Identification of a LOH Region on Chromosome 9p Associated with a Specific Gene Expression Signature in Adult B-Lineage ALL through Integration of High Density Microarray Expression and SNP Analyses.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1119-1119
Author(s):  
Sabina Chiaretti ◽  
Xiaochun Li ◽  
Robert Gentleman ◽  
Cheng Li ◽  
Antonella Vitale ◽  
...  
Keyword(s):  
Gene Expression ◽  
Malignant Transformation ◽  
Copy Number ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
High Density ◽  
Snp Analysis ◽  
Molecular Abnormalities ◽  
Chromosome 9P ◽  
B Lineage

Abstract Acute lymphoblastic leukemia (ALL) is characterized by the presence of specific rearrangements associated with distinct gene expression signatures defined by high density microarray. Rearrangements of MLL, E2A/PBX1, BCR/ABL and TEL/AML1 are examples of this phenomenon, which also provide insights into the mechanisms of malignant transformation in these cases. Nevertheless, many cases of ALL do not carry known molecular abnormalities and do not exhibit unique gene expression profiles. In these cases, the mechanisms of malignant transformation remain unknown. Our goal was to develop an integrated genetic approach to discover new mechanisms of transformation in ALL and to define patterns of expression associated with these genetic abnormalities. Gene expression profiles were determined in B-lineage ALL from 95 adult patients using Affymetrix U95Av2 GeneChips. Within this group, high density SNP analysis was performed on 16 paired samples of normal and leukemia cells from the same patient using Affymetrix Mapping 10K Arrays. SNP analysis of normal and ALL DNA based on chromosome copy number interference revealed the presence of several regions of amplification, the most frequent involving chromosome X (3 samples, plus 1 Klinefelter syndrome, minimal amplified region: Xp22.31 to Xp11.1) and chromosome 21 (3 samples plus 1 Down syndrome, minimal amplified regions 21q223.13 to 21q22.2). Further analysis showed a frequent occurrence of LOH on chromosome 3, 6, and 21. Remarkably, this analysis revealed the presence of LOH in a portion of chromosome 9p (9p13.3 to 9p24.3) in 25% of cases. FISH analysis confirmed the presence of a homozygous deletion at 9p21 in 2 of these samples, whereas the 2 remaining cases showed a normal copy number, suggesting that in these 2 patients a deletion followed by duplication occurred. Analysis of gene expression based on genes located in this deleted region identified two genes with reduced expression: tropomyosin 2, a putative tumor suppressor gene and a transcript whith an unknown function. Analysis of gene expression in these cases revealed differential expression of 124 genes: of these, only 25 were highly expressed in the “9p LOH cases”. The use of this gene set in a heat map of all the cases without molecular abnormalities revealed a cluster that included 10 cases. 5 have known 9p abnormalities involving p15 and/or p16, 2 have 9p LOH by SNP analysis and 2 did not have sufficient material for further analysis. Given these results, we evaluated to what extent there was an overlap between these two phenomena. This revealed 34 transcripts that were consistently selected, suggesting that these genes represent a unique signature reflecting leukemic transformation involving the 9p region. These results demonstrate that integrated analysis of gene expression and SNP-based comparison of leukemia and normal cells can identify previously unknown groups of tumors with distinct genetic profiles. Further studies can now be undertaken to better define the mechanisms of transformation in these leukemias.

scholarly journals Gene expression profiles of CMS2-epithelial/canonical colorectal cancers are largely driven by DNA copy number gains

Oncogene ◽  
2019 ◽  
Vol 38 (33) ◽  
pp. 6109-6122 ◽  
Author(s):  
Kaja C. G. Berg ◽  
Anita Sveen ◽  
Maren Høland ◽  
Sharmini Alagaratnam ◽  
Marianne Berg ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Colorectal Cancers ◽  
Dna Copy Number

Cytogenetic Analysis of Multiple Myeloma Identifies Cytogenetic Alterations Implicated in Disease Complexity and Progression

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3360-3360
Author(s):  
Erik Wendlandt ◽  
Guido J. Tricot ◽  
Benjamin Darbro ◽  
Fenghuang Zhan
Keyword(s):  
Gene Expression ◽  
Multiple Myeloma ◽  
Cathepsin B ◽  
Copy Number ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Enrichment Analysis ◽  
Copy Number Variations ◽  
Expression Arrays ◽  
Gene Expression Arrays

Abstract Background: Multiple myeloma is the second most common blood borne neoplasia, accounting for nearly 10% of all diagnosed hematologic malignancies and has a disproportionately high incidence in elderly populations. Here we explored copy number variations using the high fidelity CytoScan HD arrays to develop a detailed map of copy number variations and identify novel mediators of disease progression. The results from CytoScan HD microarrays provide a detailed view of the entire genome with a resolution up to 25kb. Furthermore, 750,000 single-nucleotide polymorphisms are included and the array provides information about loss of heterozygosity and uniparental disomy. Materials and methods: CytoScan HD arrays were performed on 97 myeloma patient samples to identify cytogenetic regions important to the development and progression of the disease. Gene expression profiles from 351 patients were analyzed to identify genes with a change in gene expression of 1.5 fold or more. Data from CytoScan and gene expression arrays was combined to perform chromosomal positional enrichment analysis to identify cytogenetic driver lesions, or lesions that provide a small, but significant growth and survival advantage to the cell. Furthermore, Kaplan-Meier, log-rank test and Hazard ratio analyses were performed to identify gene within the driver lesions that have a significant impact on survival when dysregulated. Results: The results from the CytoScan HD analysis closely mirrored what has been shown by FISH and SNP arrays, with gains to the odd numbered chromosomes, specifically 3, 5, 7, 9, 11, 15 and 17 as well as losses to chromosomes 1p and 13. Interestingly, we identified gains to a small region within chromosome 8p, contrary to published reports demonstrating a large scale loss of this region. We identified numerous genes within this region that are important for survival and their overexpression resulted in a decreased progression free survival. For example, Cathepsin B (CTSB) is encoded for in chromosome 8p22-p21 with an increased gene expression of at least 1.5 fold over normal controls, among others. Furthermore, Cathepsin B, a cysteine protease, has been linked to cancer of the ileum, suggesting that a similar role may be present within myeloma. We then integrated the 97 copy number profiles results with 351 myeloma gene expression profiles to identify cytogenetic driver lesions in myeloma important for disease development, progression and poor clinical outcome. Chromosomal positional enrichment analysis was employed to identify global myeloma cytogenetic driver aneuploidies as well as develop unique cytogenetic copy number profiles. Our results identified portions of chromosomes 1q, 3, 8p, 9, 13q and 16q, among others, as important driver lesions with changes to these regions providing growth advantages to the cell. Furthermore, our analysis identified five unique cytogenetic classifications based on common cytogenetic lesions. We continue to explore these driver regions to identify lesions important for the oncogenic properties of the larger regions. Conclusion: The data presented here represents a novel and highly sensitive approach for the identification of novel copy number variations and driver lesions. Furthermore, correlations between copy number variations and gene expression arrays identified novel targets important for disease progression and patient survival. CytoScan HD arrays in conjunction with gene expression analysis provided a high resolution image of important cytogenetic lesions in myeloma and identified potentially important therapeutic targets for drug development. Further work is needed to validate our findings and determine the therapeutic efficacy of the identified targets. Disclosures No relevant conflicts of interest to declare.

scholarly journals Comprehensive Profiling of Primary and Metastatic ccRCC Reveals a High Homology of the Metastases to a Subregion of the Primary Tumour

Cancers ◽  
2019 ◽  
Vol 11 (6) ◽  
pp. 812 ◽  
Author(s):  
Paranita Ferronika ◽  
Joost Hof ◽  
Gursah Kats-Ugurlu ◽  
Rolf H. Sijmons ◽  
Martijn M. Terpstra ◽  
...  
Keyword(s):  
Gene Expression ◽  
Copy Number ◽  
Lung Metastases ◽  
Expression Profiles ◽  
Clonal Evolution ◽  
Primary Tumour ◽  
Vena Cava ◽  
Gene Expression Profiles ◽  
Cell Renal Cell Carcinoma ◽  
Number Pattern

While intratumour genetic heterogeneity of primary clear cell renal cell carcinoma (ccRCC) is well characterized, the genomic profiles of metastatic ccRCCs are seldom studied. We profiled the genomes and transcriptomes of a primary tumour and matched metastases to better understand the evolutionary processes that lead to metastasis. In one ccRCC patient, four regions of the primary tumour, one region of the thrombus in the inferior vena cava, and four lung metastases (including one taken after pegylated (PEG)-interferon therapy) were analysed separately. Each sample was analysed for copy number alterations and somatic mutations by whole exome sequencing. We also evaluated gene expression profiles for this patient and 15 primary tumour and 15 metastasis samples from four additional patients. Copy number profiles of the index patient showed two distinct subgroups: one consisted of three primary tumours with relatively minor copy number changes, the other of a primary tumour, the thrombus, and the lung metastases, all with a similar copy number pattern and tetraploid-like characteristics. Somatic mutation profiles indicated parallel clonal evolution with similar numbers of private mutations in each primary tumour and metastatic sample. Expression profiling of the five patients revealed significantly changed expression levels of 57 genes between primary tumours and metastases, with enrichment in the extracellular matrix cluster. The copy number profiles suggest a punctuated evolution from a subregion of the primary tumour. This process, which differentiated the metastases from the primary tumours, most likely occurred rapidly, possibly even before metastasis formation. The evolutionary patterns we deduced from the genomic alterations were also reflected in the gene expression profiles.

Integrative Analysis of Genomic Aberration and Gene Expression Suggests That MPD with Loss of Heterozygosity or Gain of Chromosome 9 Represents a Distinct Entity

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3735-3735
Author(s):  
Weijia Zhang ◽  
Benjamin L. Ebert ◽  
Windy Berkofsky-Fessler ◽  
Monica Buzzai ◽  
Yezhou Sun ◽  
...  
Keyword(s):  
Gene Expression ◽  
Genomic Instability ◽  
Loss Of Heterozygosity ◽  
Copy Number ◽  
Expression Profiles ◽  
Gene Expression Profiles ◽  
Chromosome 8 ◽  
Chromosome 9 ◽  
Chromosomal Anomalies ◽  
Multiple Testing Correction

Abstract Polycythemia vera (PV), essential thrombocythemia (ET) and idiopathic myelofibrosis (IMF) can all be associated with the JAK2V617F gain of function mutation. MPDs are also associated with gross cytogenetic anomalies including genomic gain/loss or loss of heterozygosity (LOH) due to mitotic homologous recombination. To determine whether genomic anomalies may be associated with JAK mutation status/disease phenotype we subjected genomic DNA from the granulocytes of 87 patients with PV, ET or IMF to analysis using high resolution Affymetrix 250K Nsp SNP arrays with an average probe spacing of 12Kb. Firstly this analysis precisely mapped previously identified anomalies in MPD patients such as gain of chromosome 1q chromosome 9 (Chr9), chromosome 8, and deletion of 20q and 13q indicating the robustness of the technique. By removing genomic Copy Number Polymorphisms (CNPs) ascertained from 90 normal individuals from the HapMap dataset, we further detected a number of novel alterations such as frequent gain of Chr9p33–34 harboring among other genes, Notch1. MPD patients heterozygous for the JAK V617F mutation exhibited higher genomic instability than JAK2 V617 homozygous or wild type patients. IMF patients had overall more aberrations than PV or ET patients but unsupervised hierarchical clustering of chromosomal anomalies could not distinguish patients with PV, ET or IMF. Whole chromosomal gain or loss was equally frequent among the three diseases, however IMF patients had more frequent alteration of 10Mb or greater when compared to ET or PV (p<0.01) and ET and IMF patients both more frequently exhibited changes ranging from 1–10Mb in size than PV patients (p<0.01). Correlation of gene expression profiles from the granulocytes of 38 MPD patients with copy number profiles from DNA of the patients indicated that gene expression in regions of copy number gain or loss correlated with gene dosages in general. From 2493 genes residing in regions of copy number change region, 259 genes exhibited a positive correlation between copy number and gene expression. By calculating the t–statistics of expression values between samples with and without chromosomal aberrations we further identified 28 genes that showed a change of at least 1.5 fold (p<0.05), 27 of which were located on chromosome 9. Among these were Smarca2, NOTCH1 JAK2 itself. JAK2V617F expression was highly elevated by gain of Chr9 or Chr9p LOH. LOH on chr9p was detected in 16 patients, the majority of whom were confirmed as homozygous for JAK2V617F. To investigate how the over-expression of JAK2V617F might affect the expression of other genes and pathways, gene expression profiles of patients with Chr9 abnormality including Chr9 gain or Chr9p LOH were compared to samples with a normal copy number for Chr9. We identified 493 genes including 210 up-regulated and 283 down-regulated genes by at least 1.5 fold at a p value of 0.05 after multiple-testing correction. As a control gene expression patterns in JAK2-wildtype MPD granulocytes were compared to expression in normal granulocytes. This analysis identified an almost completely different set of genes; 441/493 (89%) of genes differentially expressed in Chr9 abnormal cases versus Chr9 normal cases were not found in the Chr9 normal versus normal control dataset. Up-regulated genes in Chr9 abnormal cases included CD177, CDK5RAP2, BIRC1, STAT5, TLR4 and down-regulated genes include KLRB1, Myc, RUNX3, P53CSV, Pathway analysis of dysregulated genes in Chr9 gain/LOH cases showed that genes involved in p38/MAP kinase, Toll-like receptor and Fc epsilon RI signaling were up-regulated and the genes involved in pathways of protein synthesis/translation and T cell receptor signaling were down-regulated. Collectively these findings suggest that MPD associated with Chr9 gain or 9pLOH and increased expression of JAK2V617F represents a distinct subset of MPD, characterized by less genomic instability than other cases. Furthermore, increased JAK2 and STAT5 expression and activity in these cases may induce distinct downstream pathways and alterations in gene expression.

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