Multiple Secondary Genetic Events Inducing Histologic Progression (HP) of Non-MALT Marginal Zone Lymphoma (MZL): An Integrated Genomic Analysis of Genome-Wide Copy-Number-Changes (CNC) and Transcriptomic Data.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1198-1198
Author(s):  
Lise Willems ◽  
Josette Briere ◽  
Mahatsangy Raharijaona ◽  
Benoit Ballester ◽  
Samuel Quentin ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Proliferation ◽  
Array Cgh ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Integrated Analysis ◽  
Comparative Genomic ◽  
Transcriptomic Data ◽  
Genome Wide ◽  
Cyclin G

Abstract HP of indolent B cell lymphoma to a high grade lymphoma is usually associated with a rapidly progressive clinical course and a short survival. The risk of HP in MZL is evaluated around 10–20%, and can be detected at diagnosis or during the evolution of the disease. No criteria have been yet formally adopted to range HP, even in the more recent OMS classification, although therapeutic impact is important. In this study we wished to determine the genetic alterations implicated in the HP of non-MALT MZL, using an integrated analysis of genome-wide CNC and transcriptomic data. Fresh-frozen tumor biopsies and clinical data were obtained from 66 untreated non-MALT MZL patients of 3 institutions (SLS, HD, CHLS, France). Features reviews including morphologic aspect, immunophenotype, and conventional cytogenetics, classified 52 cases as MZL and 14 cases as MZL with HP (HP-MZL). HP was assessed by the presence of large cells, the presence of cohesive sheets of larges cells, and elevated Ki67. CNC were analysed in 20 splenic MZL (SMZL), in 6 HP-SMZL cases including 2 matched cases, and in 3 germ-line DNA of these cases using array comparative genomic hybridization (array-CGH) (Agilent, 105K). Normalization of the array-CGH data was realized by Lowess correction. Transcriptomic analysis of 32 SMZL and 8 HP-MZL, including 2 matched cases, was performed with a nylon DNA microarray of 9,216 human genes. After Lowess correction, data were visualized by hierarchical clustering allowing to distinguish patterns of gene expression corresponding to precise functions, cell or tissue subtype. The ability of individual transcripts to distinguish MZL and HP-MZL subtypes was calculated using discriminating score and bootstrap resampling. The most common imbalances detected by cytogenetics were gains of 3/3q (n=11/61, 18 %) and 18q (n=13/61, 21%), and deletions in 7q (n=18/61, 17%), and were detected in both groups, SMZL and HP-SMZL. Array-CGH analysis showed that no recurrent CNC was specific of all HP-SMZL. Only 1 CNC was present in 4 of the 6 HP-SMZL cases, 3 in 3 cases, and 29 in 2 cases. These CNC could also be seen in SMZL. Comparing the matched pairs, we identified secondary CNC changes. One was located in 4p and includes 9 genes. Among them, was Cyclin G associated kinase. This CNC was also present in 2 other HP-MZL cases. Another was located in 6p and includes 4 genes, comprising IRF4. Another HP-SMZL case exhibited a HP-SMZL specific CN gain of the oncogene Myc in 8q. These 3 genes are known to be involved in proliferation. Gene expression profiling showed overexpression of genes involved in proliferation and underexpression of p53 in HP-MZL cases compared to SMZL cases. The proliferation signature included PCNA, genes involved in glycolysis (GAPD, LDHA), in cell cycle (CDC10, CDK4), and cell proliferation (TNFRSF13B, MCL1). Two other signatures included genes overexpressed specifically in HP-MZL: one specific to the stroma with MIG, STAT1, Cathepsin B and C, CREG, IGFR2R; and a cluster of unknown function regrouping several oncogenes (DEK, DJ-1), genes related to cell machinery and cell motility (HMMR, PRPF4, PPOX) and genes involved in signal transduction (ZNF146, FLJ10618, PBXL2). In addition to p53, HP-MZL underexpressed genes included PMSB1 in the proteasome, KLF2 and PFC. In conclusion, integrated genetic and transcriptomic analyses of non-MALT MZL and HP-MZL showed that histologic progression was related to the alteration of cell proliferation. Beside chromosomal alterations typical to SMZL, secondary CNC could be detected in HP-SMZL cases. These CNC included genes associated with cell proliferation: Cyclin G associated Kinase, IRF4, and Myc. These results highlight that deregulation of different pathways drive the MZL cells toward a higher proliferative rate charateristic of histologic progression.

High Resolution Array-CGH in Splenic Marginal Zone B-Cell Lymphoma: Correlation of Copy Number Imbalances with HCV Status and Prognostic Categories.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2620-2620
Author(s):  
Francesca Novara ◽  
Luca Arcaini ◽  
Michele Merli ◽  
Francesco Passamonti ◽  
Silvia Zibellini ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Copy Number ◽  
Marginal Zone ◽  
Array Cgh ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Mutational Status

Abstract In splenic marginal zone B-cell lymphoma (SMZL) no specific genetic alterations are known. Abnormalities of chromosome 7p and of p53 are reported as adverse prognostic factors. In a recent multicentre study (Arcaini et al Blood 2006), a prognostic model based on hemoglobin, albumin and LDH identified 3 risk categories. HCV infection was present in nearly 20% of patients (pts). At now, no data are available on genetic alterations in the HCV-positive subset of SMZL and in the different prognostic categories. The aims of the study were: a) to analyze copy number alterations (CNAs) by means of array comparative genomic hybridization (array-CGH) with a resolution of ∼100 kb; b) to compare CNAs in HCV-positive and HCV-negative pts; c) to identify potential genetic alterations related to the clinical features and to the prognostic categories. We analyzed marrow and blood samples from 34 pts with SMZL: 22 were HCV-negative (serology and HCV-RNA) and 12 were HCV-positive (genotype 2a/2c in 10 pts, genotype 1 in 2). DNA was extracted from bone marrow (16) and peripheral blood lymphocytes (18) and was hybridized with pooled blood lymphocyte reference DNA on Agilent’s 44K oligonucleotide microarray (kit 44B). Images and data were analyzed using Agilent’s Feature Extraction (v9.1) and CGH analytics (v3.4.27) softwares. Ten cases (4 HCV+ and 6 HCV-) did not show CNAs. A single alteration was present in 7 pts, 2 to 5 alterations in 11 and >5 in 6. All CNAs were detected in mosaicism (from 20% to 90%). A median of 5.6 (range 1 to 20) and 3.8 (range 1 to 13) CNAs were detected in HCV+ and in HCV- cases, respectively. The most frequent CNAs were hetereogeneous in size with the following common regions: losses of 1p36.21-p35.3 (3 pts), 7q31.1-q32.3 (7 pts), 8p21.3-p12 (6 pts), 13q14.2-q14.3 (6 pts), 14q32.12-q32.13 (4 pts) and 17pter-p12 (8 pts); gains of 3q21.1-q29 (5 pts), 12q13.1-q21.31 (5 pts), 17q24.1-qter (4 pts), Xpter-p11.23 (4pts). A homozygous 13q14.2 deletion, overlapping that found in CLL and including Rb1 gene, was found in one HCV- pt. The del(7)(q31.1-q32.3) was the more frequent and it ranges from 14,1Mb to 34Mb. No difference in number of CNAs and in specific common regions alterations was found between HCV+ and HCV- cases except for dup(X)(pter-p11.23) (p=0.01, 4 HCV+ pts and none HCV- pt). High-risk prognostic category was significantly associated with del(7)(q31.1-q32.3) (p=0.01) and del(17)(pter-p12) (p=0.02). Mutational status of immunoglobulin variable heavy-chain gene was related to del(7)(q31.1-q32.3) (p=0.04) and dup(12)(q13.1-q21.31) (p=0.03). The presence of villous lymphocytes was associated with del(1)(p36.21-p35.3) (p=0.02); del(8)(p21.3–p12) was related to an autoimmune background in the HCV+ subset (p=0.04). The number of CNAs was associated to leukemic disease (p=0.02) and to the presence of villous lymphocytes (p=0.04). In conclusion, array-CGH in SMZL does not show specific genetic abnormalities for pts with HCV-positive or HCV-negative SMZL. 7q and 17p deletions are significantly associated with the high-risk prognostic category, clinically and biologically identifying a group of pts with aggressive disease.

Genetic Abnormalities Involved in the Development and Progression of Follicular Lymphoma.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2049-2049
Author(s):  
Karen E Deffenbacher ◽  
George Wright ◽  
Javeed Iqbal ◽  
Huimin Geng ◽  
Derville O’Shea ◽  
...  
Keyword(s):  
Gene Expression ◽  
High Resolution ◽  
Follicular Lymphoma ◽  
Copy Number ◽  
Clinical Course ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Oncogenic Pathways ◽  
Insight Into

Abstract Background: Follicular lymphoma (FL) is the most common indolent B-cell lymphoma and remains incurable by current therapeutic approaches. Clinical course is variable, and transformation into an aggressive lymphoma (t-FL) with marked worsening of prognosis occurs in 20–60% of patients. While Bcl2 gene translocation is a critical initiating event in the majority of FL cases, evidence indicates it is not sufficient for the development of a FL. Characterization of the genetic alterations subsequent to Bcl2 translocation will lend insight into the oncogenic pathways that contribute to FL pathogenesis and the molecular mechanisms underlying variability in clinical course. Methods: To define recurrent genomic copy number alterations (CNA) in FL, we performed high resolution array comparative genomic hybridization (aCGH) using the Affymetrix 500K SNP array platform. aCGH data were generated on a series of 112 FL cases with available gene expression profiling (GEP) and clinical information. Gene expression data were correlated with copy number data using the Gene Expression and Dosage Integrator (GEDI) algorithm developed at the NCI. Results: Selecting for abnormalities occurring in >10% of cases, the minimal common region (MCR) for 38 losses and 31 gains were defined. Novel common regions included gains on 15q11, 16p11, 5p14 and 19q13, and losses on 3q29, and 16p13. The MCR identified by aCGH were also compared with our existing cytogenetic data on 360 FL cases. MCR residing within the most frequent cytogenetic imbalances (>5%) were selected for analysis at the gene level to further refine these regions. These include gains on 1q21, 2p16, 7q11, 8q24, 12q13, 17q21, 18q21, 21q11, and X, and losses on 1p36, 6q, 10q, 13q34, and 17p13. Recurrent amplifications were detected for the 2p16, 15q11, and 17q21 MCR, while frequent uniparental disomy (UPD) was found to overlap the region of loss on 1p36. Recurrent UPD was also noted on 6p, 12q, 15q and 16p. For the majority of selected MCR, global expression of the genes residing in the MCR demonstrated an association with copy number status. Within these abnormalities, individual genes showing significant correlation with copy number were also identified. Conclusion: The combination of high resolution aCGH and GEP facilitated the identification of functionally relevant genes within the chromosomal abnormalities in FL. Delineation of these molecular targets will provide insight into the oncogenic pathways that contribute to FL disease pathogenesis and may provide novel therapeutic targets.

Deletion in Chromosome 17p12 and Gains in Chromosome 9q33.3 by Array Comparative Hybridization Are Associated with R-CHOP Treatment Failure in Patients with Diffuse Large B Cell Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 477-477 ◽  
Author(s):  
Nathalie Johnson ◽  
Ronald J De Leeuw ◽  
Julia Chae ◽  
Sohrab P Shah ◽  
Wan L Lam ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Treatment Failure ◽  
B Cell ◽  
International Prognostic Index ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Negative Regulator ◽  
Comparative Genomic ◽  
Nfkb Pathway ◽  
Large B Cell

Abstract Background: The genetic alterations associated with survival in patients with diffuse large B cell lymphomas (DLBCL) treated with combined rituximab-CHOP (R-CHOP) chemo-immunotherapy are not well understood. Methods: 92 patients with DLBCL treated with R-CHOP who had a biopsy available at the time of diagnosis were included in the study. 31 patients were classified as treatment failures defined as progression < 6 months of completing R-CHOP and 61 patients were classified as treatment successes defined as a maintained remission >2 years after diagnosis. We used genome-wide BAC array comparative genomic hybridization (aCGH) to determine the genomic copy number imbalances. The presence of genetic gains and losses were determined using the intersection between visual annotations and a Hidden Markov model algorithm. DLBCL cell of origin (COO) subtype distinctions (GCB vs ABC) were determined using a Bayesian predictor model on gene expression derived from custom Affymetrix arrays (Dave, N Engl J Med, 2006;354:2431). A permutation test was used to identify genetic regions that were significantly different between treatment failures and treatment successes. Functional pathway analysis was performed using Ingenuity software. A novel model based clustering algorithm was applied to the normalized data to determine if any association with outcome correlated with the observed genetic alterations. Results: Lymphoma progressed in 31/92 (34%) patients < 6 months after R-CHOP (median follow-up = 4 y). All 92 patients had successful aCGH and 81 had COO available for this analysis. The International Prognostic Index (IPI) and COO were predictive of outcome (p=0.04, p=0.02, respectively). 451 regions containing 338 genes were associated with treatment failure with a p-value of <10−6. Gains in 9q33.3 were found in 13 patients (14%) and were significantly associated with treatment failure p<10−8. This region contains genes such as HSPA5, a negative regulator of apoptosis and PPP6C, a positive regulator of the cell cycle by targeting IKBe thereby removing inhibition of the NFkB pathway. Deletions in 17p12 were detected in 24 (26%) and were the most statistically significantly associated with treatment failure p<10−9. This region contains tumor necrosis factor (TNF) receptor superfamily member (TNFRSF13B or TACI) which, when deleted or mutated, has been previously shown to lead to activation of the noncanonical NFkB pathway and B cell proliferation. 21 of these 24 patients also had deletion of 17p13 at the TP53 locus (p<10−6). Neither 9p33.3 nor 17p12 deletion was associated with COO distinctions. Using Ingenuity, pathways involving apoptosis and cellular proliferation, specifically those involving P53, MYC and HSPA5 genes, were over-represented in treatment failures (p=2.04 × 10−4). Unsupervised clustering of the aCGH data demonstrated that 60% of cases could be stratified into 4 genetic sub-groups based on the presence of 1q+, 6q−, +7 and the concurrent presence of +3 and +18. Supervised analysis demonstrated that the +3/+18 group and the 6q− group were associated with ABC subtype of DLBCL whereas the +7 and 1q+ groups were associated with the GCB subtype. However, these genetic groups did not correlate with treatment outcome. Conclusions: Some genetic alterations cluster together and can distinguish COO subtypes of DLBCL. Gains on 9q33.3 and deletions of 17p12 are common alterations detected by high resolution aCGH in DLBCL. Most importantly, these alterations involve genes known to be critical in B cell proliferation and apoptosis and alterations at these sites are strongly associated with treatment failure (p values <10−8) in patients treated with R-CHOP.

scholarly journals DNA methylation signatures define molecular subtypes of diffuse large B-cell lymphoma

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. e81-e89 ◽  
Author(s):  
Rita Shaknovich ◽  
Huimin Geng ◽  
Nathalie A. Johnson ◽  
Lucas Tsikitas ◽  
Leandro Cerchietti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
B Cell ◽  
Expression Profiling ◽  
B Cell Lymphoma ◽  
Genetic Alterations ◽  
Integrated Analysis ◽  
Germinal Center B Cell ◽  
Factor Α ◽  
Large B Cell

Abstract Expression profiling has shown 2 main and clinically distinct subtypes of diffuse large B-cell lymphomas (DLBCLs): germinal-center B cell–like (GCB) and activated B cell–like (ABC) DLBCLs. Further work has shown that these subtypes are partially characterized by distinct genetic alterations and different survival. Here, we show with the use of an assay that measures DNA methylation levels of 50 000 CpG motifs distributed among more than 14 000 promoters that these 2 DLBCL subtypes are also characterized by distinct epigenetic profiles. DNA methylation and gene expression profiling were performed on a cohort of 69 patients with DLBCL. After assigning ABC or GCB labels with a Bayesian expression classifier trained on an independent dataset, a supervised analysis identified 311 differentially methylated probe sets (263 unique genes) between ABC and GCB DLBCLs. Integrated analysis of methylation and gene expression showed a core tumor necrosis factor-α signaling pathway as the principal differentially perturbed gene network. Sixteen genes overlapped between the core ABC/GCB methylation and expression signatures and encoded important proteins such as IKZF1. This reduced gene set was an accurate predictor of ABC and GCB subtypes. Collectively, the data suggest that epigenetic patterning contributes to the ABC and GCB DLBCL phenotypes and could serve as useful biomarker.

scholarly journals The role of epigenetic modifications, long-range contacts, enhancers and topologically associating domains in the regulation of glioma grade-specific genes

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ilona E. Grabowicz ◽  
Bartek Wilczyński ◽  
Bożena Kamińska ◽  
Adria-Jaume Roura ◽  
Bartosz Wojtaś ◽  
...  
Keyword(s):  
Gene Expression ◽  
Long Range ◽  
Genetic Alterations ◽  
Chromatin Organization ◽  
Open Chromatin ◽  
Low Grade ◽  
Strong Impact ◽  
Cell Matrix ◽  
Topologically Associating Domains ◽  
Genome Wide

AbstractGenome-wide studies have uncovered specific genetic alterations, transcriptomic patterns and epigenetic profiles associated with different glioma types. We have recently created a unique atlas encompassing genome-wide profiles of open chromatin, histone H3K27ac and H3Kme3 modifications, DNA methylation and transcriptomes of 33 glioma samples of different grades. Here, we intersected genome-wide atlas data with topologically associating domains (TADs) and demonstrated that the chromatin organization and epigenetic landscape of enhancers have a strong impact on genes differentially expressed in WHO low grade versus high grade gliomas. We identified TADs enriched in glioma grade-specific genes and/or epigenetic marks. We found the set of transcription factors, including REST, E2F1 and NFKB1, that are most likely to regulate gene expression in multiple TADs, containing specific glioma-related genes. Moreover, many genes associated with the cell–matrix adhesion Gene Ontology group, in particular 14 PROTOCADHERINs, were found to be regulated by long-range contacts with enhancers. Presented results demonstrate the existence of epigenetic differences associated with chromatin organization driving differential gene expression in gliomas of different malignancy.

scholarly journals Genome-wide DNA methylation and RNA-seq analyses identify genes and pathways associated with doxorubicin resistance in a canine diffuse large B-cell lymphoma cell line

PLoS ONE ◽  
2021 ◽  
Vol 16 (5) ◽  
pp. e0250013
Author(s):  
Chia-Hsin Hsu ◽  
Hirotaka Tomiyasu ◽  
Chi-Hsun Liao ◽  
Chen-Si Lin
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Rna Seq ◽  
Doxorubicin Resistance ◽  
Large B Cell Lymphoma ◽  
Genome Wide ◽  
Large B Cell

Doxorubicin resistance is a major challenge in the successful treatment of canine diffuse large B-cell lymphoma (cDLBCL). In the present study, MethylCap-seq and RNA-seq were performed to characterize the genome-wide DNA methylation and differential gene expression patterns respectively in CLBL-1 8.0, a doxorubicin-resistant cDLBCL cell line, and in CLBL-1 as control, to investigate the underlying mechanisms of doxorubicin resistance in cDLBCL. A total of 20289 hypermethylated differentially methylated regions (DMRs) were detected. Among these, 1339 hypermethylated DMRs were in promoter regions, of which 24 genes showed an inverse correlation between methylation and gene expression. These 24 genes were involved in cell migration, according to gene ontology (GO) analysis. Also, 12855 hypermethylated DMRs were in gene-body regions. Among these, 353 genes showed a positive correlation between methylation and gene expression. Functional analysis of these 353 genes highlighted that TGF-β and lysosome-mediated signal pathways are significantly associated with the drug resistance of CLBL-1. The tumorigenic role of TGF-β signaling pathway in CLBL-1 8.0 was further validated by treating the cells with a TGF-β inhibitor(s) to show the increased chemo-sensitivity and intracellular doxorubicin accumulation, as well as decreased p-glycoprotein expression. In summary, the present study performed an integrative analysis of DNA methylation and gene expression in CLBL-1 8.0 and CLBL-1. The candidate genes and pathways identified in this study hold potential promise for overcoming doxorubicin resistance in cDLBCL.

scholarly journals Identification of gene expression and DNA methylation of SERPINA5 and TIMP1 as novel prognostic markers in lower-grade gliomas

PeerJ ◽  
2020 ◽  
Vol 8 ◽  
pp. e9262
Author(s):  
Wen-Jing Zeng ◽  
Yong-Long Yang ◽  
Zhi-Peng Wen ◽  
Peng Chen ◽  
Xiao-Ping Chen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Classification System ◽  
Differentially Expressed ◽  
Integrated Analysis ◽  
Lower Grade ◽  
Kaplan Meier ◽  
Genome Wide ◽  
Genes Expression ◽  
Tumors Classification ◽  
Long Term Survivors

Background Lower-grade gliomas (LGGs) is characteristic with great difference in prognosis. Due to limited prognostic biomarkers, it is urgent to identify more molecular markers to provide a more objective and accurate tumor classification system for LGGs. Methods In the current study, we performed an integrated analysis of gene expression data and genome-wide methylation data to determine novel prognostic genes and methylation sites in LGGs. Results To determine genes that differentially expressed between 44 short-term survivors (<2 years) and 48 long-term survivors (≥2 years), we searched LGGs TCGA RNA-seq dataset and identified 106 differentially expressed genes. SERPINA5 and TIMP1 were selected for further study. Kaplan–Meier plots showed that SERPINA5 and TIMP1 expression were significantly correlated with overall survival (OS) and relapse-free survival (RFS) in TCGA LGGs patients. We next validated the correlation between the candidate genes expression and clinical outcome in CGGA LGGs patients. Multivariate analysis showed that TIMP1 mRNA expression had a significant prognostic value independent of other variables (HR = 4.825, 95% CI = 1.370–17.000, P = 0.014). Then, differential methylation sites were identified from differentially candidate gene expression groups, and all four methylation sites were significantly negatively correlated with gene expression (spearman r <  − 0.5, P < 0.0001). Moreover, hyper-methylation of four methylation sites indicated better OS (P < 0.05), and three of them also shown statistical significantly association with better RFS, except for SERPINA5 cg15509705 (P = 0.0762). Conclusion Taken together, these findings indicated that the gene expression and methylation of SERPINA5 and TIMP1 may serve as prognostic predictors in LGGs and may help to precise the current histology-based tumors classification system and to provide better stratification for future clinical trials.

scholarly journals Specific Secondary Genetic Alterations in Mantle Cell Lymphoma Provide Prognostic Information Independent of the Gene Expression–Based Proliferation Signature

2007 ◽  
Vol 25 (10) ◽  
pp. 1216-1222 ◽  
Author(s):  
Itziar Salaverria ◽  
Andreas Zettl ◽  
Sílvia Beà ◽  
Victor Moreno ◽  
Joan Valls ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cyclin D1 ◽  
Expression Profiles ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Survival Prediction ◽  
Specific Gene ◽  
Prognostic Information ◽  
Substantial Impact ◽  
Mantle Cell

Purpose To compare the genetic relationship between cyclin D1–positive and cyclin D1–negative mantle cell lymphomas (MCLs) and to determine whether specific genetic alterations may add prognostic information to survival prediction based on the proliferation signature of MCLs. Patients and Methods Seventy-one cyclin D1–positive and six cyclin D1–negative MCLs previously characterized by gene expression profiling were examined by comparative genomic hybridization (CGH). Results Cyclin D1–negative MCLs were genetically characterized by gains of 3q, 8q, and 15q, and losses of 1p, 8p23-pter, 9p21-pter, 11q21-q23, and 13q that were also the most common alterations in conventional MCLs. Parallel analysis of CGH aberrations and locus-specific gene expression profiles in cyclin D1–positive patients showed that chromosomal imbalances had a substantial impact on the expression levels of the genes located in the altered regions. The analysis of prognostic factors revealed that the proliferation signature, the number of chromosomal aberrations, gains of 3q, and losses of 8p, 9p, and 9q predicted survival of MCL patients. A multivariate analysis showed that the gene expression-based proliferation signature was the strongest predictor for shorter survival. However, 3q gains and 9q losses provided prognostic information that was independent of the proliferative activity. Conclusion Cyclin D1–positive and –negative MCLs share the same secondary genetic aberrations, supporting the concept that they correspond to the same genetic entity. The integration of genetic information on chromosome 3q and 9q alterations into a proliferation signature-based model may improve the ability to predict survival in patients with MCL.

Development and Implementation of an Analysis Tool for Array-based Comparative Genomic Hybridization

2007 ◽  
Vol 46 (05) ◽  
pp. 608-613 ◽  
Author(s):  
M. Rosolowski ◽  
H. Berger ◽  
C. Schwaenen ◽  
S. Wessendorf ◽  
M. Loeffler ◽  
...  
Keyword(s):  
Gene Expression ◽  
Comparative Genomic Hybridization ◽  
Gene Expression Data ◽  
Array Cgh ◽  
Comparative Genomic ◽  
Analysis Tool ◽  
Expression Data ◽  
Mrna Gene ◽  
Mrna Gene Expression ◽  
Chip Analysis

Summary Objectives: Array-comparative genomic hybridization (aCGH) is a high-throughput method to detect and map copy number aberrations in the genome. Multi-step analysis of high-dimensional data requires an integrated suite of bioinformatic tools. In this paperwe detail an analysis pipeline for array CGH data. Methods: We developed an analysis tool for array CGH data which supports single and multi-chip analyses as well as combined analyses with paired mRNA gene expression data. The functions supporting relevant steps of analysis were implemented using the open source software R and combined as package aCGHPipeline. Analysis methods were illustrated using 189 CGH arrays of aggressive B-cell lymphomas. Results: The package covers data input, quality control, normalization, segmentation and classification. For multi-chip analysis aCGHPipeline offers an algorithm for automatic delineation of recurrent regions. This task was performed manuallyup to now. The package also supports combined analysis with mRNA gene expression data. Outputs consist of HTML documents to facilitate communication with clinical partners. Conclusions: The R package aCGHPipeline supports basic tasks of single and multi-chip analysis of array CGH data.

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