 is an oncogene in bladder cancer, and implicate the GPI anchoring system as a potential oncogenic pathway and therapeutic target in human cancers.

Animals↗
PubMed1997

Apparent protection from instability of repeat sequences in cancer-related genes in replication error positive gastrointestinal cancers.

Genomic instability at simple repeated sequences has been observed in various types of human cancers and is considered an important mechanism in tumorigenesis. Alterations at microsatellite loci have been reported scattered throughout the genome. Recently, the transforming growth factor-beta receptor type II (TGF-beta RII) and the insulin-like growth factor II receptor (IGF-IIR) genes were shown to have inactivating mutations within coding microsatellite sequences. The demonstration of mutations in two growth regulatory genes supports the idea that other regulatory genes with repeat sequences may also be targets in tumours with defective mismatch repair. We examined genes involved in tumour suppression, cell adhesion and cell cycle regulation for mutations at small repeat sequences in replication error positive gastrointestinal cancers. Several polymorphisms were found which exhibited instability, but no other instability was present in the regions examined.

Activin Receptors, Type I↗
PubMed2001

Cancer and genomics.

Identification of the genes that cause oncogenesis is a central aim of cancer research. We searched the proteins predicted from the draft human genome sequence for paralogues of known tumour suppressor genes, but no novel genes were identified. We then assessed whether it was possible to search directly for oncogenic sequence changes in cancer cells by comparing cancer genome sequences against the draft genome. Apparently chimaeric transcripts (from oncogenic fusion genes generated by chromosomal translocations, the ends of which mapped to different genomic locations) were detected to the same degree in both normal and neoplastic tissues, indicating a significant level of false positives. Our experiment underscores the limited amount and variable quality of DNA sequence from cancer cells that is currently available.

Base Sequence↗
PubMed2003

Anticancer drug discovery using chemical genomics.

Cancer is the leading cause of death in United States and World wide. Drug discovery and development for cancer therapeutics takes several years before a patient is benefited from a new drug. The average time length from start to finish is approximately 15 years. This time length includes 4-5 years of basic research, discovery, preclinical development and validation studies. Next, it takes approximately 7-10 years for a drug to go through human clinical trials. This time length is too long and need to be shortened to benefit patients quickly from new technologies and product development ideas. Furthermore, with the recent explosion of genomics and proteomics information, it is now becoming difficult to make rapid and logical decisions on hundreds of potential drug targets available. Thus, there is immediate need to develop and integrate tools and technologies that will not only reduce the time length but also the risk of late clinical drug failure. Chemical Genomics is an emerging field in which tools and technologies from biology and chemistry are utilized in a parallel and cyclic fashion very early in the development process. In addition chemical genomics proposes to integrate latest developments in tools and technologies from a variety of modern fields such as combinatorial chemistry, informatics, synthesis chemistries, cell based assays, microarrays, genomics and proteomics tools to accelerate drug discovery and development. Thus, in cancer therapeutics the aim of chemical genomics is not only to reduce the time length of pre-clinical development but also the risk of late clinical failure by making smart decisions early in the process.

Animals↗
PubMed2004

Mutation analysis of the 8p candidate tumour suppressor genes DBC2 (RHOBTB2) and LZTS1 in bladder cancer.

Genomic deletions of the short arm of chromosome 8 are common in many human cancers and are frequently associated with a more aggressive tumour phenotype. One of the regions of loss of heterozygosity (LOH) on 8p22 identified in bladder cancer contains two genes, LZTS1 (FEZ1) and DBC2 (RHOBTB2) that have been shown to be mutated at low frequency in other cancers. We screened a panel of bladder tumours and bladder tumour-derived cell lines for mutations in these genes. Forty two percent of the tumours were found to have LOH in the 8p22 region and many of the cell lines have known loss of 8p. Several known polymorphisms and novel polymorphisms were detected. One possible mutation of LZTS1 (G374S) was found in a cell line. The functional significance of this is unknown but the novel serine residue created may represent a novel phosphorylation site. In DBC2, we found a single somatic mutation in a tumour (E349D) that lies in a highly conserved region of the protein. mRNA levels for both genes were reduced in the majority of bladder cancer cell lines. We conclude that neither LZTS1 nor DBC2 is commonly mutated in bladder cancer. However, neither can yet be excluded as the target of 8p22 LOH. The finding of a somatic mutation of DBC2 in a tumour sample and the down-regulation of both gene transcripts in bladder tumour cell lines may indicate that an alternative mechanism of inactivation of the second allele, for example promoter hypermethylation, is more common than mutation and this must now be examined.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Highlights from the Society of Urologic Oncology 4th annual meeting.

PURPOSE: The 4th annual meeting of the Society of Urologic Oncology (SUO) was held December 5-6, 2003 in Bethesda, Maryland. The meeting was attended by urologists, medical and radiation oncologists, and researchers whose focus is genitourinary (GU) malignancies. More than 500 participants registered for the meeting. MATERIALS AND METHODS: The agenda for the SUO meeting included more than 50 speakers and discussion panels, and addressed a broad range of topics in GU oncology. Transcripts of the proceedings and submitted slide presentations were reviewed for content following the meeting, and the highlights were summarized. These written materials can be accessed through the SUO web site at http://societyofurologiconcology.org. RESULTS: Reviewed session topics included epidemiology of GU malignancies, biomarkers for GU malignancies, cancer genomics, bladder cancer, testis cancer, minimally invasive treatments for GU malignancies, molecular therapeutics and advanced prostate cancer. Significant advances in these fields have directly impacted clinical care and improved patient outcomes across the many disciplines associated with treatment of GU cancers. CONCLUSIONS: The SUO meeting is unique in its multidisciplinary forum and focus on urological oncology. The 2003 meeting highlighted recent advances in epidemiology, clinical management and emerging molecular approaches in the diagnosis and treatment of urological malignancies with several state-of-the-art presentations.

Humans↗
PubMed1996

Monoallelic expression of the insulin-like growth factor-2 gene in ovarian cancer.

Genomic imprinting is defined as a gamete-specific modification causing differential expression of the two alleles of a gene in somatic cells and is becoming increasingly recognized as playing an important role in a number of human diseases including cancer. We have reported that the loss of the insulin-like growth factor-2 (IGF2) gene imprinting results in the deregulation of both IGF2 alleles, which may contribute to the onset of Wilms tumor. It is important to see whether such abnormal genomic imprinting is implicated in the etiology of common adulthood cancers. In the present study we have examined the expression level and imprinting status of the IGF2 gene in human ovaries and ovarian cancers. We confirm that IGF2 is significantly expressed in ovaries and ovarian cancers. In normal ovaries, both surface epithelium and the ovary proper demonstrate monoallelic IGF2 expression. Among 27 tumors, all 11 heterozygous for the IGF2 locus show monoallelic IGF2 expression (2 of them are proven to be from the paternal allele). The data suggest that the increased IGF2 gene expression in ovarian cancer may be achieved by a mechanism other than loss of imprinting.

Alleles↗
PubMed2004

Allelic variation of BAT-25 and BAT-26 mononucleotide repeat loci in tumours from a group of young women with breast cancer.

Genomic instability in the form of repeat number variation at microsatellite loci has been reported in several human cancers. To resolve current confusion regarding frequency of microsatellite instability (MSI), standardised protocols have proposed use of a consensus set of informative loci; it is claimed that analysis of 2 apparently quasi-homozygous, quasi-monomorphic, mononucleotide repeats (BAT-25 and BAT-26) is sufficiently accurate to define MSI (obviating need for corresponding constitutive DNA). We examined these loci in 163 breast cancers, 108 of which had previously been analysed at 11-24 other loci and found to have MSI in 38% of them. For BAT-26 only 1/153 (homozygous) tumours showed a contracted allele, with minor size variations (1-6 bp) between individuals. For BAT-25 repeat contractions were unambiguously observed in 12 (7.4%) tumours; only 4 of these were previously designated MSI+. DNA from normal individuals showed significant allelic variation in 8/159 (5%) cases for BAT-25; no instance of heterozygosity was seen for BAT-26. Subsequently, we analysed normal DNA from the 12 individuals whose tumours had MSI at BAT-25; in 2 cases there was germline heterozygosity. We conclude that analysis with BAT-26 (in contrast to other loci) was not a useful detector of MSI. With BAT-25, a low frequency of MSI not much greater than germline polymorphism, also limits the utility of this marker for determining MSI in breast cancer.

Alleles↗
PubMed2002

Cytotoxic agents in the era of molecular targets and genomics.

Cancer treatment is evolving due to the development of molecularly targeted agents and the utilization of pharmacogenomics and pharmacogenetics to identify patients who are at an increased risk for toxicity or may be uniquely responsive to cytotoxic therapies. By identifying polymorphisms in the human genome that confer changes in the ability to metabolize or activate cancer agents, a more patient-specific treatment approach can be initiated. Molecularly targeted therapies such as PS-341, flavopiridol, Iressa, and anti-vascular endothelial growth factor antibodies may help to overcome resistance to cytotoxic therapies by lowering the apoptotic threshold and increasing cytotoxicity. Using molecularly targeted agents in combination with traditional cytotoxic agents may increase the percentage of patients who achieve disease stabilization and prolonged survival. With the development of genetic tools and genotyping of tumor and patient prior to initiating treatment, antitumor efficacy may be increased with a substantial reduction in toxicity.

Antineoplastic Agents, Alkylating↗
PubMed2004

Importance of DNA repair in tumor suppression.

The transition from a normal to cancerous cell requires a number of highly specific mutations that affect cell cycle regulation, apoptosis, differentiation, and many other cell functions. One hallmark of cancerous genomes is genomic instability, with mutation rates far greater than those of normal cells. In microsatellite instability (MIN tumors), these are often caused by damage to mismatch repair genes, allowing further mutation of the genome and tumor progression. These mutation rates may lie near the error catastrophe found in the quasispecies model of adaptive RNA genomes, suggesting that further increasing mutation rates will destroy cancerous genomes. However, recent results have demonstrated that DNA genomes exhibit an error threshold at mutation rates far lower than their conservative counterparts. Furthermore, while the maximum viable mutation rate in conservative systems increases indefinitely with increasing master sequence fitness, the semiconservative threshold plateaus at a relatively low value. This implies a paradox, wherein inaccessible mutation rates are found in viable tumor cells. In this paper, we address this paradox, demonstrating an isomorphism between the conservatively replicating (RNA) quasispecies model and the semiconservative (DNA) model with post-methylation DNA repair mechanisms impaired. Thus, as DNA repair becomes inactivated, the maximum viable mutation rate increases smoothly to that of a conservatively replicating system on a transformed landscape, with an upper bound that is dependent on replication rates. On a specific single fitness peak landscape, the repair-free semiconservative system is shown to mimic a conservative system exactly. We postulate that inactivation of post-methylation repair mechanisms is fundamental to the progression of a tumor cell and hence these mechanisms act as a method for the prevention and destruction of cancerous genomes.

Animals↗
PubMed1999

Associations among telomerase activity, p53 protein overexpression, and genetic instability in lung cancer.

Genomic instability is a driving force for tumorigenesis. p53 and telomerase play central roles in maintaining genomic integrity. The purpose of this study was to assess the associations among p53 protein overexpression, telomerase activity and genetic instability in lung cancer. We found that telomerase activity was detectable in 80% of 100 lung tumours, but only 7.7% of 91 paired adjacent normal tissues. p53 protein was overexpressed in 63% of the tumours but only 2% of the normal tissues. p53 was overexpressed in 56 of the 80 (70%) tumour tissues with telomerase activity but only seven of the 20 (35%) without telomerase activity. p53 protein overexpression carried a 6.7-fold (95% confidence interval, 1.7-27.7) increased risk for positive telomerase activity after adjustment by age, sex, ethnicity, smoking status and family history of lung cancer. The mean in vitro bleomycin-induced breaks per cell (a marker of cancer susceptibility) was significantly higher (0.92) for patients who overexpressed p53 in lung tumour tissue than that for patients with no detectable p53 expression in lung tumour tissue (0.65). Our data suggest that p53 protein overexpression may be common in individuals genetically susceptible to carcinogen exposure. p53 status may be related to telomerase expression.

Adult↗