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 13,001 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The B-cell lymphoproliferative malignancies B-cell chronic lymphocytic leukemia (B-CLL) and mantle cell lymphoma (MCL) share characteristics, including overlapping chromosomal aberrations with deletions on chromosome bands 13q14, 11q23, 17p13, and 6q21 and gains on chromosome bands 3q26, 12q13, and 8q24. To elucidate the biochemical processes involved in the pathogenesis of B-CLL and MCL, we analyzed the expression level of a set of genes that play central roles in apoptotic or cell proliferation pathways and of candidate genes from frequently altered genomic regions, namely ATM, BAX, BCL2, CCND1, CCND3, CDK2, CDK4, CDKN1A, CDKN1B, E2F1, ETV5, MYC, RB1, SELL, TFDP2, TNFSF10, and TP53. Performing real-time quantitative reverse transcription polymerase chain reaction in a panel of patients with MCL and B-CLL and control samples, significant overexpression and underexpression was observed for most of these genes. Statistical analysis of the expression data revealed the combination of CCND1 and CDK4 as the best classifier concerning separation of both lymphoma types. Overexpression in these malignancies suggests ETV5 as a new candidate for a pathogenic factor in B-cell lymphomas. Characteristic deregulation of multiple genes analyzed in this study could be combined in a comprehensive picture of 2 distinctive pathomechanisms in B-CLL and MCL. In B-CLL, the expression parameters are in strong favor of protection of the malignant cells from apoptosis but did not provide evidence for promoting cell cycle. In contrast, in MCL the impairment of apoptosis induction seems to play a minor role, whereas most expression data indicate an enhancement of cell proliferation.
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PMID:Evidence for distinct pathomechanisms in B-cell chronic lymphocytic leukemia and mantle cell lymphoma by quantitative expression analysis of cell cycle and apoptosis-associated genes. 1203 88

As many as 5% of human cancers appear to be of hereditable etiology. Of the more than 50 characterized familial cancer syndromes, most involve disease affecting multiple organs and many can be traced to one or more abnormalities in specific genes. Studying these syndromes in humans is a difficult task, especially when it comes to genes that may manifest themselves early in gestation. It has been made somewhat easier with the development of genetically engineered mice (GEM) that phenotypically mimic many of these inheritable human cancers. The past 15 years has seen the establishment of mouse lines heterozygous or homozygous null for genes known or suspected of being involved in human cancer syndromes, including APC, ATM, BLM, BRCA1, BRCA2, LKB1, MEN1, MLH, MSH, NF1, TP53, PTEN, RB1, TSC1, TSC2, VHL, and XPA. These lines not only provide models for clinical disease and pathology, but also provide avenues to investigate molecular pathology, gene-gene and protein-tissue interaction, and, ultimately, therapeutic intervention. Possibly of even greater importance, they provide a means of looking at placental and fetal tissues, where genetic abnormalities are often first detected and where they may be most easily corrected. We will review these mouse models, examine their usefulness in medical research, and furnish sources of animals and references.
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PMID:Mouse models of human familial cancer syndromes. 1520 8

The clonal origin of multiple tumors in the same individual has long been debated. The main aim of this study is to find out whether multiple tumors in same individuals originated from a single clone. In our previous work (Pathol. Res. Pract. 199 (2003) 313-321), the deletion at chromosome1p36 was found to occur early because of common allelic loss in the bilateral tumors. In order to further investigate the findings about the clonality of tumors, eight tumors from four patients (two synchronous bilateral breast carcinoma [biBC], one case with breast carcinoma in one breast and multiple calcified fibroadenoma nodules in another breast, and one case with multifocal fibroadenosis in one breast) were subjected to polymerase chain reaction (PCR) to detect (a) loss of heterozygosity (LOH) and microsatellite size alterations (MA) using microsatellite markers distributed over five chromosomal arms 11p/q, 13q and 17p/q, and (b) Cyclin D1 amplification. Some markers were intragenic for BRCA1, BRCA2, BRCAX, ATM, TP53, and RB1. Although a few cases were studied, our findings suggest that in at least a proportion of patients multiple tumors may arise from a single clone.
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PMID:Molecular study of clonality in multifocal and bilateral breast tumors. 1564 12

The average length of linkage disequilibrium (LD) blocks in European populations is about 22 kb. In this study, we have selected 20 genes with LD blocks larger than 60 kb (with a median length of 88 kb) from a total of 121 cancer-related genes. We observed limited haplotype diversity, with an average of three haplotypes per gene accounting for more than 90% of the diversity, two of these being a Yin-Yang pair in 95% of the LD blocks. The mean frequency of the most common haplotype in the Spanish population was just below 50%, similar to those for the HapMap CEU and African samples, but lower than the 60% observed in Asian samples. Genes involved in the regulation of nucleobases and nucleic acid metabolism were overrepresented among these 20 genes with long LD blocks (eight genes ATM, BRCA1, BRCA2, ERCC6, MLH1, MSH3, RAD54B and XRCC4) relative to the other 101 cancer-related genes studied (P=1.23 x 10(-6)). The ancestral haplotype was observed at a frequency greater than 3 in 67% of the genes either in the Spanish or one of the HapMap sampled populations. When observed, the ancestral haplotype had an average 15% frequency in the Spanish sample, less than half that observed in Asian and African samples. The Spanish Yin-Yang haplotype pair represented over 35% of haplotypes in African samples and over 65% in non-African samples. We detected differences in SNP frequencies between populations for five genes (ALDH2, APC, PIK3CB, RB1 and XRCC4, all with Fst>0.4); however, these genes did not show evidence of positive selection. Finally, we found no evidence that the haplotypes formed by SNPs in the 20 genes are associated with breast cancer.
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PMID:Haplotype patterns in cancer-related genes with long-range linkage disequilibrium: no evidence of association with breast cancer or positive selection. 1800 May 25

Mantle cell lymphoma (MCL) is a well-defined lymphoid neoplasm characterized by a proliferation of mature B lymphocytes expressing CD5 that may show a spectrum of morphological and phenotypic features broader than initially described. Although some patients may follow an indolent clinical evolution, in most of them the tumour has an aggressive behaviour with poor response to conventional chemotherapy. The genetic hallmark is the t(11;14)(q13;q32) translocation leading to the overexpression of cyclin D1, which is considered the initial oncogenic event. In addition to this translocation, MCL may carry a high number of secondary chromosomal and molecular alterations that target regulatory elements of the cell cycle machinery and senescence (BMI1/INK4/ARF/CDK4/RB1), DNA damage response pathways (ATM/CHK2/p53), and cell survival signals. The knowledge of these mechanisms and their influence on the behaviour of the tumour are facilitating the development of prognostic models with a more precise prediction of the clinical evolution of the patients. This information coupled with the availability of a new generation of innovative drugs targeting basic molecular process of the tumour cells, should facilitate the design of new therapeutic protocols able to overcome the resistance of this aggressive lymphoma to conventional treatments and improve the life expectancy of the patients.
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PMID:Advances in the understanding of mantle cell lymphoma. 1841 Apr 53

The growing number of human cancers is the main reason for the search for new effective treatment strategies. The molecular basis for cancer transformation has to be elucidated in order to improve cancer treatment. It is stated that HNSCCs make up at least 5% of all registered malignant tumors in Poland. Exogenous factors influence HNSCC etiology. The prevalence of HNSCC is increased by several carcinogens, including tobacco smoke, life style, and others, such as oncogenous viral infections. It is more often emphasized that endogenous agents can also increase the risk of HNSCC development, especially genetic factors. The most recently characterized genetic factors for head and neck cancer are mutations in xenobiotic metabolism enzyme genes (GSTM1, GSTT1, GSTP1), suppressors mutations (TP53, RB1, BRCA1, ATM), polymorphisms of DNA repair genes (OGG1, XRCC1, XPD, RAD51), and mutations in mitochondrial DNA. It has been observed that single-gene polymorphisms could affect treatment, whereas the coincidence of other gene mutations may increase the risk of human head and neck cancer development.
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PMID:[Genetic predeterminations of head and neck cancer]. 1883 34

Determining the genetic basis of cancer requires comprehensive analyses of large collections of histopathologically well-classified primary tumours. Here we report the results of a collaborative study to discover somatic mutations in 188 human lung adenocarcinomas. DNA sequencing of 623 genes with known or potential relationships to cancer revealed more than 1,000 somatic mutations across the samples. Our analysis identified 26 genes that are mutated at significantly high frequencies and thus are probably involved in carcinogenesis. The frequently mutated genes include tyrosine kinases, among them the EGFR homologue ERBB4; multiple ephrin receptor genes, notably EPHA3; vascular endothelial growth factor receptor KDR; and NTRK genes. These data provide evidence of somatic mutations in primary lung adenocarcinoma for several tumour suppressor genes involved in other cancers--including NF1, APC, RB1 and ATM--and for sequence changes in PTPRD as well as the frequently deleted gene LRP1B. The observed mutational profiles correlate with clinical features, smoking status and DNA repair defects. These results are reinforced by data integration including single nucleotide polymorphism array and gene expression array. Our findings shed further light on several important signalling pathways involved in lung adenocarcinoma, and suggest new molecular targets for treatment.
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PMID:Somatic mutations affect key pathways in lung adenocarcinoma. 1894 47

The t(11;14)(q13;q32) is the hallmark of mantle cell lymphoma (MCL). Additional genetic alterations occur in the majority of cases. This study aimed to design a polymerase chain reaction (PCR) assay to determine the incidence and relevance of recurrent gene copy number aberrations in this disease. Forty-two MCL cases with frozen- or paraffin-embedded (FFPE) tissues were selected. Three different quantitative Multiplex PCR of Short Fluorescent Fragments (QMPSF) assays were designed to simultaneously analyse eight genes (CDKN2A, RB1, ATM, CDK2, TP53, MYC, CDKN1B, MDM2), to analyse the 9p21 locus (CDKN2A/CDKN2B) and FFPE tissues. Gains of MYC, CDK2, CDKN1B, and MDM2 were observed in 10% of cases. Losses of RB1, CDKN2A, ATM or TP53 were observed in 38%, 31%, 24% and 10% of cases, respectively. Analysis of the 9p21 locus indicated that, in most cases, tumours displayed a complete inactivation of p14(ARF)/p15I(NK4B)/p16I(NK4A). CDKN2A and MYC aberrations were associated with a high MCL international prognostic index (MIPI). CDK2/MDM2 gains and CDKN2A/TP53 losses correlated with an unfavourable outcome. PCR experiments with frozen and FFPE-tissues indicated that our approach is valid in a routine diagnostic setting, providing a powerful tool that could be used for patient stratification in combination with MIPI in future clinical trials.
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PMID:Detection of gene copy number aberrations in mantle cell lymphoma by a single quantitative multiplex PCR assay: clinicopathological relevance and prognosis value. 1959 47

This study was aimed to investigate the common chromosomal aberrations in chronic lymphocytic leukemia (CLL) and to explore the relationship between these chromosomal aberrations and clinical features of CLL. Sequence-specific DNA probes (D13S25, RB1, p53, ATM) and one centromeric probe CSP12 were applied to detect del(13q14), del(17p13), del(11q22-q23) and trisomy 12 by using interphase fluorescence in situ hybridization (I-FISH). 9 CLL patients with negative conventional cytogenetics or without mitotic figure were enrolled in this study. The threshold was established using 10 controls without hematopoietic malignancies. The results indicated that compared with the established threshold, all of the 9 CLL patients showed cytogenetic abnormalities. The detection using p53 and D13S25 showed positive in 7 cases, positive was observed in 5 cases by using ATM and in 4 cases by using both RB1 and CSP12. There was significant correlation between the ATM and the hemoglobin level of the patients. In addition, the elevated probability of gaining bulky lymphadenopathy was found in ATM positive patients. It is concluded that the I-FISH is a more rapid and sensitive technique for analysis of chromosome aberrations in CLL. A large series study with long-term follow-up is needed to reveal the role of cytogenetic abnormalities in the determination of CLL prognosis.
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PMID:[Chromosomal aberrations in chronic lymphocytic leukemia by interphase fluorescence in situ hybridization and their association with clinical features]. 2041 97

Prostate cancer is the most common male cancer and up to one fifth of diagnosed patients will die of their disease. Current prognostic variables including T-category (of the TNM staging), the absolute or kinetics of prostatic specific antigen (PSA) and the pathologic Gleason score (GS) are utilized to place men in low, intermediate and high-risk prostate cancer risk groupings. There is great heterogeneity within the non-indolent intermediate risk group with respect to clinical response. It is therefore imperative that further genetic and other prognostic factors be identified to better individualize treatment. Somatic alterations in prostate cancer. Herein, we review the potential for somatic alterations in tumor-associated genes (based on comparative genomic hybridization (CGH) in prostate cancers to be novel prognostic, and possibly predictive, factors for prostate cancer radiotherapy response. Intermediate risk prostate cancers show alterations in a number of genes thought to be involved in radiosensitivity, DNA repair, cell death and stem cell renewal. These include deletions at 21q (TMPRSS2: ERG), 13q (RB1), 10q (PTEN), 8p (NKX3.1), additions at 8q21 (containing c-Myc)) and haplo-insufficiency for p53, PARP1, ATM and DNA-PKcs. Conclusions. The use of high-resolution CGH for fine-mapping of deletions and amplifications in pre-radiotherapy prostate cancer biopsies is feasible. Genetic alterations may delineate localized prostate cancer from systemic disease and be used as a predictive factor in that patients would be individually triaged to local (surgery versus radiotherapy) and/or adjuvant (adjuvant androgen ablation or post-operative radiotherapy) therapies in a prospective fashion to improve outcome. The knowledge of abnormal DNA repair pathways within in a given patient could allow for the judicious use of targeted agents (PARP/ATM inhibitors) as personalized medicine.
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PMID:Array CGH as a potential predictor of radiocurability in intermediate risk prostate cancer. 2059 Mar 66


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