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Array-based comparative genomic hybridization is more informative than conventional karyotyping and fluorescence in situ hybridization in the analysis of first-trimester spontaneous abortion
Jinsong Gao, Congcong Liu, Fengxia Yao, Na Hao, Jing Zhou, Qian Zhou, Liang Zhang, Xinyan Liu, Xuming Bian, Juntao Liu
Molecular Cytogenetics , 2012, DOI: 10.1186/1755-8166-5-33
Abstract: Abnormalities were detected in 61 cases. aCGH achieved the highest detection rate (93.4%, 57/61) compared with traditional karyotyping (77%, 47/61) and FISH analysis (68.9%, 42/61). aCGH identified all chromosome abnormalities reported by traditional karyotyping and interphase FISH analysis, with the exception of four triploids. It also detected three additional aneuploidy cases in 37 specimens with ‘normal’ karyotypes, one mosaicism and 10 abnormalities in 14 specimens that failed to grow in vitro.aCGH analysis circumvents many limitations in traditional karyotyping or FISH. The accuracy and efficiency of aCGH in spontaneous abortions highlights its clinical usefulness for the future. As aborted tissues have the potential to be contaminated with maternal cells, the threshold value of detection in aCGH should be lowered to avoid false negatives.
Computational Methods for the Analysis of Array Comparative Genomic Hybridization
Raj Chari,William W. Lockwood,Wan L. Lam
Cancer Informatics , 2006,
Abstract: Array comparative genomic hybridization (array CGH) is a technique for assaying the copy number status of cancer genomes. The widespread use of this technology has lead to a rapid accumulation of high throughput data, which in turn has prompted the development of computational strategies for the analysis of array CGH data. Here we explain the principles behind array image processing, data visualization and genomic profile analysis, review currently available software packages, and raise considerations for future software development.
Application of a target array Comparative Genomic Hybridization to prenatal diagnosis
Ji Hyeon Park, Jung Hoon Woo, Sung Han Shim, Song-Ju Yang, Young Min Choi, Kap-Seok Yang, Dong Hyun Cha
BMC Medical Genetics , 2010, DOI: 10.1186/1471-2350-11-102
Abstract: We designed a target bacterial artificial chromosome (BAC)-based aCGH platform (MacArray? M-chip), which specifically targets submicroscopic deletions/duplications for 26 known genetic syndromes of medical significance observed prenatally. To validate the DNA chip, we obtained genomic DNA from 132 reference materials generated from patients with 22 genetic diseases and 94 clinical amniocentesis samples obtained for karyotyping.In the 132 reference materials, all known genomic alterations were successfully identified. In the 94 clinical samples that were also subjected to conventional karyotyping, three cases of balanced chromosomal aberrations were not detected by aCGH. However, we identified eight cases of microdeletions in the Yq11.23 chromosomal region that were not found by conventional karyotyping. This region harbors the DAZ gene, and deletions may lead to non-obstructive spermatogenesis.We have successfully designed and applied a BAC-based aCGH platform for prenatal diagnosis. This platform can be used in conjunction with conventional karyotyping and will provide rapid and accurate diagnoses for the targeted genomic regions while eliminating the need to interpret clinically-uncertain genomic regions.Speed and precision are two major requirements in prenatal chromosome analyses. Conventional G-banded karyotyping remains the gold standard in prenatal genetic diagnosis, but it is time-consuming and labor-intensive. Routinely, about 10-14 days is required to obtain the result and this may increase the patient's anxiety. To overcome these limitations, rapid fluorescent in situ hybridization (FISH), quantitative fluorescent polymerase chain reaction (QF-PCR), and multiplex ligation-dependent probe amplification (MLPA) have been developed and are widely used as adjuncts to conventional methods for detecting common chromosome aneuploidies such as trisomies 21, 13, 18, X and Y [1-6]. However, only a few loci may be tested at a time, so all those methods can usually be
Array comparative genomic hybridization in prenatal diagnosis of first trimester pregnancies at high risk for chromosomal anomalies  [cached]
Filges Isabel,Kang Anjeung,Klug Vanessa,Wenzel Friedel
Molecular Cytogenetics , 2012, DOI: 10.1186/1755-8166-5-38
Abstract: Objective To describe the diagnostic performance of array comparative genomic hybridization (aCGH) as a potential first line diagnostic method in first trimester high risk pregnancies. Method In a retrospective study we performed aCGH using a targeted array BAC platform (Constitutional Chip 4.0, PerkinElmer, Turku Finland, median resolution 600 kB) and the Affymetrix Cytogenetics Whole Genome 2.7 M array (at a resolution of 400kB) on 100 anonymized prenatal samples from first trimester high risk pregnancies with normal conventional karyotype. We studied the technical feasibility and turn-around-time as well as the detection rate of pathogenic submicroscopic chromosome anomalies and CNVs of unknown significance. Results We obtained results in 98 of 100 samples in 3 to a maximum of 5 days after DNA extraction. At the given resolution we did not identify any additional pathogenic CNVs but two CNVs of unknown significance in the chromosomal regions 1q21.1q21.2 (deletion) and 5p15.33 (duplication) (2%). Conclusion In accordance with a growing number of reports this study supports the concept that aCGH at a resolution of 400-600kB may be used as a first line prenatal diagnostic test with high diagnostic safety and rapid turn-around time in high-risk first trimester pregnancies. Detection rate of CNVs of unknown significance, considered as a major hindrance for replacing conventional karyotyping by aCGH, is 2%, but the diagnosis of additional submicroscopic anomalies in this heterogeneous group of patients seems to be rare.
Detection of pathogenic copy number variants in children with idiopathic intellectual disability using 500 K SNP array genomic hybridization
JM Friedman, Shelin Adam, Laura Arbour, Linlea Armstrong, Agnes Baross, Patricia Birch, Cornelius Boerkoel, Susanna Chan, David Chai, Allen D Delaney, Stephane Flibotte, William T Gibson, Sylvie Langlois, Emmanuelle Lemyre, H Irene Li, Patrick MacLeod, Joan Mathers, Jacques L Michaud, Barbara C McGillivray, Millan S Patel, Hong Qian, Guy A Rouleau, Margot I Van Allen, Siu-Li Yong, Farah R Zahir, Patrice Eydoux, Marco A Marra
BMC Genomics , 2009, DOI: 10.1186/1471-2164-10-526
Abstract: We performed 500 K Affymetrix GeneChip? array genomic hybridization in 100 idiopathic intellectual disability trios, each comprised of a child with intellectual disability of unknown cause and both unaffected parents. We found pathogenic genomic imbalance in 16 of these 100 individuals with idiopathic intellectual disability. In comparison, we had found pathogenic genomic imbalance in 11 of 100 children with idiopathic intellectual disability in a previous cohort who had been studied by 100 K GeneChip? array genomic hybridization. Among 54 intellectual disability trios selected from the previous cohort who were re-tested with 500 K GeneChip? array genomic hybridization, we identified all 10 previously-detected pathogenic genomic alterations and at least one additional pathogenic copy number variant that had not been detected with 100 K GeneChip? array genomic hybridization. Many benign copy number variants, including one that was de novo, were also detected with 500 K array genomic hybridization, but it was possible to distinguish the benign and pathogenic copy number variants with confidence in all but 3 (1.9%) of the 154 intellectual disability trios studied.Affymetrix GeneChip? 500 K array genomic hybridization detected pathogenic genomic imbalance in 10 of 10 patients with idiopathic developmental disability in whom 100 K GeneChip? array genomic hybridization had found genomic imbalance, 1 of 44 patients in whom 100 K GeneChip? array genomic hybridization had found no abnormality, and 16 of 100 patients who had not previously been tested. Effective clinical interpretation of these studies requires considerable skill and experience.Chromosomal imbalance has been recognized as the most frequent cause of intellectual disability (ID) for 50 years [1-3]. Until recently, most of this genomic imbalance was diagnosed by cytogenetic analysis, but studies over the past few years have found that ID is caused by constitutional gains or losses of submicroscopic genomic segme
Genomic Profiling of Submucosal-Invasive Gastric Cancer by Array-Based Comparative Genomic Hybridization  [PDF]
Akiko Kuroda,Yoshiyuki Tsukamoto,Lam Tung Nguyen,Tsuyoshi Noguchi,Ichiro Takeuchi,Masahiro Uchida,Tomohisa Uchida,Naoki Hijiya,Chisato Nakada,Tadayoshi Okimoto,Masaaki Kodama,Kazunari Murakami,Keiko Matsuura,Masao Seto,Hisao Ito,Toshio Fujioka,Masatsugu Moriyama
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0022313
Abstract: Genomic copy number aberrations (CNAs) in gastric cancer have already been extensively characterized by array comparative genomic hybridization (array CGH) analysis. However, involvement of genomic CNAs in the process of submucosal invasion and lymph node metastasis in early gastric cancer is still poorly understood. In this study, to address this issue, we collected a total of 59 tumor samples from 27 patients with submucosal-invasive gastric cancers (SMGC), analyzed their genomic profiles by array CGH, and compared them between paired samples of mucosal (MU) and submucosal (SM) invasion (23 pairs), and SM invasion and lymph node (LN) metastasis (9 pairs). Initially, we hypothesized that acquisition of specific CNA(s) is important for these processes. However, we observed no significant difference in the number of genomic CNAs between paired MU and SM, and between paired SM and LN. Furthermore, we were unable to find any CNAs specifically associated with SM invasion or LN metastasis. Among the 23 cases analyzed, 15 had some similar pattern of genomic profiling between SM and MU. Interestingly, 13 of the 15 cases also showed some differences in genomic profiles. These results suggest that the majority of SMGCs are composed of heterogeneous subpopulations derived from the same clonal origin. Comparison of genomic CNAs between SMGCs with and without LN metastasis revealed that gain of 11q13, 11q14, 11q22, 14q32 and amplification of 17q21 were more frequent in metastatic SMGCs, suggesting that these CNAs are related to LN metastasis of early gastric cancer. In conclusion, our data suggest that generation of genetically distinct subclones, rather than acquisition of specific CNA at MU, is integral to the process of submucosal invasion, and that subclones that acquire gain of 11q13, 11q14, 11q22, 14q32 or amplification of 17q21 are likely to become metastatic.
Analysis of Molecular Cytogenetic Alteration in Rhabdomyosarcoma by Array Comparative Genomic Hybridization  [PDF]
Chunxia Liu, Dongliang Li, Jinfang Jiang, Jianming Hu, Wei Zhang, Yunzhao Chen, Xiaobin Cui, Yan Qi, Hong Zou, WenJie Zhang, Feng Li
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0094924
Abstract: Rhabdomyosarcoma (RMS) is the most common pediatric soft tissue sarcoma with poor prognosis. The genetic etiology of RMS remains largely unclear underlying its development and progression. To reveal novel genes more precisely and new therapeutic targets associated with RMS, we used high-resolution array comparative genomic hybridization (aCGH) to explore tumor-associated copy number variations (CNVs) and genes in RMS. We confirmed several important genes by quantitative real-time polymerase chain reaction (QRT-PCR). We then performed bioinformatics-based functional enrichment analysis for genes located in the genomic regions with CNVs. In addition, we identified miRNAs located in the corresponding amplification and deletion regions and performed miRNA functional enrichment analysis. aCGH analyses revealed that all RMS showed specific gains and losses. The amplification regions were 12q13.12, 12q13.3, and 12q13.3–q14.1. The deletion regions were 1p21.1, 2q14.1, 5q13.2, 9p12, and 9q12. The recurrent regions with gains were 12q13.3, 12q13.3–q14.1, 12q14.1, and 17q25.1. The recurrent regions with losses were 9p12–p11.2, 10q11.21–q11.22, 14q32.33, 16p11.2, and 22q11.1. The mean mRNA level of GLI1 in RMS was 6.61-fold higher than that in controls (p = 0.0477) by QRT-PCR. Meanwhile, the mean mRNA level of GEFT in RMS samples was 3.92-fold higher than that in controls (p = 0.0354). Bioinformatic analysis showed that genes were enriched in functions such as immunoglobulin domain, induction of apoptosis, and defensin. Proto-oncogene functions were involved in alveolar RMS. miRNAs that located in the amplified regions in RMS tend to be enriched in oncogenic activity (miR-24 and miR-27a). In conclusion, this study identified a number of CNVs in RMS and functional analyses showed enrichment for genes and miRNAs located in these CNVs regions. These findings may potentially help the identification of novel biomarkers and/or drug targets implicated in diagnosis of and targeted therapy for RMS.
Validation and implementation of array comparative genomic hybridisation as a first line test in place of postnatal karyotyping for genome imbalance
Joo Wook Ahn, Kathy Mann, Sally Walsh, Marwa Shehab, Sarah Hoang, Zoe Docherty, Shehla Mohammed, Caroline Mackie Ogilvie
Molecular Cytogenetics , 2010, DOI: 10.1186/1755-8166-3-9
Abstract: Following a validation period, an oligoarray platform was chosen. In order to minimise costs and increase efficiency, a patient/patient hybridisation strategy was used, and analysis criteria were set to optimise detection of pathogenic imbalance. A customised database application with direct links to a number of online resources was developed to allow efficient management and tracking of patient samples and facilitate interpretation of results. Following introduction into our routine diagnostic service for patients with suspected genome imbalance, array CGH as a follow-on test for patients with normal karyotypes (n = 1245) and as a first-line test (n = 1169) gave imbalance detection rates of 26% and 22% respectively (excluding common, benign variants). At least 89% of the abnormalities detected by first line testing would not have been detected by standard karyotype analysis. The average reporting time for first-line tests was 25 days from receipt of sample.Array CGH can be used in a diagnostic service setting in place of G-banded chromosome analysis, providing a more comprehensive and objective test for patients with suspected genome imbalance. The increase in consumable costs can be minimised by employing appropriate hybridisation strategies; the use of robotics and a customised database application to process multiple samples reduces staffing costs and streamlines analysis, interpretation and reporting of results. Array CGH provides a substantially higher diagnostic yield than G-banded chromosome analysis, thereby alleviating the burden of further clinical investigations.Karyotype analysis of G-banded chromosomes is the cytogenetic standard for the detection of copy number imbalance across the genome, or balanced chromosome rearrangements, in children with such features as idiopathic developmental delay, learning difficulties, congenital abnormalities or autism. However, this technique has a resolution of only 3-5 Mb, and interpretation is operator-dependent, req
Genomic Profiling of Oral Squamous Cell Carcinoma by Array-Based Comparative Genomic Hybridization  [PDF]
Shunichi Yoshioka, Yoshiyuki Tsukamoto, Naoki Hijiya, Chisato Nakada, Tomohisa Uchida, Keiko Matsuura, Ichiro Takeuchi, Masao Seto, Kenji Kawano, Masatsugu Moriyama
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0056165
Abstract: We designed a study to investigate genetic relationships between primary tumors of oral squamous cell carcinoma (OSCC) and their lymph node metastases, and to identify genomic copy number aberrations (CNAs) related to lymph node metastasis. For this purpose, we collected a total of 42 tumor samples from 25 patients and analyzed their genomic profiles by array-based comparative genomic hybridization. We then compared the genetic profiles of metastatic primary tumors (MPTs) with their paired lymph node metastases (LNMs), and also those of LNMs with non-metastatic primary tumors (NMPTs). Firstly, we found that although there were some distinctive differences in the patterns of genomic profiles between MPTs and their paired LNMs, the paired samples shared similar genomic aberration patterns in each case. Unsupervised hierarchical clustering analysis grouped together 12 of the 15 MPT-LNM pairs. Furthermore, similarity scores between paired samples were significantly higher than those between non-paired samples. These results suggested that MPTs and their paired LNMs are composed predominantly of genetically clonal tumor cells, while minor populations with different CNAs may also exist in metastatic OSCCs. Secondly, to identify CNAs related to lymph node metastasis, we compared CNAs between grouped samples of MPTs and LNMs, but were unable to find any CNAs that were more common in LNMs. Finally, we hypothesized that subpopulations carrying metastasis-related CNAs might be present in both the MPT and LNM. Accordingly, we compared CNAs between NMPTs and LNMs, and found that gains of 7p, 8q and 17q were more common in the latter than in the former, suggesting that these CNAs may be involved in lymph node metastasis of OSCC. In conclusion, our data suggest that in OSCCs showing metastasis, the primary and metastatic tumors share similar genomic profiles, and that cells in the primary tumor may tend to metastasize after acquiring metastasis-associated CNAs.
High resolution genomic analysis of sporadic breast cancer using array-based comparative genomic hybridization
Tara L Naylor, Joel Greshock, Yan Wang, Theresa Colligon, QC Yu, Virginia Clemmer, Tal Z Zaks, Barbara L Weber
Breast Cancer Research , 2005, DOI: 10.1186/bcr1356
Abstract: We employed high-resolution array comparative genomic hybridization with 4,134 bacterial artificial chromosomes that cover the genome at 0.9 megabase resolution to analyze 47 primary breast tumors and 18 breast cancer cell lines.Common amplicons included 8q24.3 (amplified in 79% of tumors, with 5/47 exhibiting high level amplification), 1q32.1 and 16p13.3 (amplified in 66% and 57% of tumors, respectively). Moreover, we found several positive correlations between specific amplicons from different chromosomes, suggesting the existence of cooperating genetic loci. Queried by gene, the most frequently amplified kinase was PTK2 (79% of tumors), whereas the most frequently lost kinase was PTK2B (hemizygous loss in 34% of tumors). Amplification of ERBB2 as measured by comparative genomic hybridization (CGH) correlated closely with ERBB2 DNA and RNA levels measured by quantitative PCR as well as with ERBB2 protein levels. The overall frequency of recurrent losses was lower, with no region lost in more than 50% of tumors; the most frequently lost tumor suppressor gene was RB1 (hemizygous loss in 26% of tumors). Finally, we find that specific copy number changes in cell lines closely mimicked those in primary tumors, with an overall Pearson correlation coefficient of 0.843 for gains and 0.734 for losses.High resolution CGH analysis of breast cancer reveals several regions where DNA copy number is commonly gained or lost, that non-random correlations between specific amplicons exist, and that specific genetic alterations are maintained in breast cancer cell lines despite repeat passage in tissue culture. These observations suggest that genes within these regions are critical to the malignant phenotype and may thus serve as future therapeutic targets.Genomic instability is a hallmark of cancer, and specific subchromosomal copy number changes are thought to play a driving role in the transformation of normal cells to malignant clones. These genomic copy number changes may result
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