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.

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.

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.

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)

scholarly journals Utility of Oligonucleotide Array–Based Comparative Genomic Hybridization for Detection of Target Gene Deletions

2008 ◽  
Vol 54 (7) ◽  
pp. 1141-1148 ◽  
Author(s):  
Lee-Jun C Wong ◽  
David Dimmock ◽  
Michael T Geraghty ◽  
Richard Quan ◽  
Uta Lichter-Konecki ◽  
...  
Keyword(s):  
Comparative Genomic Hybridization ◽  
Copy Number ◽  
Array Cgh ◽  
Oligonucleotide Array ◽  
Pcr Analysis ◽  
Comparative Genomic ◽  
Genomic Hybridization ◽  
Oligonucleotide Arrays ◽  
Gene Deletions ◽  
Direct Dna Sequencing

Abstract Background: Direct DNA sequencing is the primary clinical technique for identifying mutations in human disease, but sequencing often does not detect intragenic or whole-gene deletions. Oligonucleotide array–based comparative genomic hybridization (CGH) is currently in clinical use to detect major changes in chromosomal copy number. Methods: A custom oligonucleotide-based microarray was constructed to provide high-density coverage of an initial set of 130 nuclear genes involved in the pathogenesis of metabolic and mitochondrial disorders. Standard array CGH procedures were used to test patient DNA samples for regions of copy number change. Sequencing of regions of predicted breakpoints in genomic DNA and PCR analysis were used to confirm oligonucleotide array CGH data. Results: Oligonucleotide array CGH identified intragenic exonic deletions in 2 cases: a heterozygous single-exon deletion of 4.5 kb in the SLC25A13 gene [solute carrier family 25, member 13 (citrin)] in an individual with citrin deficiency and a homozygous 10.5-kb deletion of exons 13–17 in the ABCB11 gene [PFIC2, ATP-binding cassette, sub-family B (MDR/TAP), member 11] in a patient with progressive familial intrahepatic cholestasis. In 2 females with OTC deficiency, we also found 2 large heterozygous deletions of approximately 7.4 Mb and 9 Mb on the short arm of the X chromosome extending from sequences telomeric to the DMD gene [dystrophin (muscular dystrophy, Duchenne and Becker types)] to sequences within or centromeric to the OTC gene (ornithine carbamoyltransferase). Conclusions: These examples illustrate the successful use of custom oligonucleotide arrays to detect either whole-gene deletions or intragenic exonic deletions. This technology may be particularly useful as a complementary diagnostic test in the context of a recessive disease when only one mutant allele is found by sequencing.

Comparative genomic hybridization analysis in adult T-cell leukemia/lymphoma: correlation with clinical course

Blood ◽  
2001 ◽  
Vol 97 (12) ◽  
pp. 3875-3881 ◽  
Author(s):  
Kunihiro Tsukasaki ◽  
Johannes Krebs ◽  
Kazuhiro Nagai ◽  
Masao Tomonaga ◽  
H. Phillip Koeffler ◽  
...  
Keyword(s):  
T Cell ◽  
Comparative Genomic Hybridization ◽  
Clinical Course ◽  
Comparative Genomic ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Genomic Hybridization ◽  
Adult T Cell Leukemia ◽  
Paired Samples ◽  
Sequential Samples

Sixty-four patients with adult T-cell leukemia/lymphoma (ATL; 18 patients with indolent subtype and 46 with aggressive subtype) associated with human T-lymphotropic virus type 1 (HTLV-1) were analyzed using comparative genomic hybridization (CGH). The most frequent observations were gains at chromosomes 14q, 7q, and 3p and losses at chromosomes 6q and 13q. Chromosome imbalances, losses, and gains were more frequently observed in aggressive ATL than in indolent ATL, with significant differences between the 2 ATL subtypes at gains of 1q and 4q. An increased number of chromosomal imbalances was associated with a significantly shorter survival in all patients. A high number of chromosomal losses was associated with a poor prognosis in indolent ATL, whereas the presence of 7q+ was marginally associated with a good prognosis in aggressive ATL. Paired samples (ie, samples obtained at different sites from 4 patients) and sequential samples from 13 patients (from 6 during both chronic disease and acute crisis and from 7 during both acute onset and relapse) were examined by CGH and Southern blotting for HTLV-1. All but 2 paired samples showed differences on CGH assessment. Two chronic/crisis samples showed distinct results regarding both CGH and HTLV-1 integration sites, indicating clonal changes in ATL at crisis. In 11 patients, the finding of identical HTLV-1 sites and clonally related CGH results suggested a common origin of sequential samples. In contrast to chronic/crisis samples, CGH results with all acute/relapse sample pairs showed the presence of clonally related but not evolutional subclones at relapse, thereby suggesting marked chromosomal instability. In summary, clonal diversity is common during progression of ATL, and CGH alterations are associated with clinical course.

scholarly journals Amplification at 9p in Cervical Carcinoma by Comparative Genomic Hybridization

2001 ◽  
Vol 22 (3) ◽  
pp. 159-163 ◽  
Author(s):  
Kowan J. Jee ◽  
Young Tak Kim ◽  
Kyu Rae Kim ◽  
Yan Aalto ◽  
Sakari Knuutila
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Comparative Genomic Hybridization ◽  
Copy Number ◽  
Comparative Genomic ◽  
Malignant Cells ◽  
Genomic Hybridization ◽  
Carcinoma Of Cervix ◽  
Chromosome Arm ◽  
Copy Number Changes

DNA copy number changes were studied by comparative genomic hybridization on 10 tumor specimens of squamous cell carcinoma of cervix obtained from Korean patients. DNA was extracted from paraffin‐embedded sections after removal of non‐malignant cells by microdissection technique. Copy number changes were found in 8/10 tumors. The most frequent changes were chromosome 19 gains (n=6) and losses on chromosomes 4 (n=4), 5 (n=3), and 3p (n=3). A novel finding was amplification in chromosome arm 9p21‐pter in 2 cases. Gains in 1, 3q, 5p, 6p, 8q, 16p, 17, and 20q and losses at 2q, 6q, 8p, 9q, 10p, 11, 13, 16q, and 18q were observed in at least one of the cases.

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