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Genomic subtypes of breast cancer identified by array-comparative genomic hybridization display distinct molecular and clinical characteristics
G?ran J?nsson, Johan Staaf, Johan Vallon-Christersson, Markus Ringnér, Karolina Holm, Cecilia Hegardt, Haukur Gunnarsson, Rainer Fagerholm, Carina Strand, Bjarni A Agnarsson, Outi Kilpivaara, Lena Luts, P?ivi Heikkil?, Kristiina Aittom?ki, Carl Blomqvist, Niklas Loman, Per Malmstr?m, H?kan Olsson, Oskar Th Johannsson, Adalgeir Arason, Heli Nevanlinna, Rosa B Barkardottir, ?ke Borg
Breast Cancer Research , 2010, DOI: 10.1186/bcr2596
Abstract: We applied global DNA copy number and gene-expression profiling in 359 breast tumors. All tumors were classified according to intrinsic gene-expression subtypes and included cases from genetically predisposed women. The Genomic Identification of Significant Targets in Cancer (GISTIC) algorithm was used to identify significant DNA copy-number aberrations and genomic subgroups of breast cancer.We identified 31 genomic regions that were highly amplified in > 1% of the 359 breast tumors. Several amplicons were found to co-occur, the 8p12 and 11q13.3 regions being the most frequent combination besides amplicons on the same chromosomal arm. Unsupervised hierarchical clustering with 133 significant GISTIC regions revealed six genomic subtypes, termed 17q12, basal-complex, luminal-simple, luminal-complex, amplifier, and mixed subtypes. Four of them had striking similarity to intrinsic gene-expression subtypes and showed associations to conventional tumor biomarkers and clinical outcome. However, luminal A-classified tumors were distributed in two main genomic subtypes, luminal-simple and luminal-complex, the former group having a better prognosis, whereas the latter group included also luminal B and the majority of BRCA2-mutated tumors. The basal-complex subtype displayed extensive genomic homogeneity and harbored the majority of BRCA1-mutated tumors. The 17q12 subtype comprised mostly HER2-amplified and HER2-enriched subtype tumors and had the worst prognosis. The amplifier and mixed subtypes contained tumors from all gene-expression subtypes, the former being enriched for 8p12-amplified cases, whereas the mixed subtype included many tumors with predominantly DNA copy-number losses and poor prognosis.Global DNA copy-number analysis integrated with gene-expression data can be used to dissect the complexity of breast cancer. This revealed six genomic subtypes with different clinical behavior and a striking concordance to the intrinsic subtypes. These genomic subtypes may pro
Genomic profiling of plasmablastic lymphoma using array comparative genomic hybridization (aCGH): revealing significant overlapping genomic lesions with diffuse large B-cell lymphoma
Chung-Che Chang, Xiaobo Zhou, Jesalyn J Taylor, Wan-Ting Huang, Xianwen Ren, Federico Monzon, Yongdong Feng, Pulivarthi H Rao, Xin-Yan Lu, Facchetti Fabio, Susan Hilsenbeck, Chad J Creighton, Elaine S Jaffe, Ching-Ching Lau
Journal of Hematology & Oncology , 2009, DOI: 10.1186/1756-8722-2-47
Abstract: Examination of genomic data in PL revealed that the most frequent segmental gain (> 40%) include: 1p36.11-1p36.33, 1p34.1-1p36.13, 1q21.1-1q23.1, 7q11.2-7q11.23, 11q12-11q13.2 and 22q12.2-22q13.3. This correlated with segmental gains occurring in high frequency in DLBCL (AIDS-related and non AIDS-related) cases. There were some segmental gains and some segmental loss that occurred in PL but not in the other types of lymphoma suggesting that these foci may contain genes responsible for the differentiation of this lymphoma. Additionally, some segmental gains and some segmental loss occurred only in PL and AIDS associated DLBCL suggesting that these foci may be associated with HIV infection. Furthermore, some segmental gains and some segmental loss occurred only in PL and PCM suggesting that these lesions may be related to plasmacytic differentiation.To the best of our knowledge, the current study represents the first genomic exploration of PL. The genomic aberration pattern of PL appears to be more similar to that of DLBCL (AIDS-related or non AIDS-related) than to PCM. Our findings suggest that PL may remain best classified as a subtype of DLBCL at least at the genome level.Plasmablastic lymphoma (PL), one of the most frequent oral malignancies in human immunodeficiency virus (HIV) infected patients, was first characterized by Delecluse et al [1]. They proposed that this constituted a new subtype of diffuse large B cell lymphoma (DLBCL); it was suggested as a distinct entity based on its blastic morphology, its clinical behavior involving predominantly extramedullary sites (particularly oral cavity), and its limited antigenic phenotype data suggesting differentiation toward plasmacytic differentiation (CD20-, CD79a+ and VS38c+). The incidence of PL has increased following the introduction of highly active antiretroviral therapy (HAART) [2,3]. By WHO Classification, PL is categorized as a subtype of DLBCL associated with HIV and Epstein-Barr virus [1,4,5].Recent morph
Genomic instability influences the transcriptome and proteome in endometrial cancer subtypes
Jens K Habermann, Nana K Bündgen, Timo Gemoll, Sampsa Hautaniemi, Caroline Lundgren, Danny Wangsa, Jana Doering, Hans-Peter Bruch, Britta Nordstroem, Uwe J Roblick, Hans J?rnvall, Gert Auer, Thomas Ried
Molecular Cancer , 2011, DOI: 10.1186/1476-4598-10-132
Abstract: DNA image cytometry classified 25 endometrioid cancers to be either diploid (n = 16) or aneuploid (n = 9), and all uterine papillary serous cancers (UPSC) to be aneuploid (n = 8). All samples were subjected to comparative genomic hybridization and gene expression profiling. Identified genes were subjected to Ingenuity pathway analysis (IPA) and were correlated to protein expression changes.Comparative genomic hybridization revealed ploidy-associated specific, recurrent genomic imbalances. Gene expression analysis identified 54 genes between diploid and aneuploid endometrioid carcinomas, 39 genes between aneuploid endometrioid cancer and UPSC, and 76 genes between diploid endometrioid and aneuploid UPSC to be differentially expressed. Protein profiling identified AKR7A2 and ANXA2 to show translational alterations consistent with the transcriptional changes. The majority of differentially expressed genes and proteins belonged to identical molecular functions, foremost Cancer, Cell Death, and Cellular Assembly and Organization.We conclude that the grade of genomic instability rather than the histopathological subtype correlates with specific gene and protein expression changes. The identified genes and proteins might be useful as molecular targets for improved diagnostic and therapeutic intervention and merit prospective validation.Endometrial cancer is the most common malignancy of the female genital tract in the Western world and the fourth common cancer in women [1]. In general it is considered to have a favorable prognosis since it usually becomes symptomatic at an early tumor stage. Thus, about 70% of the affected women are detected at tumor stage I. At this stage, the mean survival of five years has been estimated to be 87%. However, one histopathological subtype, uterine papillary serous cancer (UPSC), presents with an aggressive clinical course characterized by early metastasis, reduced survival rates and inferior prognosis compared to endometrioid carcinomas [
Genomic Instability: The Driving Force behind Refractory/Relapsing Hodgkin’s Lymphoma  [PDF]
Hans Knecht,Christiaan Righolt,Sabine Mai
Cancers , 2013, DOI: 10.3390/cancers5020714
Abstract: In classical Hodgkin’s lymphoma (HL) the malignant mononuclear Hodgkin (H) and multinuclear, diagnostic Reed-Sternberg (RS) cells are rare and generally make up <3% of the total cellular mass of the affected lymph nodes. During recent years, the introduction of laser micro-dissection techniques at the single cell level has substantially improved our understanding of the molecular pathogenesis of HL. Gene expression profiling, comparative genomic hybridization analysis, micro-RNA expression profiling and viral oncogene sequencing have deepened our knowledge of numerous facets of H- and RS-cell gene expression deregulation. The question remains whether disturbed signaling pathways and deregulated transcription factors are at the origin of refractory/relapsing Hodgkin’s lymphoma or whether these hallmarks are at least partially related to another major factor. We recently showed that the 3D nuclear organization of telomeres and chromosomes marked the transition from H- to RS-cells in HL cell lines. This transition is associated with progression of telomere dysfunction, shelterin disruption and progression of complex chromosomal rearrangements. We reported analogous findings in refractory/relapsing HL and identified the shelterin proteins TRF1, TRF2 and POT1 as targets of the LMP1 oncogene in post-germinal center B-cells. Here we summarize our findings, including data not previously published, and propose a model in which progressive disruption of nuclear integrity, a form of genomic instability, is the key-player in refractory/relapsing HL. Therapeutic approaches should take these findings into account.
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.
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.
An Improved Method for Genomic In situ Hybridization in Oryza Species  [PDF]
Muhammad Asghar,Darshan S. Brar
Pakistan Journal of Biological Sciences , 2000,
Abstract: For molecular characterization of F1 hybrid of 0. sativa x 0. officinalis and its backcross-I generation (BC1) with 0. sativa through genomic in situ hybridization (GISH), biotin labelled total genomic DNA from 0. officinalis was used as probe. Cytological preparations were made by enzymatic maceration technique. Probe was hybridized onto chromosomal preparations at 37°C and signals were detected by colorimetric method using 3-amino-9-ethylcarbazole. Labelling efficiency of probe was determined by dot blot method prior to hybridization reaction. Based on the appearance of signal on chromosomes, it was inferred that there exists partial homoeology between the genomes of 0. sativa and 0. officinalis and there are higher chances of gene(s) transfer from 0. officinalis to 0. sativa . More over the study shows that GISH is a powerful technique for genomic characterization of breeding material at any generation.
CGI: Java Software for Mapping and Visualizing Data from Array-based Comparative Genomic Hybridization and Expression Profiling
Joyce Xiuweu-Xu Gu,Michael Yang Wei,Pulivarthi H. Rao,Ching C. Lau
Gene Regulation and Systems Biology , 2007,
Abstract: With the increasing application of various genomic technologies in biomedical research, there is a need to integrate these data to correlate candidate genes/regions that are identified by different genomic platforms. Although there are tools that can analyze data from individual platforms, essential software for integration of genomic data is still lacking. Here, we present a novel Java-based program called CGI (Cytogenetics-Genomics Integrator) that matches the BAC clones from array-based comparative genomic hybridization (aCGH) to genes from RNA expression profiling datasets. The matching is computed via a fast, backend MySQL database containing UCSC Genome Browser annotations. This program also provides an easy-to-use graphical user interface for visualizing and summarizing the correlation of DNA copy number changes and RNA expression patterns from a set of experiments. In addition, CGI uses a Java applet to display the copy number values of a specifi c BAC clone in aCGH experiments side by side with the expression levels of genes that are mapped back to that BAC clone from the microarray experiments. The CGI program is built on top of extensible, reusable graphic components specifically designed for biologists. It is cross-platform compatible and the source code is freely available under the General Public License.
Genomic Markers Reveal Introgressive Hybridization in the Indo-West Pacific Mangroves: A Case Study  [PDF]
Mei Sun,Eugenia Y. Y. Lo
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0019671
Abstract: Biodiversity of mangrove ecosystems is difficult to assess, at least partly due to lack of genetic verification of morphology-based documentation of species. Natural hybridization, on the one hand, plays an important role in evolution as a source of novel gene combinations and a mechanism of speciation. However, on the other hand, recurrent introgression allows gene flow between species and could reverse the process of genetic differentiation among populations required for speciation. To understand the dynamic evolutionary consequences of hybridization, this study examines genomic structure of hybrids and parental species at the population level. In the Indo-West Pacific, Bruguiera is one of the dominant mangrove genera and species ranges overlap extensively with one another. Morphological intermediates between sympatric Bruguiera gymnorrhiza and Bruguiera sexangula have been reported as a variety of B. sexangula or a new hybrid species, B. × rhynchopetala. However, the direction of hybridization and extent of introgression are unclear. A large number of species-specific inter-simple sequence repeat (ISSR) markers were found in B. gymnorrhiza and B. sexangula, and the additive ISSR profiling of B. × rhynchopetala ascertained its hybrid status and identified its parental origin. The varying degree of scatterness among hybrid individuals in Principal Coordinate Analysis and results from NewHybrids analysis indicate that B. × rhynchopetala comprises different generations of introgressants in addition to F1s. High genetic relatedness between B. × rhynchopetala and B. gymnorrhiza based on nuclear and chloroplast sequences suggests preferential hybrid backcrosses to B. gymnorrhiza. We conclude that B. × rhynchopetala has not evolved into an incipient hybrid species, and its persistence can be explained by recurrent hybridization and introgression. Genomic data provide insights into the hybridization dynamics of mangrove plants. Such information can assist in biodiversity assessment by helping detect novel taxa and/or define species boundaries.
Molecular Karyotyping of Human Single Sperm by Array- Comparative Genomic Hybridization  [PDF]
Cristina Patassini, Andrea Garolla, Alberto Bottacin, Massimo Menegazzo, Elena Speltra, Carlo Foresta, Alberto Ferlin
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0060922
Abstract: No valid method is currently available to analyze the entire genome of sperm, including aneuploidies and structural chromosomal alterations. Here we describe the optimization and application of array-Comparative Genomic Hybridization (aCGH) on single human sperm. The aCGH procedure involves screening of the entire chromosome complement by DNA microarray allowing having a molecular karyotype, and it is currently used in research and in diagnostic clinical practice (prenatal diagnosis, pre-implantation genetic diagnosis), but it has never been applied on sperm. DNA from single human sperm isolated by micromanipulator was extracted, decondensed and amplified by whole-genome amplification (WGA) and then labeled, hybridized to BAC array, and scanned by microarray scanner. Application of this protocol to 129 single sperm from normozoospermic donors identified 7.8% of sperm with different genetic anomalies, including aneuploidies and gains and losses in different chromosomes (unbalanced sperm). On the contrary, of 130 single sperm from men affected by Hodgkin lymphoma at the end of three months of chemotherapy cycles 23.8% were unbalanced. Validation of the method also included analysis of 43 sperm from a man with a balanced translocation [46,XY,t(2;12)(p11.2;q24.31)], which showed gains and losses corresponding to the regions involved in the translocation in 18.6% of sperm and alterations in other chromosomes in 16.3% of sperm. Future application of this method might give important information on the biology and pathophysiology of spermatogenesis and sperm chromosome aberrations in normal subjects and in patients at higher risk of producing unbalanced sperm, such as infertile men, carriers of karyotype anomalies, men with advanced age, subjects treated with chemotherapy, and partners of couples with repeated miscarriage and repeated failure during assisted reproduction techniques.
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