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At least 325 records · Page 18Linked to original sources
PubMed2002

Identification of amplified and expressed genes in breast cancer by comparative hybridization onto microarrays of randomly selected cDNA clones.

Microarray analysis using sets of known human genes provides a powerful platform for identifying candidate oncogenes involved in DNA amplification events but suffers from the disadvantage that information can be gained only on genes that have been preselected for inclusion on the array. To address this issue, we have performed comparative genome hybridization (CGH) and expression analyses on microarrays of clones, randomly selected from a cDNA library, prepared from a cancer containing the DNA amplicon under investigation. Application of this approach to the BT474 breast carcinoma cell line, which contains amplicons at 20q13, 17q11-21, and 17q22-23, identified 50 amplified and expressed genes, including genes from these regions previously proposed as candidate oncogenes. When considered together with data from microarray expression profiles and Northern analyses, we were able to propose five genes as new candidate oncogenes where amplification in breast cancer cell lines was consistently associated with higher levels of RNA expression. These included the HB01 histone acetyl transferase gene at 17q22-23 and the TRAP100 gene, which encodes a thyroid hormone receptor-associated protein coactivator, at 17q11-21. The results demonstrate the utility of this microarray-based CGH approach in hunting for candidate oncogenes within DNA amplicons.

Breast Neoplasms↗
PubMed2002

Somatic mitochondrial DNA mutations in human chromophobe renal cell carcinomas.

We sequenced the entire mitochondrial genome in 8 chromophobe renal cell carcinomas (RCCs) and corresponding normal kidneys. Our study disclosed 68 known and 45 new sequence variations occurring 132 and 45 times, respectively. We found 6 somatic nucleotide changes in 5 out of the 8 chromophobe RCCs. One A --> T substitution occurred in the D-loop region and an insertion of a 9-bp sequence in the noncoding region of the MTNC7. One G --> A substitution and one C --> T substitution were seen in the MTRNR1 and MTRNR2 genes, respectively. One C deletion in MTND5 and one T insertion in the MTND3 gene resulted in frameshift mutations in two tumors. All somatic alterations, with the exception of the 9-bp insertion, were heteroplasmic changes. Although somatic mtDNA mutations are found in chromophobe RCCs, their role in the maintenance of tumor cell phenotype or in tumorigenesis remains to be elucidated.

Carcinoma, Renal Cell↗
PubMed2004

Multistep tumorigenesis and the microenvironment.

Early-stage cancers have long been considered to be less aggressive than late-stage cancers because it is assumed that they have accumulated fewer of the mutations that are required for full metastatic potential. For breast cancer, recent gene expression profiling data have challenged this paradigm by identifying early-stage cancers with similar gene expression profiles to fully metastatic cancers. In this review, multistep carcinogenesis is reconsidered in light of these new data. The concept that the tumor stroma plays a key role in determining whether a metastatic tumor cell will remain dormant or become invasive is discussed. Recent studies demonstrating the feasibility of targeting tumor stroma for cancer prevention and treatment are presented.

Animals↗
PubMed2006

Accelerated growth of intestinal tumours after radiation exposure in Mlh1-knockout mice: evaluation of the late effect of radiation on a mouse model of HNPCC.

Mlh1-knockout mice have been developed as a useful model of hereditary non-polyposis colorectal cancer (HNPCC). In this study, we analyzed the pathology of gastrointestinal tumours (GIT) in these mice in detail and examined the possible effects of ionizing radiation on the induction of intestinal tumours to evaluate the late response to radiotherapy in HNPCC. Mlh1-/- mice spontaneously developed GIT and thymic lymphomas by 48 weeks. GIT included not only well differentiated adenocarcinomas but also poorly differentiated and mucinous adenocarcinomas, suggesting that this mouse is a good model for HNPCC. In contrast to colon cancers from HNPCC patients, however, carcinomas of Mlh1-/- mice expressed p53 and showed a lack of transforming growth factor (TGF)-betaRII mutation, which resulted in the expression of TGF-betaRII protein. Irradiation of 10-week-old Mlh1-/- mice accelerated GIT development but had little effect at 2 weeks. Mlh1+/- and Mlh1+/+ mice were not susceptible to spontaneous or radiation-induced thymic lymphomas and GIT until 72 weeks after birth. The development and pathology of GIT in Mlh1-/- mice suggest that this mouse is a good model for HNPCC, although tumour-related responsible genes might be different from HNPCC. As X-ray exposure promoted carcinogenesis of GIT in adult Mlh1-/- mice, an increased risk of secondary cancers after radiotherapy for HNPCC patients should be taken into consideration.

Adaptor Proteins, Signal Transducing↗
PubMed1998

Cloning of a new Kunitz-type protease inhibitor with a putative transmembrane domain overexpressed in pancreatic cancer.

In a previous large scale screen for differentially expressed genes in pancreatic cancer, we identified a gene highly overexpressed in cancer encoding a novel putative transmembrane protein with two Kunitz-type serine protease inhibitor domains. The identified gene named kop (Kunitz domain containing protein overexpressed in pancreatic cancer) was assigned to chromosome 19 in the region 19q13.1. Kop was detected at high levels in pancreatic cancer cell lines and was overexpressed in pancreatic cancer tissues as compared to both, normal pancreas and chronic pancreatitis tissues. Being a member of the Kunitz-type serine protease inhibitor family, this new gene may participate in tumour cell invasion and metastasis and in the development of the marked desmoplastic reaction typical for human pancreatic cancer tissues. In this context, the fact that kop has a putative transmembrane domain may have functional implications of particular interest.

Adenocarcinoma↗
PubMed2006

[Gene therapy approaches to gastrointestinal tumors].

Gene therapy offers an elegant alternative to toxic chemotherapy regimens, mostly without severe side effects. Gene therapy for cancer was one of the first applications. Following the enthusiasm in the early 1990 s, a more rationale view is preferred today. This general review looks at the tools of gene therapy and their principle elements (vector, promoter, targeting, therapeutic genes). The principles of gene therapy such as gene-directed enzyme prodrug therapy (GDEPT) and gene-directed tumor vaccination are explained. Furthermore, published protocols and clinical studies in gastrointestinal oncology are reviewed. Finally, an outlook is given on the latest developments, some of them going beyond the realm of conventional gene therapy.

Gastrointestinal Neoplasms↗
PubMed1999

[Individual predisposition to lung neoplasm--the role of genes involved in metabolism of carcinogens].

Molecular epidemiology of lung cancer analyses relationship between environment and individual susceptibility. Studying biomarkers of risk at the molecular level allows better understanding of chemical carcinogenesis processes and makes possible early detection of the disease as well as helps its prevention. Risk biomarkers include genetic polymorphism of CYP, GST and NAT genes that participate in metabolic biotransformation of various endo- and exogenous compounds including carcinogens. Exposure to potentially carcinogenic environmental factors plays an important role in etiology of lung cancer, which remains a leading cause of cancer death worldwide. This review presents current knowledge about molecular basis and impact of individual variations in carcinogen metabolism on lung cancer risk.

Biomarkers, Tumor↗
PubMed2003

Fast and sensitive multiple alignment of large genomic sequences.

BACKGROUND: Genomic sequence alignment is a powerful method for genome analysis and annotation, as alignments are routinely used to identify functional sites such as genes or regulatory elements. With a growing number of partially or completely sequenced genomes, multiple alignment is playing an increasingly important role in these studies. In recent years, various tools for pair-wise and multiple genomic alignment have been proposed. Some of them are extremely fast, but often efficiency is achieved at the expense of sensitivity. One way of combining speed and sensitivity is to use an anchored-alignment approach. In a first step, a fast search program identifies a chain of strong local sequence similarities. In a second step, regions between these anchor points are aligned using a slower but more accurate method. RESULTS: Herein, we present CHAOS, a novel algorithm for rapid identification of chains of local pair-wise sequence similarities. Local alignments calculated by CHAOS are used as anchor points to improve the running time of DIALIGN, a slow but sensitive multiple-alignment tool. We show that this way, the running time of DIALIGN can be reduced by more than 95% for BAC-sized and longer sequences, without affecting the quality of the resulting alignments. We apply our approach to a set of five genomic sequences around the stem-cell-leukemia (SCL) gene and demonstrate that exons and small regulatory elements can be identified by our multiple-alignment procedure. CONCLUSION: We conclude that the novel CHAOS local alignment tool is an effective way to significantly speed up global alignment tools such as DIALIGN without reducing the alignment quality. We likewise demonstrate that the DIALIGN/CHAOS combination is able to accurately align short regulatory sequences in distant orthologues.

Algorithms↗
PubMed1980

Differential expression of H-2 gene products in tumour cells in associated with their metastatogenic properties.

Many neoplasms seem to be heterogeneous in nature, producing metastases by pre-existing variant cells with inherent biochemical and biological properties. The survival and proliferation of metastatic cells depend on various biological properties, such as enzymes which degrade basement membranes, resistance to various host defence systems, association with host cellular components, adhesiveness and expression of certain membrane glycoproteins. Recent studies have indicated that metastatic cells may differ from the local tumour cells in the expression of immune recognizable membrane-associated antigens. Such antigenic differences may result from an immunoselection of cells with distinct antigenic properties due to a specific immune response evoked against the local tumour. In view of the role of the major histocompatibility complex (MHC) system in controlling and restricting the function of immune effector cells against modified self-components, one could assume that the modulation of the expression of MHC-encoded antigens on the membrane of tumour cells influenced the interclonal relationship within a local heterogeneous tumour cell population and the subsequent generation of metastasis. The modulation of the expression of H-2 antigens on several murine tumours is well documented; however, practically no attempts were made to relate H-2 modulation with invasiveness. We now describe principal differences in the expression of H-2 parental haplotypes between a local F1 methylcholanthrene-induced tumour and its descendant pulmonary metastases. These results suggest that both the expression and the immunogenicity of MHC products strongly influence the immune relationship between the tumour and the host's immune system, thus determining the generation and dissemination of metastases.

Animals↗
PubMed2000

Cytolytic T lymphocytes raised against a human bladder carcinoma recognize an antigen encoded by gene MAGE-A12.

Human bladder carcinoma line LB831-BLC expresses several distinct Ags that are recognized by different autologous CTL. Here, we show that one of these Ags is presented by HLA-Cw7 and encoded by gene MAGE-A12. This is the first time that CTL directed against a MAGE-encoded Ag have been derived from the lymphocytes of a patient with cancer other than melanoma. This new Ag was found to be nonapeptide VRIGHLYIL, corresponding to position 170-178 of the MAGE-A12 protein. Gene MAGE-A12 is silent in normal tissues except in male germline cells, which do not express HLA molecules. It is expressed in 26-62% of melanomas, infiltrating bladder carcinomas, lung carcinomas, esophageal carcinomas, and head and neck carcinomas. Because HLA-Cw7 is present in 43% of Caucasians, this new Ag is shared by many tumors and should be a useful target for cancer immunotherapy.

Aged↗
PubMed2005

Dominant negative effects of the AML1/ETO fusion oncoprotein.

The t(8;21)(q22;q22) translocation, present in 10-15% of acute myeloid leukemia (AML) cases results in the production of the AML1/ETO fusion protein. Expression of AML1/ETO in patients or mouse models is not sufficient to induce AML. Despite convincing evidence that AML1/ETO is directly involved in the pathogenesis of AML, the underlying mechanism is not well understood. Genetic and biochemical experiments suggest that AML1/ETO is a dominant inhibitor of the core binding factor (CBF) transcription complex that includes AML1 (RUNX1), the N-terminal fusion partner in the t(8;21). We generated and recently characterized a novel strain of transgenic mice in which the AML1/ETO cDNA was inserted into the Ly-6A gene that encodes Sca1, a well-characterized marker of murine hematopoietic stem cells. Unexpectedly, transgene expression assessed by flow cytometry was significantly lower than predicted in lymphocytes from these mice. We have confirmed this finding at the mRNA level and suggest that this phenotype is a consequence of dominant inhibition of transgene expression by AML1/ETO. The dominant negative characteristics of AML1/ETO may be important for AML pathogenesis and may provide a molecular target for therapeutic intervention.

Acute Disease↗
PubMed2004

Multiclass discovery in array data.

BACKGROUND: A routine goal in the analysis of microarray data is to identify genes with expression levels that correlate with known classes of experiments. In a growing number of array data sets, it has been shown that there is an over-abundance of genes that discriminate between known classes as compared to expectations for random classes. Therefore, one can search for novel classes in array data by looking for partitions of experiments for which there are an over-abundance of discriminatory genes. We have previously used such an approach in a breast cancer study. RESULTS: We describe the implementation of an unsupervised classification method for class discovery in microarray data. The method allows for discovery of more than two classes. We applied our method on two published microarray data sets: small round blue cell tumors and breast tumors. The method predicts relevant classes in the data sets with high success rates. CONCLUSIONS: We conclude that the proposed method is accurate and efficient in finding biologically relevant classes in microarray data. Additionally, the method is useful for quality control of microarray experiments. We have made the method available as a computer program.

Breast Neoplasms↗
PubMed2006

A genome-wide map of aberrantly expressed chromosomal islands in colorectal cancer.

BACKGROUND: Cancer development is accompanied by genetic phenomena like deletion and amplification of chromosome parts or alterations of chromatin structure. It is expected that these mechanisms have a strong effect on regional gene expression. RESULTS: We investigated genome-wide gene expression in colorectal carcinoma (CRC) and normal epithelial tissues from 25 patients using oligonucleotide arrays. This allowed us to identify 81 distinct chromosomal islands with aberrant gene expression. Of these, 38 islands show a gain in expression and 43 a loss of expression. In total, 7.892 genes (25.3% of all human genes) are located in aberrantly expressed islands. Many chromosomal regions that are linked to hereditary colorectal cancer show deregulated expression. Also, many known tumor genes localize to chromosomal islands of misregulated expression in CRC. CONCLUSION: An extensive comparison with published CGH data suggests that chromosomal regions known for frequent deletions in colon cancer tend to show reduced expression. In contrast, regions that are often amplified in colorectal tumors exhibit heterogeneous expression patterns: even show a decrease of mRNA expression. Because for several islands of deregulated expression chromosomal aberrations have never been observed, we speculate that additional mechanisms (like abnormal states of regional chromatin) also have a substantial impact on the formation of co-expression islands in colorectal carcinoma.

Chromosome Aberrations↗
PubMed1996

The FHIT gene, spanning the chromosome 3p14.2 fragile site and renal carcinoma-associated t(3;8) breakpoint, is abnormal in digestive tract cancers.

A 200-300 kb region of chromosome 3p14.2, including the fragile site locus FRA3B, is homozygously deleted in multiple tumor-derived cell lines. Exon amplification from cosmids covering this deleted region allowed identification of the human FHIT gene, a member of ther histidine triad gene family, which encodes a protein with 69% similarity to an S. pombe enzyme, diadenosine 5', 5''' P1, P4-tetraphosphate asymmetrical hydrolase. The FHIT locus is composed of ten exons distributed over at least 500 kb, with three 5' untranslated exons centromeric to the renal carcinoma-associated 3p14.2 breakpoint, the remaining exons telomeric to this translocation breakpoint, and exon 5 within the homozygously deleted fragile region. Aberrant transcripts of the FHIT locus were found in approximately 50% of esophageal, stomach, and colon carcinomas.

Acid Anhydride Hydrolases↗
PubMed2006

Microsatellite instability in colorectal cancer.

BACKGROUND: Microsatellite instability (MSI) causes hereditary non-polyposis colorectal cancer (HNPCC), and occurs in about 15 per cent of sporadic colorectal cancers. Although the basic mechanisms are not clear, there is increased understanding of the clinicopathological consequences of MSI. METHODS: Medline was searched for articles with a combination of keywords relating to MSI in colorectal cancer, focusing on molecular mechanisms, clinicopathological implications, and prognostic and predictive value. Emphasis was placed on articles from the past 5 years. RESULTS: The genetic mechanisms differ in hereditary (germline mutation) and sporadic (epigenetic silencing) colorectal cancer. The MSI pathway frequently has altered transforming growth factor beta receptor II and BAX genes, often beta-catenin, and occasionally p16INK4A and PTEN. Changes in K-ras, adenomatous polyposis coli and p53 are rare. Polymerase chain reaction testing for MSI is superior to immunohistochemistry, but complicated by the number and types of nucleotide markers. The Bethesda panel guides HNPCC testing, but guidelines are lacking for general screening. The presence and role of low-frequency MSI remains controversial. Tumours with MSI tend to occur in the proximal colon and be large, but they have a good prognosis. Their reduced response to adjuvant chemotherapy requires confirmation. CONCLUSION: Research on colorectal cancer needs to be stratified according to microsatellite status in order further to explore the molecular mechanisms and clinicopathological consequences of MSI.

Base Pair Mismatch↗