Variety Of Chromosomal Aberrations Research Articles

Non Random Distribution of Chromosome-21 in Syndromic Cases of Wilms’ Tumors

Wilms’ tumors are the common embryonic childhood solid tumor of kindney and heterogeneous in nature. Karyotypic analysis of Wilms’ tumor has shown a variety of chromosomal aberrations with different (%) frequency of structural and numerical changes in somatic cell. Present study were carried out in eleven cases (n=11) of Wilms’ tumors with different age group (betwen 1.5 year to 10 year). Most striking feature is the involvement of high frequency (>60%) of Wilms’ tumor shows extra copy of chromosome-21 in the karyotypes after using high resolution of GTG banding and FISH analysis. Interestingly, 18% cases of Wilms’ tumor shows loss of Y-chromosome and appearance of (r)Y reporting first time in India. Beside this, short arm of chromosome - 6 and 16 shows two new break points i.e. 6q21.22 and 16q23 might have play an significant role in Wilms’ tumors progression. The other relevant findings were the association of either gain (trisomy) or loss (monosomy) of chromosome with chromatid break points, ring, dicentric or rearrangements of chromosome (translocation) with different frequency. However, this is a rare coincidence that environmental factor (s) might have increase risk of developing Down syndrome (47,XY+21) in Wilms’ tumors, due non - disjunction event and unequal crossing over in cell- division of the disease outcome.

Comparison of genomic and gene expression profile between cancer and healthy samples.

e13001 Background: A variety of chromosomal aberrations underlie developmental abnormalities and cancer. Use of techniques such as microarrays provides an opportunity to perform gene expression analysis. A recent approach is the use of array based comparative genomic hybridization (aCGH) to detect genomic abnormalities in human tumors. The aim of this study is to compare genomic and gene expression profile between cancer patients and healthy individuals. Methods: DNA and RNA were isolated from peripheral blood mononuclear cells from 9 patients, with different types of cancer and 4 normal donors. aCGH (Agilent-60K) and gene expression microarrays (Microarrays Inc.-whole genome platform) were performed using commercial reference samples. Data were analyzed with Array-Pro analyzer and Cytogenomics software. Results: The aCGH data demonstrated the majority of gains and amplifications were observed in cancer samples, while the deletions and losses were higher in normal individuals. Among aberrations, common genes in both types of samples were detected. These genes included ACAD8, ACP1, B3GAT1, IDI1, IDI2, IGSF9B, IRX1, IRX2, JAM3, MYT1L, NTM, OPCML, PXDN, THYN1, TPO. However, there were abnormalities that included genes, which appeared only in cancer samples, like cadherins ( CDH11, CDH8 and CDH5) and EPHA5, while genes such as ACOX1, PTPRN2, TYMS and genes of zinc-finger proteins were observed only in normal samples. No statistical significant difference in gene expression, between cancer and normal samples, was observed. On the contrary, overexpression was observed in genes that were not detected in aCGH. Conclusions: Whereas it is acceptable that great achievements have been carried out in cancer field, the mechanism of tumorigenesis is not clear understood. The present study demonstrated that even though genomic aberrations exist, these are not always representative at gene expression level. However, the combination of both techniques could be used for more accurate and reliable data. This requires study in more samples including different cancer types so to be used at clinical level.

Chromosomal Aberrations in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are a group of clonal hematopioetic disorders characterized by myelodysplasia, decreased peripheral blood cells and high-risk of transformation into acute leukemia. MDS are often accompanied by a variety of chromosomal aberrations which play a role in disease pathogenesis, and are crucial in diagnosis and prognostic evaluation of this disease. About half of the patients with MDS have chromosomal abnormalities, mainly unbalanced chromosomal aberration. Different chromosomal aberration types are associated with different clinical outcome of this disease. Though balanced chromosomal translocations are not common in MDS, it seems that the patients with them have a higher leukemia transformation rate than those with other type of chromosomal aberrations. In this review, the chromosomal aberrations in MDS and their clinical significance for diagnosis and prognosis are briefly summarized.

Structure, regulation, signaling, and targeting of abl kinases in cancer.

Abl kinases are prototypic cytoplasmic tyrosine kinases and are involved in a variety of chromosomal aberrations in different cancers. This causes the expression of Abl fusion proteins, such as Bcr-Abl, that are constitutively activated and drivers of tumorigenesis. Over the past decades, biochemical and functional studies on the molecular mechanisms of Abl regulation have gone hand in hand with progression of our structural understanding of autoinhibited and active Abl conformations. In parallel, Abl oncoproteins have become prime molecular targets for cancer therapy, using adenosine triphosphate (ATP)-competitive kinase inhibitors, such as imatinib. Abl-targeting drugs serve as a paradigm for our understanding of kinase inhibitor action, specificity, and resistance development. In this review article, I will review the molecular mechanisms that are responsible for the regulation of Abl kinase activity and how oncogenic Abl fusions signal. Furthermore, past and ongoing efforts to target Abl oncoproteins using ATP-competitive and allosteric inhibitors, as well as future possibilities using combination therapy, will be discussed.

A Patient With Familial Bone Marrow Failure and an Inversion of Chromosome 8

Familial bone marrow failure has been associated with a variety of chromosomal aberrations. Chromosome 8 abnormalities have been described in association with neoplastic and hematologic disorders; however, to our knowledge, inversion of the long arm of chromosome 8 has not been described in the context of familial bone marrow failure. We describe a 9-year-old female with familial bone marrow failure and an inversion of chromosome 8 [inv (8) (q22, q24.3)]. Given the importance of considering the genetic determinants of familial bone marrow failure, the potential role of chromosome 8 abnormalities in the development of marrow failure is discussed.

The role of fluorescence in situ hybridization and gene expression profiling in myeloma risk stratification

Multiple myeloma patients' survival under treatment varies from a few months to more than 15 years. Clinical prognostic factors, especially beta2-microglobulin (B2M) and the international staging system (ISS), allow risk assessment to a certain extent, but do not identify patients at very high risk. As malignant plasma cells are characterized by a variety of chromosomal aberrations and changes in gene expression, a molecular characterization ofCD138-purified myeloma cells by interphase fluorescence in situ hybridization (iFISH) and gene expression profiling (GEP) can be used for improved risk assessment, iFISH allows a risk stratification with presence of a translocation t(4;14) and/or deletion of 17p13 being the best documented adverse prognostic factors. A deletion of 13q14 is no longer considered to define adverse risk. Patients harbouring a t(4;14) seems to benefit from a bortezomib- or lenalidomide containing regimen, whereas patients with deletion 17p13 seem only to benefit from a high dose therapy approach using long term bortezomib (in induction and maintenance) and autologous tandem-transplantation as used in the GMMG-HD4 trial, or the total therapy 3 concept. Gene expression profiling allows the assessment of high risk scores (IFM, UAMS), remaining prognostic despite treatment with novel agents, and prognostic surrogates of biological factors (e.g. proliferation) and (prognostic) target gene expression (e.g. Aurora-kinase A). Thus, assessment of B2M and ISS-stage, iFISH, and GEP is considered extended routine diagnostics in therapy requiring multiple myeloma patients for risk assessment and, even now, to a certain extent selection of treatment.

Analysis of genotoxic damage induced by dacarbazine: an in vitro study

Dacarbazine is one of the alkylating anticancer drugs being routinely used for the treatment of a number of neoplasias. Besides targeting cancer cells, these anticancer drugs also interact with genetic material of normal cells. In the present study, in vitro genotoxic effects of dacarbazine have been assessed employing cytogenetic assays. A variety of chromosomal aberrations were scored and significant increase in micronucleus and chromosomal aberration frequency was observed. Nuclear division index showed cell cycle delay towards higher concentrations. A number of necrotic and apoptotic cells were also observed at higher concentrations. Dacarbazine was found to be a potent inducer of genotoxic damage in human lymphocytes in vitro.

CUP-Syndrom

Carcinoma of unknown primary (CUP) is an intriguing clinical finding defined as biopsy-proven metastasis from a malignancy in the absence of an identifiable primary site after a complete clinical workup. CUP is a relatively common clinical entity, accounting for approximately 3-5% of all cancer diagnoses, and consists of a heterogeneous group of tumors that have acquired the capacity to metastasize before the development of a clinically evident primary lesion. The mechanisms responsible for early metastasis and lack of a detectable primary tumor are largely unknown. Although remarkable tools have been developed for immunohistological classification of CUP on the basis of the likely tissue of origin, data on molecular pathogenesis and biology of this disorder are rare. A wide variety of chromosomal aberrations are seen in CUP, with aberrations of chromosomes 1, 6, 7, and 11 having been most frequently described. 66-75% of CUP express epidermal growth factor receptor while overexpression of Her2/neu seems to be rare. In contrast to most other tumor entities p53 mutations have been found only in a minority of CUP tumors. Recently, several independent studies have demonstrated proof of principle for the use of gene expression microarrays in identifying a primary site for CUP. Therefore, gene expression and also genomic profiling tools represent promising analytical approaches to assist with the management of CUP patients.

Chromosomal instability in the lymphocytes of breast cancer patients.

Genomic instability in the tumor tissue has been correlated with tumor progression. In the present study, chromosomal aberrations (CAs) in peripheral blood lymphocytes (PBLs) of breast tumor patients were studied to assess whether chromosomal instability (CIN) in PBLs correlates with aggressiveness of breast tumor (i.e., disease stage) and has any prognostic utility. Cultured blood lymphocyte metaphases were scored for aberrations in 31 breast cancer patients and 20 healthy age and sex-matched controls. A variety of CAs, including aneuploidy, polyploidy, terminal deletions, acentric fragments, double minutes, chromatid separations, ring chromosome, marker chromosome, chromatid gaps, and breaks were seen in PBLs of the patients. The CAs in patients were higher than in controls. A comparison of the frequency of metaphases with aberrations by grouping the patients according to the stage of advancement of disease did not reveal any consistent pattern of variation in lymphocytic CIN. Neither was any specific chromosomal abnormality found to be associated with the stage of cancer. This might be indicative of the fact that cancer patients have constitutional CIN, which predisposes them to the disease, and this inherent difference in the level of genomic instability might play a role in disease progression and response to treatment.

Correlation Between Cytogenetic Aberrations Detected by Conventional Chromosome Banding Analysis and Specific Immunophenotypes in Patients with B-Cell Lymphoproliferative Diseases

While typical cytogenetic aberrations and immunophenotypes, respectively, have been identified in distinct entities of B-cell lymphoproliferative diseases (B-LPD) their specificity is not complete in every case. Thus, the t(14;18), which is characteristic of follicular lymphoma, is present also in cases with other B-LPD. Furthermore, expression of CD5 can be observed in cases with B-LPD other than mantle cell lymphoma and chronic lymphocytic leukemia. Moreover, a variety of chromosome aberrations has been described which has not yet been assigned to distinct B-LPD subentities. Accordingly, immunophenotypes are not clear-cut for distinct B-LPD subentities but rather overlap with regard to some features, e.g. between marginal zone lymphoma and lymphoplasmacytic lymphoma. The aim of the present study therefore has been to characterize cases with B-LPD (excluding B-CLL) by conventional chromosome analysis and by multiparameter immunophenotyping and to assess whether and to which degree relations between the results of both methods exist. A total of 346 patients have been evaluated. The frequencies of the respective chromosomal aberrations were (more than one aberration occurred in some cases): t(8;14), 16 (4.6%); t(11;14) without additional aberrations, 10 (2.9%); t(11;14) with additional aberrations, 43 (12.4%); trisomy 12, 48 (13.9%); t(14;18), 18 (5.2%); t(14;19), 6 (1.7%); trisomy 3, 23 (6.6%); trisomy 8, 3 (0.9%); del7q, 9 (2.6%); del13q, 30 (8.7%); 17p-, 30 (8.7%); complex (≥3) aberrations, 58 (16.8%) while a normal karyotype was found in 126 (36.4%) cases. The comparison with immunophenotypes revealed various previously reported findings like the stronger expression of CD10 in cases with t(8;14) (33.4 vs. 14.6%, p=0.001) and of CD5 in cases with t(11;14) (73.3 vs. 48.4%, p<0.001). Furthermore, the respective chromosome aberrations were found to be associated with a significantly (p<0.05 for all comparisons) higher(+)/lower(−) expression of the following antigens: t(8;14), CD10+CD38+CD25+; t(14;18), CD10+CD11c−; t(11;14) with additional aberrations, CD38+CD20+CD22+CD5+CD 79b+FMC7+IgM+; t(11;14) without additional aberrations, CD22+; t(14;19), CD11c+; 17p−, CD38−CD22+CD79b+FMC7+CD11c+; trisomy 12, CD25+CD5+CD10−CD23+; del13q, CD25+CD20+CD22+CD5+CD79b+CD11c−; del7q, CD25−; complex aberrations, CD20+CD22+CD79b+; trisomy 8, CD5−. Accordingly, regarding the whole series distinct antigens were found coexpressed at high frequencies. Specifically, highly significant positive correlations (p<0.001, r>0.5) were found between CD20, CD22, CD79b, and FMC7. In contrast, the expression of CD10 was highly significantly negatively related (p<0.001, r<−0.2) to the expression of CD11c and CD5. Overall, however, there was no complete positive or negative correlation between any of the antigens analyzed with regard to their respective expression intensities. Hierarchical cluster analysis has been performed to assess correlations between the expression intensities of distinct antigens on the one hand and distinct chromosome aberrations on the other hand. While the majority of cases with t(11;14) clustered rather closely together, cases with other chromosome aberrations were distributed more heterogeneously. These data suggest that there are significant correlations between the expression intensities of specific antigens as well as between these expression intensities and distinct chromosome aberrations in B-LPD. However, the respective immunophenotype patterns were much more diverse and no strong correlations were found to most chromosome aberrations. Only in cases with t(11;14) or with t(8;14) strong correlations have been observed with highly significant differences in antigen expression as compared to cases with other cytogenetic aberrations. The data suggest that the biologic background in most B-LPD is heterogeneous from the diagnostic point of view which is in contrast to other and also genetically clearly defined hematologic malignancies such as CML or APL. To clarify the more diverse biology and its clinical significance also in conjunction with histologic findings further studies are warranted.

Establishment of a Cell Line Derived from a Canine Prostate Carcinoma with a Highly Rearranged Karyotype

Akin to the situation in humans, dogs are frequently affected by tumors of the prostate. The malignancies share many similarities between both species, for example, median age at the onset of the disease and metastatic behavior. In human prostatic tumor samples, investigations of prepared metaphase spreads showed a variety of chromosomal aberrations, with trisomies of chromosomes 7, 8, and 17 as the leading cytogenetic abnormalities. In this article we present one case of a canine adenocarcinoma of the prostate, including clinical examination and establishment of a cell line from a tumor sample obtained from the affected 10-year-old male Briard. Searching for similarities between both species in respect to chromosomal changes within the tumor samples, we investigated prepared metaphases of the canine cell line cytogenetically. These investigations presented a highly rearranged karyotype showing a large biarmed marker consisting of material from chromosomes 1 and 2 in addition to centromeric fusions between dog chromosomes 1 and 5 that both could be identified in every metaphase investigated, while centric fusions of chromosomes 4 and 5 occurred in up to 50% of the metaphases. The cell line grew very well and showed evidence of being spontaneously immortalized when it crossed the 20th passage.

Cytogenetic Findings in Cancerous and Non-Cancerous Lesions of the Digestive System

Chromosome instability provides a predisposing background to malignancy, contributing to the crucial genetic changes in multistep carcinogenesis. It is generally accepted that cancer is a genetic disease resulting from multiple genome rearrangements. A variety of chromosomal aberrations have been identified in various cancerous and non-cancerous lesions of the gastrointestinal tract. Certain aberrations observed in non-cancerous lesions were identical to those of cancerous lesion.

Emerging roles of centrosomal amplification and genomic instability in cancer

The carcinogenic process is multistep in terms of its etiology and multifactor in terms of its evolution. In this context, the temporal accumulation of multiple genetic changes during multistage carcinogenesis that can be mediated at least in part by genomic instability may represent crucial components of tumor cell evolution. Evidence is accumulating indicating a close link between genomic instability and cancer initiation and progression. Neoplastic cells typically possess numerous genomic lesions, which may include sequence alterations (point mutations, small deletions, and insertions) and/or gross structural abnormalities in one or more chromosomes (large-scale deletions, rearrangements, gene amplifications). Furthermore karyotypic alterations, including whole chromosome loss or gain, ploidy changes (aneuploidy and polyploidy) and a variety of chromosome aberrations are common in tumor cells. Genomic instability also involves mitotic defects associated with centrosome abnormalities. However, the question of whether abnormal centrosomes cause genomic instability or develop secondary to other changes has not been conclusively resolved. In this review, the recent studies investigating genomic instability and aneuploidy in human cancer, centrosome amplification and the role of centrosomal duplication in chromosomal mis-segregetion, and genes implicated in regulating chromosome segregation, centrosomal amplification and progression in cancer cells are discussed.

Centrosome replication, genomic instability and cancer.

Karyotypic alterations, including whole chromosome loss or gain, ploidy changes, and a variety of chromosome aberrations are common in cancer cells. If proliferating cells fail to coordinate centrosome duplication with DNA replication, this will inevitably lead to a change in ploidy, and the formation of monopolar or multipolar spindles will generally provoke abnormal segregation of chromosomes. Indeed, it has long been recognized that errors in the centrosome duplication cycle may be an important cause of aneuploidy and thus contribute to cancer formation. This view has recently received fresh impetus with the description of supernumerary centrosomes in almost all solid human tumors. As the primary microtubule organizing center of most eukaryotic cells, the centrosome assures symmetry and bipolarity of the cell division process, a function that is essential for accurate chromosome segregation. In addition, a growing body of evidence indicates that centrosomes might be important for initiating S phase and completing cytokinesis. Centrosomes undergo duplication precisely once before cell division. Recent reports have revealed that this process is linked to the cell division cycle via cyclin-dependent kinase (cdk) 2 activity that couples centriole duplication to the onset of DNA replication at the G(1)/S phase transition. Alterations in G(1)/S phase regulating proteins like the retinoblastoma protein, cyclins D and E, cdk4 and 6, cdk inhibitors p16(INK4A) and p15(INK4B), and p53 are among the most frequent aberrations observed in human malignancies. These alterations might not only lead to unrestrained proliferation, but also cause karyotypic instability by uncontrolled centrosome replication. Since several excellent reports on cell cycle regulation and cancer have been published, this review will focus on the role of centrosomes in cell cycle progression, as well as causes and consequences of aberrant centrosome replication in human neoplasias.

Biological Effects of Carbon Ions with Medium Energy on Plant Seeds

The biological effects of 46.6 MeV/u 12C6+ ions on four kinds of plant seeds were studied at the Heavy Ion Research Facility in Lanzhou (HIRFL), Institute of Modern Physics (IMP), Academia Sinica. The results show that germination of the seeds is inhibited by exposure to ions. In root tip cells of irradiated seeds, a great variety of chromosomal aberrations were observed. Sensitivities in terms of inhibition of germination and induction of chromosomal aberrations in the four species are correlated.

SV40 T antigen induced chromosomal changes reflect a process that is both clastogenic and aneuploidogenic and is ongoing throughout neoplastic progression of human fibroblasts

In human fibroblasts, the expression of SV40 large T antigen is known to cause a variety of chromosomal aberrations and especially dicentric chromosomes. In some cases, the later aberrations have been reported to be reversible telomeric associations. We report here aberration and chromosome number studies of twenty-nine T antigen positive lineages, studied from their initiation by transfection of T antigen sequences into human diploid fibroblasts, until crisis or immortalization occured or, in some cases until the lines became tumorigenic in nude mice. The data show that T antigen consistently produced chromosomal instability of both number and structure by an active process that began before transformation indicators were positive and continued throughout neoplastic progression. The most frequently observed aberrations were dicentric chromosomes, which were shown to be true dicentrics by examination by in situ hybridization with telomeric sequences. These data are consistent with the hypothesis that T antigen causes human fibroblasts to become neoplastically transformed by successive rounds of chromosomal mutation and lineage evolution.