Characterization of the Copy-Number Changes In Primary CNS Lymphomas (PCNSL) by High-Resolution Array-Based Comparative Genomic Hybridization

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 995-995
Author(s):  
Esteban Braggio ◽  
Brian Patrick O'Neill ◽  
William Macon ◽  
Maria Beatriz Lopes ◽  
David Schiff ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
B Cell ◽  
Comparative Genomic Hybridization ◽  
Pathway Analysis ◽  
Copy Number ◽  
Research Funding ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Genomic Hybridization

Abstract Abstract 995 PCNSL is an aggressive primary brain tumor characterized by a perivascular accumulation of malignant lymphoid cells. Most PCNSLs (90%) are diffuse large B-cell lymphoma (DLBCL); the remaining 10% are poorly characterized low-grade, Burkitt, and T-cell lymphomas. Since most patients are biopsed, genomic analyses are challenging. To determine the pattern of genetic alterations in PCNSL, frozen samples and formalin fixed embedded paraffin sections from 17 EBV and HIV negative and immunocompetent patients were studied by array-based comparative genomic hybridization (aCGH) using Sureprint G3 (1 million probes) array (Agilent). B-cell differentiation status was characterized by immunostains for CD10, MUM-1, and BCL-6. All cases were characterized by complex genomic aberrations with a median of 21 copy-number abnormalities (CNA) per patient (range 10–49). Overall, 22 minimal deleted regions (MDR) and 14 minimal amplified regions (MAR) were found in more than 20% of patients. Focal deletion affecting CDKN2A (9p21) was the most common CNA, found in 14 of 17 cases (82%); biallelic in six cases. Losses of 6q were observed in 71% of cases. Deletions of 6q23.3 (TNFAIP3) and 6q21 (PRDM1) were found in 59% (10/17) and 47% (8/17) of cases, respectively. Other common CNA were deletions of 6p21 (9/17; 53%), 3p21.1 (5/17; 29%), 3q26.32 (5/17; 29%), 8q12.1 (5/17; 29%), 10p14-p15.3 (5/17; 29%), 12q24.31 (5/17; 29%) and gains of 12q21-q24 (9/17; 53%), 7q21-q31 (6/17; 35%), 19q13 (6/17; 35%), 3q27.3 (5/17; 29%) and 11q24.1-q25 (5/17; 29%). Interestingly, several CNA were unique to PCNSL and were not identified in related entities as the typical DLBCL. Besides in CDKN2A, homozygous deletions were recurrently found in TMEM30A and TOX, the latter a regulator of T-cell development. Another 64 genes, including B2M, CD58, ETV6, LAPTM, MHC class II genes, PRDM1, TNFRSF10A and TNFRSF10B were also homozygously deleted. CD58, which encodes for a member of the immunoglobulin family and regulates the adhesion and activation of T lymphocytes, was also recurrently affected by focal monoallelic losses from 15 nucleotides to 1–2 exons, affecting the Ig-like C2-type domain as was confirmed by DNA resequencing. Focal heterozygous deletions affect TBL1XR1, a negative regulator of the NF-kB and Wnt pathways, and the putative tumor suppressor BCL7A in 29% of cases each. Pathway analysis done including the most commonly affected genes (Ingenuity Pathway Analysis) highlights the importance of networks associated with apoptosis and lymphocyte differentiation and proliferation, especially of T lymphocytes. In summary, this study showed evidence for a highly complex genome and identified target genes of potential relevance in the pathogenesis of PCNSL. The genomic profile described here is unique to PCNSL, thus helping to genetically differentiate this entity from the typical DLBCL and other related lymphomas. Disclosures: Fonseca: Genzyme: Consultancy; Medtronic: Consultancy; BMS: Consultancy; AMGEN: Consultancy; Otsuka: Consultancy; Celgene: Consultancy, Research Funding; Intellikine: Consultancy; Cylene: Research Funding; Onyx: Research Funding; FISH probes prognostication in myeloma: Patents & Royalties.

Comparative genomic hybridization analysis of craniopharyngiomas

2003 ◽  
Vol 98 (1) ◽  
pp. 162-164 ◽  
Author(s):  
Shlomit Rienstein ◽  
Eric F. Adams ◽  
David Pilzer ◽  
Ayala Aviram Goldring ◽  
Boleslaw Goldman ◽  
...  
Keyword(s):  
Comparative Genomic Hybridization ◽  
Copy Number ◽  
Molecular Mechanisms ◽  
Genetic Alterations ◽  
Genomic Alteration ◽  
Comparative Genomic ◽  
Genomic Hybridization ◽  
Dna Copy Number ◽  
Content Type ◽  
Fine Print

Object. Craniopharyngioma is the most common childhood brain tumor and is thought to arise from embryonic remnants of the Rathke pouch. Some craniopharyngiomas are monoclonal in origin and hence presumably harbor somatic genetic alterations, although the precise molecular mechanisms involved in craniopharyngioma development are unknown. The goal of this study was to identify genetic alterations in craniopharyngiomas. Methods. To gain insight into the molecular mechanisms involved in development of these tumors, the authors analyzed nine adamantinomatous craniopharyngiomas by using comparative genomic hybridization. Six tumors (67%) displayed at least one genomic alteration, and three had six or more alterations. Only two tumors displayed a decrease in DNA copy number, and in all others an increase in DNA copy number was noted. Conclusions. The authors conclude that a subset of craniopharyngiomas consists of monoclonal tumors arising from activation of oncogenes located at specific chromosomal loci.

scholarly journals Genomic Profiling by Array Comparative Genomic Hybridization Reveals Novel DNA Copy Number Changes in Breast Phyllodes Tumours

2009 ◽  
Vol 31 (1) ◽  
pp. 31-39
Author(s):  
Arno Kuijper ◽  
Antoine M. Snijders ◽  
Els M. J. J. Berns ◽  
Vibeke Kuenen-Boumeester ◽  
Elsken van der Wall ◽  
...  
Keyword(s):  
Comparative Genomic Hybridization ◽  
Copy Number ◽  
Array Comparative Genomic Hybridization ◽  
Copy Number Change ◽  
Genetic Alterations ◽  
Comparative Genomic ◽  
Genomic Profiling ◽  
Genomic Hybridization ◽  
Dna Copy Number ◽  
Copy Number Changes

Breast phyllodes tumour (PT) is a rare fibroepithelial tumour. The genetic alterations contributing to its tumorigenesis are largely unknown. To identify genomic regions involved in pathogenesis and progression of PTs we obtained genome-wide copy number profiles by array comparative genomic hybridization (CGH).DNA was isolated from fresh-frozen tissue samples. 11 PTs and 3 fibroadenomas, a frequently occurring fibroepithelial breast tumour, were analyzed. Arrays composed of 2464 genomic clones were used, providing a resolution of ~1.4 Mb across the genome. Each clone contains at least one STS for linkage to the human genome sequence.No copy number changes were detected in fibroadenomas. On the other hand, 10 of 11 PT (91%) showed DNA copy number alterations. The mean number of chromosomal events in PT was 5.5 (range 0–16) per case. A mean of 2.0 gains (range 0–10) and 3.0 losses (range 0–9) was seen per case of PT. Three cases showed amplifications. DNA copy number change was not related to PT grade. We observed recurrent loss on chromosome 1q, 4p, 10, 13q, 15q, 16, 17p, 19 and X. Recurrent copy number gain was seen on 1q, 2p, 3q, 7p, 8q, 16q, 20.In this study we used array CGH for genomic profiling of fibroepithelial breast tumours. Whereas most PT showed chromosomal instability, fibroadenomas lacked copy number changes. Some copy number aberrations had not previously been associated with PT. Several well-known cancer related genes, such as TP53 and members of the Cadherin, reside within the recurrent regions of copy number alteration. Since copy number change was found in all benign PT, genomic instability may be an early event in PT genesis.

Array CGH Analysis for PTCL-U Revealed Two Genetically Distinct Subgroups.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2054-2054
Author(s):  
Masao Nakagawa ◽  
Aya Oshiro ◽  
Hiroyuki Tagawa ◽  
Sivasundaram Karnan ◽  
Shinobu Tsuzuki ◽  
...  
Keyword(s):  
T Cell ◽  
Comparative Genomic Hybridization ◽  
Copy Number ◽  
Array Cgh ◽  
Comparative Genomic ◽  
Simple Type ◽  
Genomic Hybridization ◽  
Complex Type ◽  
Average Copy Number ◽  
Average Copy

Abstract Peripheral T-cell lymphoma, unspecified (PTCL-U) is the most common group among Peripheral T-cell lymphomas (PTCLs). This category consists of the cases which do not belong to any of the recognizable subtypes of PTCLs in WHO classification. PTCL-U comprises heterogeneous groups in morphology and phenotype. Molecular basis of clinical heterogeneity is needed to identify distinct subgroups with clnical relevance. Several reports of conventional cytogenetic studies including comparative genomic hybridization (CGH) showed some recurrent aberrations, but failed to identify the genetic hallmarks to categorize distinct subgroups. So far, no array-based comparative genomic hybridization (array CGH) study for PTCL-U has been reported. Here we analyzed 29 cases of PTCL-U by means of array CGH consisting of 2265 artificial chromosome clones that cover the whole genome at a 1.3 mega base resolution. The analysis clearly divided these cases into two distinct subgroups on the basis of frequency of genomic alterations. One group consists of 17 cases which showed significant lower copy number changes (average copy number gains: 0.5 regions, average copy number losses: 0.1 regions). The other group had average copy number gains of 15.7 regions and losses of 15.0 regions in 12 cases. We designate the former as “simple type” and the latter as “complex type”. In the complex type, regions of recurrent (>20%) gain are detected on chromosome 1q23.3-24.2, 3q25.31-tel, 4p15.1-16.1, 4q28.3-31.23, 5q34, 6p24.1-25.1, 7p21.3-tel, 7p21.1, 7q, 8q24.23, 11q13.4-tel, 12p11.21-11.22, 16p12.3-13.3, 17q11.2-22. Regions of recurrent (>20%) losses are detected on chromosome 1p13.1-13.3, 2q37.3, 4q21.21-21.23, 4q34.3-35.1, 5q21.2-23.1, 6p12.1-q14.3, 6q23.2-24.1, 6q25.1-26, 7p14.3-22.1, 9p21.3, 10p14-qtel, 12p13.1-13.2, 13, 14q12, 16q, 17p, 18p, 20q13-2, 22q11.21-12.2. Median age is 62 years in the simple type and 73 years in the complex type, respectively. Median survival is 27 months in the simple type and 11 months in the complex type. Log-rank test for overall survival between the simple type and the complex type showed inferior survival for the complex type but significance was marginal (p=0.21). Our findings showed that PTCL-U comprised two genetically distinct subgroups, implying that distinct mechanisms underlay in molecular pathogenesis of PTCL-U. Furthermore cilinicopathological features of each group are also being studied.

Anayisis of Chromosomal Alterations by Array-Based Comparative Genomic Hybridization in 25 Patients with Sézary Syndrome.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2714-2714
Author(s):  
Giorgia Saporiti ◽  
Laura Corti ◽  
Francesco Onida ◽  
Daniele Fanoni ◽  
Luigia Venegoni ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Comparative Genomic Hybridization ◽  
Peripheral Blood ◽  
Copy Number ◽  
Chromosome 17 ◽  
Comparative Genomic ◽  
Genomic Hybridization ◽  
Chromosomal Alterations ◽  
Genome Wide

Abstract Abstract 2714 Sézary Syndrome (SS) is an aggressive type of cutaneous CD4+ T-cell lymphoma characterized by erythroderma, generalized lymphadenopathy and presence of malignant T cells in peripheral blood. Patients with SS have a generally poor median survival (2–4 years), with allogeneic stem cell transplantation as the only curative treatment option. Genome-wide analysis of chromosomal alterations represents a current powerful tool to investigate pathophysiology in hematological malignancies, possibly leading to development of new therapeutic agents. A recent important study reported gain of 17q22–25 and 8q22–24, as well as loss of 17p13 and 10q25 as characteristic genomic aberrations in SS. In this study, by array-based comparative genomic hybridization (a-CGH), we aimed to further explore genomic alterations in 25 patients with Sézary Syndrome (SS) referred to our Institution. The patient series included 11 males and 14 females, with a median age of 65 years (range 29 to 85). At diagnosis, 3 patients were in stage IIIB, 18 in stage IVA1 and 4 in stage IVA2. Flow cytometry analysis unveiled typical CD4+/CD7±/CD26- lymphocytic immunophenotype, while molecular analysis showed clonal rearrangement of T-cell receptor beta and/or gamma chains in all patients. At the time of blood samples collection, 21% of patients were untreated. Among treated ones, photopheresis alone was used in 37% whereas all the others received also chemotherapy-based therapies. Lymphocyte count was higher than 3000/mcL in 75% of patients, higher than 6000/mcL in 46% and higher than 9000/mcL in 25%. Elevated LDH levels were observed in 29%. Genomic DNA was isolated from peripheral blood mononuclear cells of 10 patients and from CD4+/CD14− cells of 15 patients, selected by an immunomagnetic method. Quantity and quality of all gDNA samples were assessed using UV- VIS spectrophotometry and agarose gel electrophoresis. Genome-wide array-based comparative genomic hybridization (aCGH) was performed using the Agilent Human Genome CGH Microarray Kit 4×44K. Copy number profiles from CGH arrays were compared using Integrative Genome Viewer. Most frequently observed recurrent copy number alterations involved gains in chromosomes 7, 8 and 17 and losses in chromosome 10, 17 and 19. In particular, chromosomal gains involved 7q11.21-7q11.23 in 32% of patients, 7q21.3-7q22.1 in 36%, 8q24.2-8q24.3 in 44% (with amplification of the MYC oncogene in 36%), while chromosomal losses involved 10p11.22 in 44% of patients, 10q11.22–21.1 in 48%, 10q23.3 (harbouring the PTEN tumor suppressor gene) in 40%, 10q24 (involving NFkB2 gene) in 56%, 10q25.1-q26.3 in 56%, and 19p13.3 (involving the cell growth/apoptosis regulating GADD45B gene) in 32%. With regard to chromosome 17, we observed loss of region 17p13.1 (containing the TP53 gene) in 60% of cases, whereas a gain in 17q21 (harbouring genes coding for STAT3, STAT5A e STAT5B) was documented in 64% of patients. Worth mentioning, 52% of cases showed both losses in the p arm and gains in the q arm within chromosome 17. In summary, our results partially confirmed those previously reported with regard to alterations in chromosomes 7, 8, 10 and 17, resulting in amplification of oncogenes and deletion of tumor suppressor genes. We also observed genome alterations associated with activation of the signal transduction JAK/STAT pathway, possibly involved in SS malignant phenotype. Further genome alterations emerged in this study, such as those in chromosome 7 and 19, are also worth investigating for their possible pathophysiological meanings. Disclosures: No relevant conflicts of interest to declare.

A High Resolution Comparative Genomic Hybridization Array of Adult T-Cell Leukemia-Lymphoma in Individuals of African Descent.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4241-4241
Author(s):  
Rosangela Gomes de Lima ◽  
Suying Xu ◽  
Dale Hedges ◽  
Carlos Brites ◽  
Glen N. Barber ◽  
...  
Keyword(s):  
T Cell ◽  
High Resolution ◽  
Comparative Genomic Hybridization ◽  
African Descent ◽  
Genetic Alterations ◽  
Cell Leukaemia ◽  
Comparative Genomic ◽  
Genomic Hybridization ◽  
Preliminary Results ◽  
Potential Cancer

Abstract Abstract 4241 Adult T-cell leukaemia/lymphoma (ATLL) is a highly aggressive malignancy with a poor prognosis caused by the human T-cell lymphotropic virus type-1 (HTLV-I). While no specific chromosome or genetic abnormalities have been clearly proven to contribute to the pathogenesis of ATLL, recent comparative genomic hybridization (CGH) studies have demonstrated frequent genetic lesions (gains and losses) involving specific chromosomal regions containing a number of genes of potential cancer relevance. In this study, using a high resolution Agilent platform, we performed a comprehensive CGH analysis of 60 ATLL DNA specimens obtained from individuals of African descent from the United States, the Caribbean, and Brazil. Our preliminary results demonstrate the presence of some alterations already reported by others, such as gains in chromosomes 1q22, 4p16, 7p22, 8q24, 9q33-34, 14q31-q32, 16q16, 18q23, 19p13 and deletions at 6q14, 9p21 and q21 and 14q11. Additionally, we have observed several genetic alterations not previously reported in a significant percentage of our ATLL tumors, such as specific gains in regions of chromosomes 1q, 2q, 5p, and 17p and q, and deletions in 13q and 15q. Most of these regions harbor potential cancer related genes but some contain genes of unknown function. Our preliminary results confirm there are common genetic alterations between ATLL patients of Japanese and African origin, but also distinct genetic lesions between both ethnic groups perhaps contributing to the pathogenesis of ATLL. A more comprehensive analysis including validated findings will be presented at the meeting. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Array comparative genomic hybridization reveals genomic copy number changes associated with outcome in diffuse large B-cell lymphomas

Blood ◽  
2006 ◽  
Vol 107 (6) ◽  
pp. 2477-2485 ◽  
Author(s):  
Weiyi Chen ◽  
Jane Houldsworth ◽  
Adam B. Olshen ◽  
Gouri Nanjangud ◽  
Seeta Chaganti ◽  
...  
Keyword(s):  
B Cell ◽  
Comparative Genomic Hybridization ◽  
Copy Number ◽  
Array Comparative Genomic Hybridization ◽  
Array Cgh ◽  
B Cell Lymphoma ◽  
Comparative Genomic ◽  
Genomic Hybridization ◽  
Copy Number Changes ◽  
Large B Cell

Abstract To identify, in high-resolution regions of DNA, the copy number changes associated with outcome in patients with diffuse large B-cell lymphoma (DLBCL), a disease with an approximately 50% mortality rate, we performed array comparative genomic hybridization (array-CGH) on specimens from 64 patients with newly diagnosed DLBCL treated with anthracycline-based chemotherapy. For the entire cohort, 55 commonly gained/lost regions, ranging in size from less than 1 Mbp to entire chromosomes, were identified using 1- to 2-Mbp and 2- to 4-Mbp resolution BAC arrays. Copy number changes of 9 minimal regions significantly correlated with overall survival, of which 6 were 10 Mbp or smaller. On multivariate analysis, loss of chromosomes 2 (2.4-4.1 Mbp) and 16 (33.8-35.6 Mbp) were found to be prognostic indicators of poor survival, independent of clinical features routinely used to predict outcome. Loss of chromosome 1 (78.2-79.1 Mbp) was predictive of good outcome. For a subset of 55 specimens classified according to cell-of-origin expression signature subtype, gain of chromosome 12 (45.4-53.8 Mbp) was found to be significantly associated with the germinal center B-cell-like DLBCL subtype. Overall, array-CGH identified relatively small genomic regions associated with outcome, which, along with follow-up expression studies, may reveal target genes important in DLBCL clinical behavior. (Blood. 2006;107:2477-2485)

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