High-Resolution CGH Analysis of CD34+ Cells from Lower-Risk Myelodysplastic Patients Reveals Cryptic Copy Number Alterations and Predicts Overall and Leukemia-Free Survival.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2431-2431
Author(s):  
Daniel T. Starczynowski ◽  
Suzanne Vercauteren ◽  
Adele Telenius ◽  
Sandy Sung ◽  
Kaoru Tohyama ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Copy Number ◽  
Lower Risk ◽  
Array Cgh ◽  
Comparative Genomic ◽  
Whole Genome ◽  
Copy Number Alterations ◽  
Ancillary Test ◽  
Cd34 Cells ◽  
Marrow Cells

Abstract The myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematologic malignancies characterized by peripheral cytopenias, a hypercellular marrow with ineffective hematopoiesis and a propensity to progress to acute myeloid leukemia (AML). MDS is thought to arise from a primitive (CD34+) hematopoietic cell that has acquired genetic and/or epigenetic abnormalities. Risk stratification according to the International Prognostic Scoring System (IPSS) defines patient categories that correlate with survival and the likelihood of transformation to AML. Greater than 50% of individuals diagnosed with MDS are in the lower-risk groups. The importance of cytogenetics in risk stratification has been verified in several studies, but is of limited value in patients with lower-risk subtypes because approximately 50% of these patients do not have karyotypic abnormalities detectable using standard techniques. To further our biological understanding of lower-risk subtypes of MDS, and to identify potential MDS-initiating alterations in the genome, we looked for alterations in DNA extracts from purified CD34+ marrow cells from 44 MDS lower-risk patients using a submegabase bacterial artificial chromosome (BAC) array to perform whole genome comparative genomic hybridization (CGH) analyses. These studies identified numerous cryptic structural DNA alterations that were not detectable by standard cytogenetic analysis and were also not found in 15 age-matched normal controls. Although most patients tested had a normal karyotype, 23 recurring, novel copy number alterations of a median size of 0.6 megabases were identified. These included gains at 11q24.2-qter, 17q11.2 and 17q12, and losses at 2q33.1-q33.2 and 14q12. Comparison of changes in CD34+ marrow cells with DNA from CD3+ cells isolated from the same patients showed that a recurring duplication at band 17q12 was exclusive to the CD34+ cells in 2 of 3 patients. Validation of this copy number gain at chr 17q12 by FISH confirmed duplication of the locus. In addition, whole genome array CGH analysis of CD34+ marrow cells from karyotypically normal (n = 25) and abnormal (n = 15) lower risk MDS patients revealed extensive genome alterations (involving >3 Mb) correlated with poorer overall survival, and was more frequently associated with transformation to AML as compared to IPSS stratification alone. Our studies suggest that array CGH may be useful as an ancillary test to better stratify lower-risk subtypes of MDS and, at the same time lead to the identification of early mutations that contribute to disease initiation.

High-resolution whole genome tiling path array CGH analysis of CD34+ cells from patients with low-risk myelodysplastic syndromes reveals cryptic copy number alterations and predicts overall and leukemia-free survival

Blood ◽  
2008 ◽  
Vol 112 (8) ◽  
pp. 3412-3424 ◽  
Author(s):  
Daniel T. Starczynowski ◽  
Suzanne Vercauteren ◽  
Adele Telenius ◽  
Sandy Sung ◽  
Kaoru Tohyama ◽  
...  
Keyword(s):  
Myelodysplastic Syndromes ◽  
Copy Number ◽  
Prognostic Significance ◽  
Normal Karyotype ◽  
Low Risk ◽  
International Prognostic Scoring System ◽  
Comparative Genomic ◽  
Whole Genome ◽  
Copy Number Alterations ◽  
Cd34 Cells

Abstract Myelodysplastic syndromes (MDSs) pose an important diagnostic and treatment challenge because of the genetic heterogeneity and poorly understood biology of the disease. To investigate initiating genomic alterations and the potential prognostic significance of cryptic genomic changes in low-risk MDS, we performed whole genome tiling path array comparative genomic hybridization (aCGH) on CD34+ cells from 44 patients with an International Prognostic Scoring System score less than or equal to 1.0. Clonal copy number differences were detected in cells from 36 of 44 patients. In contrast, cells from only 16 of the 44 patients displayed karyotypic abnormalities. Although most patients had normal karyotype, aCGH identified 21 recurring copy number alterations. Examples of frequent cryptic alterations included gains at 11q24.2-qter, 17q11.2, and 17q12 and losses at 2q33.1-q33.2, 5q13.1-q13.2, and 10q21.3. Maintenance of genomic integrity defined as less than 3 Mb total disruption of the genome correlated with better overall survival (P = .002) and was less frequently associated with transformation to acute myeloid leukemia (P = .033). This study suggests a potential role for the use of aCGH in the clinical workup of MDS patients.

Genomic DNA Copy Number Alterations Present in AML Bone Marrow Samples with Normal Cytogenetics.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 142-142 ◽  
Author(s):  
Matthew J. Walter ◽  
Rhonda E. Ries ◽  
Jon Armstrong ◽  
Brian O’Gara ◽  
James W. Vardiman ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Copy Number ◽  
Genomic Dna ◽  
Array Cgh ◽  
Comparative Genomic ◽  
Copy Number Alterations ◽  
Dna Copy Number ◽  
Prognostic Information ◽  
Normal Cytogenetics ◽  
Copy Number Changes

Abstract Cytogenetics and comparative genomic hybridization (CGH) have been used to identify large genomic amplifications and deletions in all subtypes of acute myeloid leukemia (AML). Up to 15–20% of AML patients have a normal karyotype at diagnosis. While cytogenetic abnormalities confer important prognostic information for patients with AML, there remain differences in the therapeutic response and outcome among patients with the same cytogenetic profile, implying that other, more subtle, genetic abnormalities may exist. We hypothesized that a subset of AML patients with normal cytogenetics may contain genomic DNA copy number changes that are too small to be detected using standard cytogenetic techniques. To address this possibility, we used high-resolution bacterial artificial chromosome (BAC) array CGH technology to examine 31 AML patients with normal cytogenetics. The BAC arrays contain 2,464 BAC clones spotted in triplicate on glass slides, and provide a 1 Mb resolution of the entire human genome. Technical generation of the arrays, hybridization parameters, and analysis were similar to that reported for murine BAC array CGH (Nat Genet. 2001 Dec;29(4):459–64). The 31 AML samples included 4 M0, 8 M1, 10 M2, and 9 M4 patients. Array CGH experiments were performed using 500 nanograms of Cyanine 5 labeled genomic DNA from unmanipulated AML bone marrow, mixed with an equal amount of control DNA (a pool of DNA from 4 cancer-free individuals) labeled with Cyanine 3. Using the human 1 Mb BAC arrays, we identified amplifications and deletions from multiple samples that were confirmed with G-banding cytogenetics [del(7)(q31), del(7)(p11.2), +8, del(11)(q13q23), +21, add(21)(q22), −X, −Y, +Y]. In addition, BAC arrays robustly detected copy number alterations that were identified in as few as 4/21 metaphases. We identified 5/31 (16%) patients with normal cytogenetics that contained altered genomic DNA copy numbers using BAC array CGH. Copy number changes were confirmed for several of these genomic loci using a dye-swap experiment, where the AML DNA was labeled with Cyanine 3, and the control DNA with Cyanine 5. Two of the 5 patients with abnormalities detected using array CGH would be reclassified from “intermediate” to “unfavorable” cytogenetics [del(7)(q31.31q34), add(11)(q23.3qter), and 17(p12pter)]. These results suggest that a subset of AML patients with normal cytogenetics contain genomic copy number alterations that may effect treatment and outcome. Patient # FAB subtype Genomic location Gain or loss Size (Megabase) Dye-Swap confirmed 1 M0 7(q31.31q34) loss 2.0 Not done 1 11(q23.3qter) gain 16.5 Not done 2 M1 11(p14) loss 7.4 Yes 3 M1 11(q13.2q14.1) gain 15.8 Yes 3 19(p) gain 64.0 Yes 4 M2 17(p12pter) gain 8.6 Not Done 5 M2 19(p13.1pter) loss 14.8 Yes 5 12(q13) loss 5.0 Yes

Targeted Oligonucleotide Array Assessment of Genomic Copy Number Alterations for Risk Stratification in Chronic Lymphocytic Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1773-1773
Author(s):  
Jane Houldsworth ◽  
Asha Guttapalli ◽  
Xiao J. Yan ◽  
Charles Ma ◽  
Weiyi Chen ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Copy Number ◽  
Array Cgh ◽  
Lymphocytic Leukemia ◽  
P Value ◽  
Copy Number Alterations ◽  
Mutation Status ◽  
Copy Number Changes ◽  
Gain Loss ◽  
Genomic Regions

Abstract Abstract 1773 Risk stratification in chronic lymphocytic leukemia (CLL) is highly desirable and should comprise not only evaluation of clinical features but also molecular prognostic markers. Currently such molecular markers include loss of 17p13, 11q22, 13q14, 6q22, and gain of chromosome 12 as assessed by fluorescence in situ hybridization (FISH) and mutation status of the variable region of the IGH gene (IGHV) by sequencing. In recent years, genome-wide scanning technologies such as array-comparative genomic hybridization (array-CGH) have revealed novel and refined known copy number alterations (CNAs) in the CLL genome. In order to evaluate the potential of array-CGH in prognostication in mature B-cell neoplasms, including CLL, and implement array-CGH in a clinical diagnostic laboratory, a targeted oligonucleotide-based microarray was custom designed to represent genomic regions exhibiting gain/loss in these lymphoid neoplasms. The 4 × 44K formatted array included 2 × 17,348 probes for the 80 selected genomic regions (average resolution of 34kbp), and recommended controls including a 1Mbp genome backbone. DNA extracted from two CLL datasets were submitted to array-CGH using an equimixture of commercially available male/female DNA as a reference. CNAs were detected using Genomics Workbench Lite (Agilent Technologies, Inc.) with the ADM2 algorithm. Analytical sensitivity was assessed by cell line DNA dilution and by FISH (116 specimens) and was 30–40% and 20–25%, respectively. Recurrent CNAs in previously untreated patients, greater than 1.5Mbp in size, were analyzed for association with time to first treatment (TTFT) and overall survival (OS) by the log rank test. Association with IGHV mutation status was tested using the Fisher's two-sided exact test. In both datasets for untreated specimens, unmutated IGHV negatively correlated with both TTFT and OS significantly (p < 0.05). Gain of chromosome 12 was detected in 11–12% of untreated specimens in both datasets and as expected did not associate with outcome. Loss of 13q14 as a sole abnormality (excluding copy number changes arising at known sites of normal variation) was associated with an overall favorable outcome, but specimens with loss of both loci (MIR15A/16-1 and RB1) versus one locus (MIR15A/16-1) did not display significantly different outcomes. As expected loss of 17p13 associated with shorter TTFT and OS, and was observed at higher levels in treated specimens. A similar result was observed for 11q22 loss but not in the second dataset, perhaps due to the relatively short follow-up time. Importantly, four additional copy number changes (gain of 2p, 3q, and 8q, and loss of 8p) were found to associate with shorter TTFT and/or OS, and also occurred at higher frequency in treated specimens. Notably, all but one specimen exhibiting two of these CNAs, were Rai Stage 0-II. After multiple comparisons correction, gain of 2p and 3q, and loss of 8p remained significantly associated with an unfavorable outcome. Gain of 2p25.3-p15 was observed exclusively in unmutated IGHV specimens. Loss of 18p and gain of 17q24 were not considered further for testing due to low frequency or lower frequency in treated specimens (data not shown). Uniquely, these data demonstrate in low-intermediate risk CLL cohorts the prognostic value of genomic gain/loss at multiple sites and support implementation of array-CGH into a clinical setting for risk stratification in CLL where genomic gain or loss of multiple clinically relevant genomic regions can be assessed simultaneously. Dataset 1 Untreated n = 81 TTFT p-value OS p-value Treated n = 38 Dataset 2 n = 169 TTFT p-value OS p-value Treated n = 28 Median TTFT 87.6 mo 24.1 mo Median OS 117.7 mo 37.2 mo Rai Stage     0 25 77     I-II 42 48     III-IV 5 1     na 9 43 Unmutated IGHV 46% (n=80) 0.0003 0.0004 38% (n=163) 0.002 0.044 13q14 loss (sole abnormality) 52.5% 0.038‡ 0.087‡ 33.7% 0.144‡ 0.008‡ MIR15A/16-1, RB1 27.5% 0.77 0.337 11.2% 0.011 1 MIR15A/16-1 25.0% 22.5% 11q22 loss (ATM) 12.3% 0.125 0.009 23.7% 8.3% 0.393 0.977 14.3% 17p13 loss (TP53) 2.5% 0.010 0.012 15.8% 4.7% 0.006 <.0001 10.7% 2p25.3-p15 gain 6.2% 0.002 <.0001 10.5% 3.0% 0.702 0.025 10.7% 8q24 gain 2.5% 0.238 0.014 7.9% 4.1% 0.564 0.007 0.0% 3q26-q27 gain 2.5% <.0001 <.0001 5.3% 3.0% 0.850 <.0001 7.1% 8p23-p21 loss 2.5% 0.002 0.016 10.5% 1.2% 1 <.0001 7.1% Unless otherwise noted, all values associated with shorter times ‡ Associated with longer time na not available Disclosures: Houldsworth: Cancer Genetics, Inc.: Employment. Guttapalli:Cancer Genetics, Inc.: Employment. Ma:Cancer Genetics, Inc.: Employment. Chen:Cancer Genetics, Inc.: Employment. Patil:Cancer Genetics, Inc.: Consultancy.

Array CGH As a Complementary Tool in the Diagnosis of Myelodysplastic Syndromes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3827-3827
Author(s):  
María Abáigar ◽  
Eva Lumbreras ◽  
Irene Rodríguez ◽  
Javier Sánchez-del-Real ◽  
María Díez-Campelo ◽  
...  
Keyword(s):  
Risk Stratification ◽  
Myelodysplastic Syndromes ◽  
Copy Number ◽  
Normal Karyotype ◽  
Chromosome 8 ◽  
Comparative Genomic ◽  
Whole Genome ◽  
Acgh Analysis ◽  
Conventional Cytogenetics ◽  
Copy Number Changes

Abstract Abstract 3827 Background: Myelodysplastic syndromes (MDS) are a heterogeneous group of hematological disorders in which diagnosis, risk stratification, and treatment selection are based on morphological and cytogenetic studies in bone marrow (BM) samples. MDS are characterized by several recurrent chromosomal abnormalities, most of them unbalanced, with a widely variable prognosis. The assessment of these genomic defects is essential for a correct risk stratification of these patients. However, conventional cytogenetic (CC) techniques are not sufficient for the study of all MDS patients, because of the high proportion of normal karyotypes (40–50%) and unsuccessful cytogenetics (10%) (defined as the absence of mitosis). Array-based comparative genomic hybridization (aCGH) technology allows the screening of copy number changes among the whole genome in one single experiment and offers a higher resolution than conventional cytogenetics. Aims: To assess the potential application of aCGH in the clinical diagnosis of MDS as complementary tool to conventional cytogenetics. Patients and Methods: The study cohort comprises a total of 263 patients: MDS (203) and MDS/MPN (60) patients that have been previously studied by CC and FISH. Among the whole series, 33 (12.5%) patients had no successful cytogenetic results due to the absence of mitosis. In the remaining 230 patients with evaluable metaphases, 42 (16%) had an aberrant, while 188 (71.5%) presented a normal karyotype. Within this last group, 141 had ≥20 good-quality metaphases evaluated, 37 had 10–20 metaphases studied, and 10 patients had ≤10 successful metaphases. Copy number changes were analysed in all patients included in the study using NimbleGen Human CGH 12×135K Whole-Genome Tiling Array (Roche NimbleGen). Sex-matched human commercial DNA samples were used as reference. Data were analysed using the segMNT algorithm in NimbleScanv2.6 Software. Subsequently all genomic abnormalities found by aCGH analysis were confirmed by FISH. Results: Using aCGH methodology, copy number changes (greater than 600 bp) were detected in 54 patients of the global series: 4.3% of the normal karyotype patients, 88.1% of cases with abnormal cytogenetics, and 27.3% of patients with unsuccessful cytogenetics. Overall a high correlation (94.3%) between the cytogenetic changes observed by CC and CGH arrays was observed. Thus aCGH analysis revealed the same genomic abnormalities showed by CC in 88.1% of patients. In the remaining 11.9% genomic results were discordant between aCGH and CC, because of the presence of balanced translocations, not assessable by aCGH, and clonal cell populations below 30%. Furthermore, additional genomic abnormalities (n=36) not detected by CC were found by aCGH. The most frequent aberrations were losses affecting chromosomes 5 (33%), 7/7q (17%), 20q (14%), and Y (14%), as well as gains involving chromosome 8 (14%). Interestingly, other abnormalities, mainly losses, were found in chromosomes 4, 12, and 17. Focusing on the 188 patients with normal karyotype by CC, the aCGH profiling results were concordant with cytogenetics in 98% of those patients with ≥20 metaphases studied and in 92% of those with 10–20 metaphases. However, only 80% of those patients with ≤10 successful metaphases and no changes by CC displayed no copy number changes by aCGH. The most frequent abnormality found by aCGH among these normal karyotype cases was the presence of 5q deletion (2%), while other chromosomes affected were 7, 8, 11, 12 and 20. All these abnormalities were confirmed by FISH. Regarding the patients with unsuccessful cytogenetics, 72.7% of cases displayed a normal aCGH profile, while 27.3% showed at least one genomic imbalance The most frequent genomic aberrations were losses in 4q (6%), 5q (12%) and 7q (9%), and gain of chromosome 8 (6%). In addition, three of these cases showed a complex karyotype, showing more than 5 abnormalities. Conclusion: The use of aCGH karyotyping in the diagnosis of MDS could be used as a complementary technique to conventional karyotyping in the evaluation of MDS patients. Mainly in patients with unsuccessful cytogenetics and those with normal karyotype and <20 good-quality metaphases evaluated. Disclosures: Hernández: Celgene: Research Funding.

Whole genome tiling path array CGH analysis of segmental copy number alterations in cervical cancer cell lines

2007 ◽  
Vol 120 (2) ◽  
pp. 436-443 ◽  
Author(s):  
William W. Lockwood ◽  
Bradley P. Coe ◽  
Ariane C. Williams ◽  
Calum MacAulay ◽  
Wan L. Lam
Keyword(s):  
Cervical Cancer ◽  
Cell Lines ◽  
Cancer Cell ◽  
Copy Number ◽  
Array Cgh ◽  
Cancer Cell Lines ◽  
Cervical Cancer Cell ◽  
Whole Genome ◽  
Copy Number Alterations

Genetic Alterations Detected by High-Resolution Array Comparative Genomic Hybridization in Microdissected HRS Cells Correlate with Treatment Outcome in Classical Hodgkin Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 522-522
Author(s):  
Christian Steidl ◽  
Adele Telenius ◽  
Sohrab P. Shah ◽  
K-John Cheung ◽  
Lorena Barclay ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
High Resolution ◽  
Disease Progression ◽  
Hodgkin Lymphoma ◽  
Copy Number ◽  
Whole Genome Amplification ◽  
Array Cgh ◽  
Whole Genome ◽  
Copy Number Alterations ◽  
Genome Amplification

Abstract INTRODUCTION: Clinical decision making in Hodgkin lymphoma (HL) is primarily based on clinical variables in part because the scarcity of the malignant Hodgkin Reed Sternberg cells (HRS cells) hampers their molecular characterization. However, more recently investigation using laser capture microdissection has allowed a more detailed analysis of these cells. The objective of this study was to detect genomic alterations in HRS cells and correlate these changes with treatment outcome. PATIENTS AND METHODS: We studied 53 patients with classical HL who were primarily treated at the BC Cancer Agency in Vancouver between 1984 and 2006. All received at least 4 cycles of polychemotherapy and stage-dependent radiotherapy if indicated. The cohort included 43 pretreatment samples and 10 biopsies taken at relapse. Treatment failure was defined as disease progression or relapse at any time (n=23), treatment success as absence of progression (n=30). Whole genome amplification (GenomePlex, Sigma) of pools from 500–1000 individually picked, microdissected HRS cells (Molecular Machines & Industries Cellcut with Nikon Eclipse TE2000-S microscope) was performed. 200 ng of amplified DNA was hybridized to 32k submegabase resolution BAC tiling arrays (SMRT) against sex-matched control-DNA. Scoring of array CGH data was performed by computational analysis using CNA-HMMer v0.1 (available at http://www.cs.ubc.ca/~sshah/acgh/) based on a Hidden Markov Model (HMM). Clustering of the 53 cases was performed using the K-medoids algorithm. Areas of amplification bias and known copy number polymorphisms were excluded. RESULTS: On average whole genome amplification generated 500-fold amplification of genomic DNA. The most frequent copy number alterations (&gt;20% of cases) included gains of 2p14–24.3, 9p12–24.3, 12p11.21–13.33, 16p11.2–13.3, 17p11.2–13.3, 17q11.1–25.1, 19p12–13.3, 19q12–13.43, 20q11.21–13.32, 21q22.11–22.2 and losses of 1p36.31–36.33, 6q11.1–27, 7q22.1–36.3, 8p23.1–23.3, 11q22.3–25, 13q33.3–34 and Xq11.2–28. We also identified several small changes (&lt;5 Mbs) such as loss of 1p36.32, 5q31.1 or 6q23.3 and amplification of 1q32.1, 8q24.21, 17q21.31 or 20q13.2. When comparing the different outcome groups we more frequently identified gains of chromosomal regions 12p13.31–13.33 and 16p12.1–13.3 in treatment failures (39% vs. 13%, Fisher exact p=0.05 and 43% vs. 10%, p=0.009), and losses of chromosomal regions 16q12.1–12.2 and 17p13.1–13.2 (17% vs. 0%, p=0.061 and 27% vs. 4%, p=0.061) were more frequently observed in treatment successes. We did not find significant differences of these changes between pretreatment (n=13) and relapse biopsies (n=10) of patients failing treatment. Using unsupervised analysis we identified a sample cluster of eight cases characterized by simultaneous occurrence of gains of 2p, 16p, 17p, 19q and losses of 6q. Notably, treatment failed in six of these cases. DISCUSSION: The combination of laser microdissection with subsequent WGA and high resolution array CGH provides a robust and sensitive platform for detecting chromosomal imbalances in microdissected HRS cells. We identified at high-resolution new and recurrent changes defining chromosomal regions that potentially harbor oncogenes and tumor suppressor genes crucial to the pathogenesis of HL. Furthermore, we found copy number alterations that are significantly associated with disease progression which, therefore, could serve as predictive factors for treatment outcome.

scholarly journals Whole Genome Comparative Genomic Hybridization of Ewing Sarcoma Indicates Cytoskeleton, Migration and Protein Trafficking

Proceedings ◽  
2018 ◽  
Vol 2 (25) ◽  
pp. 1547
Author(s):  
Burçin Baran ◽  
Safiye Aktaş ◽  
Hülya Tosun ◽  
Gülden Diniz ◽  
Yasemin Çakır ◽  
...  
Keyword(s):  
Comparative Genomic Hybridization ◽  
Ewing Sarcoma ◽  
Protein Trafficking ◽  
Copy Number ◽  
Rho Gtpase ◽  
Predictive Biomarkers ◽  
Comparative Genomic ◽  
Whole Genome ◽  
Copy Number Alterations ◽  
Genomic Hybridization

Ewing sarcoma is a bone and soft tissue tumor either neuroectodermal or mesenchymal originated and affecting children and adolescents. In the present study, we aimed to find out prognostic and predictive biomarkers for Ewing sarcoma. Hence, we examined the copy number alterations (and related possible genes) among ten Ewing sarcoma patient samples and possible associations with the clinical outcome. DNA extraction from formalin fixed paraffin embedded archive tissues was performed. Whole genome Comparative Genomic Hybridization (CGH) was performed by NimbleGen and recorded as single Panel Rainbow through chromosomes 1–22, X and Y. Data was interpreted by SignalMap software and genetic regions matching the deletion or amplification loci were recorded. The mean age of the patients was 8.6 years. Three of the cases were male, while seven were female. According to CGH analysis, the most common DNA copy number alterations were found in SLIT-ROBO Rho GTPase activating protein (srGAP2), RANBP2 like GRIP domain (RGPD5), nephrocystin 1 (NPHP1), GTF2I repeat domain containing 2 (GTF2IRD2), pyridoxal dependent decarboxylase domain containing 1 (PXDC1), which were found down-regulated among 7 of 10 patients. In conclusion, in our dataset the copy number alterations are mostly found in genes related with cytoskeletal elements, migration and protein trafficking among our patient group. Gene functional studies are required for better understanding the role of these genes in Ewing Sarcoma pathogenesis

Copy Number Alterations at Polymorphic Loci May Be Acquired Somatically in Patients with Myelodysplastic Syndromes.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2782-2782
Author(s):  
Daniel T. Starczynowski ◽  
Suzanne Vercauteren ◽  
Sandy Sung ◽  
Angela Brooks-Wilson ◽  
Wan L Lam ◽  
...  
Keyword(s):  
Copy Number ◽  
Conflicts Of Interest ◽  
Normal Population ◽  
Copy Number Variants ◽  
Low Risk ◽  
Comparative Genomic ◽  
Copy Number Alterations ◽  
Polymorphic Loci ◽  
Cd34 Cells ◽  
Somatic Alterations

Abstract Abstract 2782 Poster Board II-758 Myelodysplastic (MDS) clones are thought to arise from a primitive CD34+ hematopoietic cell as a result of disrupted genomic integrity. Although approximately 50% of low-risk MDS patients do not exhibit karyotypic alterations, recent studies have identified submegabase copy number alterations in a proportion (18–68%) of cytogenetically normal cases using genomic array platforms. Recently, we observed disease-associated copy number alterations in low-risk MDS patients that overlapped common loci known to be sites of copy number variants (CNV). These CNV or copy number polymorphisms are a source of structural variation in the genome of a normal population, and widely assumed to be constitutional and not relevant findings in malignant tissue. Here we show by whole genome array comparative genomic hybridization that copy number changes in the CD34+ MDS clone that occur at polymorphic loci are frequently somatic alterations rather than constitutional variants. Further, the extent of copy number variation is increased in CD34+ cells of MDS patients compared to CD34+ cells of age-matched controls. This increase in disease-associated copy number alterations at polymorphic loci shows a trend toward association with poorer overall survival. Our findings demonstrate that copy number alterations at known polymorphic loci in CD34+ cells from lower-risk MDS patients are frequently due to somatic changes rather than constitutional polymorphisms. Further, alterations in copy number at these sites are likely not benign, regardless of whether they represent constitutional or somatic alterations, and may contribute to disease progression. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Genomic imbalances detected through array CGH in fetuses with holoprosencephaly

2011 ◽  
Vol 69 (1) ◽  
pp. 3-8 ◽  
Author(s):  
Isabela Nelly Machado ◽  
Juliana Karina Heinrich ◽  
Ricardo Barini
Keyword(s):  
Copy Number ◽  
Array Cgh ◽  
Copy Number Variations ◽  
Comparative Genomic ◽  
Molecular Technique ◽  
Whole Genome ◽  
Genomic Imbalances ◽  
Whole Genome Microarray ◽  
Gains And Losses

OBJECTIVE: Holoprosencephaly (HPE) is heterogeneous in pathogenesis, integrating genetic susceptibility with the influence of environmental factors. Submicroscopic aberrations may contribute to the etiology of HPE. Our aim was to report the molecular analysis of 4 fetuses with HPE and normal metaphase karyotype. METHOD: A whole genome BAC-array based Comparative Genomic Hybridization (array CGH) was carried out in fetal blood samples. All potential cytogenetic alterations detected on the arrays were matched against the known copy number variations databases. RESULTS: The array CGH analysis showed copy number gains and losses in all cases. We found a recurrent deletion in 15q14 (clone RP11-23J11) and in 15q22 (clone RP11-537k8) in 2 out 4 cases analyzed. We also observed submicroscopic gain in 6p21 in 3 out of 4 fetuses in nearby clones. All these regions were tested in known databases and no copy number variations have been described for them. CONCLUSION: This is the first report of molecular characterization through a whole genome microarray CGH of fetuses with HPE. Our results may contribute to verify the effectiveness and applicability of the molecular technique of array CGH for prenatal diagnosis purposes, and contributing to the knowledge of the submicroscopic genomic instability characterization of HPE fetuses.

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