INTEGRATIVE ONCOGENOMIC AND HIGH-THROUGHPUT SEQUENCING ANALYSES OF THE COMMONLY DELETED REGION IN CHROMOSOME 7q32 IN SPLENIC MARGINAL ZONE LYMPHOMA
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ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Vicente Fresquet
PROVIDER: E-GEOD-35383 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
High-throughput sequencing analysis of the chromosome 7q32 deletion reveals IRF5 as a potential tumour suppressor in splenic marginal-zone lymphoma.
Fresquet Vicente V Robles Eloy F EF Parker Anton A Martinez-Useros Javier J Mena Maria M Malumbres Raquel R Agirre Xabier X Catarino Susana S Arteta David D Osaba Lourdes L Mollejo Manuela M Hernandez-Rivas Jesus M JM Calasanz Maria Jose MJ Daibata Masanori M Dyer Martin J S MJ Prosper Felipe F Vizcarra Esperanza E Piris Miguel-Ángel MÁ Oscier David D Martinez-Climent Jose Angel JA
British journal of haematology 20120723 6
Using high-resolution genomic microarray analysis, a distinct genomic profile was defined in 114 samples from patients with splenic marginal zone lymphoma (SMZL). Deletion or uniparental disomy of chromosome 7q were detected in 42 of 114 (37%) SMZLs but in only nine of 170 (5%) mature B-cell lymphomas (P < 0·00001). The presence of unmutated IGHV, genomic complexity, 17p13-TP53 deletion and 8q-MYC gain, but not 7q deletion, correlated with shorter overall survival of SMZL patients. Mapping studi ...[more]
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Project description:Using high-resolution genomic microarray analysis, a distinct genomic profile was defined in 114 samples from patients with splenic marginal zone lymphoma (SMZL). Notably, deletion or uniparental disomy of chromosome 7q were detected in 39% of SMZLs but in only 9 of 170 (5%) mature B-cell lymphomas (p<10-6). The presence of unmutated IgVH genes, genomic complexity, 17p13-P53 deletion and 8q gain including MYC gene, but not 7q deletion, were correlated with shorter overall survival. Extensive mapping analyses narrowed down the commonly deleted region to 2.7 Mb. in 7q32.1-q32.2 from SND1 to COPG2 genes. High-throughput sequencing analysis of the 7q32 deleted segment in SMZL cells did not identify bi-allelic deletions, insertions or clear pathogenic mutations, but detected six single nucleotide changes in IRF5 (n=2), TMEM209 (n=2), CALU (n=1) and ZC3HC1 (n=1). Comparative expression analysis found that IRF5, TMEM209 and CALU genes had down-regulated expression in lymphomas with 7q32 deletion vs. non-deleted tumors. Ectopic expression of IRF5 in marginal-zone lymphoma cells decreased cell proliferation and induced apoptosis. These results indicate that small deletions, insertions and/or point mutations inactivating genes within 7q32 are not common events in SMZL. Further studies are required to evaluate the putative role of IRF5 in SMZL pathogenesis. Affymetrix GeneChip 50k-XbaI and/or 250-NspI/StyI SNP microarrays were performed for 59 SMZL samples and 4 Marginal Zone cell lines according to the manufacturer's directions.
2012-07-31 | E-GEOD-35329 | biostudies-arrayexpress
Project description:Using high-resolution genomic microarray analysis, a distinct genomic profile was defined in 114 samples from patients with splenic marginal zone lymphoma (SMZL). Notably, deletion or uniparental disomy of chromosome 7q were detected in 39% of SMZLs but in only 9 of 170 (5%) mature B-cell lymphomas (p<10-6). The presence of unmutated IgVH genes, genomic complexity, 17p13-P53 deletion and 8q gain including MYC gene, but not 7q deletion, were correlated with shorter overall survival. Extensive mapping analyses narrowed down the commonly deleted region to 2.7 Mb. in 7q32.1-q32.2 from SND1 to COPG2 genes. High-throughput sequencing analysis of the 7q32 deleted segment in SMZL cells did not identify bi-allelic deletions, insertions or clear pathogenic mutations, but detected six single nucleotide changes in IRF5 (n=2), TMEM209 (n=2), CALU (n=1) and ZC3HC1 (n=1). Comparative expression analysis found that IRF5, TMEM209 and CALU genes had down-regulated expression in lymphomas with 7q32 deletion vs. non-deleted tumors. Ectopic expression of IRF5 in marginal-zone lymphoma cells decreased cell proliferation and induced apoptosis. These results indicate that small deletions, insertions and/or point mutations inactivating genes within 7q32 are not common events in SMZL. Further studies are required to evaluate the putative role of IRF5 in SMZL pathogenesis. 9 samples. 6 patient samples with 7q32 deletion and 3 patient samples without 7q32 deletion. Splenic Marginal Zone Lymphoma patient samples with 7q32 deletion vs. Splenic Marginal Zone Lymphoma patient samples without 7q32 deletion
2012-07-31 | E-GEOD-35082 | biostudies-arrayexpress
Project description:Splenic marginal zone lymphoma (SMZL) is an indolent B-cell lymphoproliferative disorder characterised by 7q32 deletion, but the target genes of this deletion remain unknown. In order to elucidate the genetic target of this deletion, we performed an integrative analysis of the genetic, epigenetic, transcriptomic and miRNomic data. High resolution array comparative genomic hybridization of 56 cases of SMZL delineated a minimally deleted region (2.8Mb) at 7q32, but showed no evidence of any cryptic homozygous deletion or recurrent breakpoint in this region. Integrative transcriptomic analysis confirmed significant under-expression of a number of genes in this region in cases of SMZL with deletion, several of which showed hypermethylation. In addition, a cluster of 8 miRNA in this region showed under-expression in cases with the deletion, and three (miR-182/96/183) were also significantly under-expressed (P <0.05) in SMZL relative to other lymphomas. Genomic sequencing of these miRNA and IRF5, a strong candidate gene, did not show any evidence of somatic mutation in SMZL. Keywords: Genome variation profiling by genome tiling array For aCGH. 21 fresh frozen splenic samples from patients with SMZL were hybridized against a reference control of pooled PBMC genomic DNA from 10 normal subjects. High-resolution oligonucleotide analysis of copy number variations in splenic marginal zone lymphoma (SMZL) in regions of recurrent alteration. Regions included on the array: 7q (2k resolution) and regions of interest on chromosomes 3q, 6q and 9q at 12k resolution.
2012-08-30 | E-GEOD-35425 | biostudies-arrayexpress
Project description:INTEGRATIVE ONCOGENOMIC AND HIGH-THROUGHPUT SEQUENCING ANALYSES OF THE COMMONLY DELETED REGION IN CHROMOSOME 7q32 IN SPLENIC MARGINAL ZONE LYMPHOMA (expression)
| PRJNA156161 | ENA
Project description:INTEGRATIVE ONCOGENOMIC AND HIGH-THROUGHPUT SEQUENCING ANALYSES OF THE COMMONLY DELETED REGION IN CHROMOSOME 7q32 IN SPLENIC MARGINAL ZONE LYMPHOMA (CGH)
| PRJNA156063 | ENA
Project description:Immunoglobulin A Nephropathy (IgAN) is a complex multifactorial disease whose genetic bases remain unknown. Distinct linkage and genome-wide association studies in both familial and sporadic IgAN suggest that there is a strong genetic component in IgAN. In this context, an intriguing role could be ascribed to copy number variants (CNVs) that have been recognized as an important source of genetic variation in humans. Here, we performed a whole-genome screening of CNVs in IgAN patients, their healthy relatives and healthy subjects (HS). A total of 217 individuals consisting of 51 IgAN cases and 166 healthy relatives were included in the initial screening. The high-throughput analysis of structural genetic variations, to find concordant aberrations across classes of samples, identified 178 IgAN-specific aberrations, specifically 114 loss and 64 gain. Several CNVs overlapped with regions evidenced by previous genome-wide genetic studies. Moreover, we found that IgAN patients characterized by deteriorated renal function carried low copy numbers of a CNV in chromosome 3 (chr3_loss:52031010-52260722). This CNV contained the TLR9 gene whose expression significantly correlated with the loss aberration in patients with progressive renal damage. Conversely, IgAN patients with normal renal function had no chr3_loss:52031010-52260722 and the TLR9 mRNA was expressed at the same level as in HS, still maintaining a strong correlation with the CNV. In conclusion, here we performed the first genome-wide CNV study in IgAN identifying some structural variants specific to IgAN patients and providing a collection of new candidate genes and loci that could help to dissect the complex genomic setting of the disease. Moreover, we identified a specific CNV, spanning the TLR9 gene, which could explain the disease severity in IgAN patients. To perform a genome-wide CNV study in IgAN identifying some structural variants specific to IgAN patients and providing a collection of new candidate genes and loci that could help to dissect the complex genomic setting of the disease.
2014-10-30 | E-GEOD-44974 | biostudies-arrayexpress
Project description:A genome-wide eQTL analysis was performed in whole blood samples collected from 76 Japanese subjects. RNA microarray analysis was performed for 3 independent samples that were genotyped in a genome-wide scan. The correlations between the genotypes of 534,404 autosomal single nucleotide polymorphisms (SNPs) and the expression levels of 30,465 probes were examined for each sample. The SNP-probe pairs with combined correlation coefficients of all 3 samples corresponding to P < 3.10 × 10-12 (i.e., Bonferroni-corrected P < 0.05) were considered significant. SNP-probe pairs with a high likelihood of cross-hybridization and SNP-in-probe effects were excluded to exclude false positive results. We identified 102 cis-acting and 5 trans-acting eQTL regions. The cis-eQTL regions were widely distributed both upstream and downstream of the gene, as well as within the gene. RNA microarray data obtained from 3 independent samples originally recruited for other studies investigating the gene expression levels in psychiatric disorders were used in the present study. For the purpose of the present analyses, genomic DNA was collected from 24 subjects (13 men and 11 women, mean age [SD] = 39.9 [7.6] years) in sample 1, 24 subjects in sample 2 (12 men and 12 women, 34.1 [11.5] years), and 28 subjects (14 men and 14 women, 41.4 [11.8] years) in sample 3. Some of the subjects had depressive symptoms, but all were physically healthy and without clinically significant systemic disease (e.g., malignant disease, diabetes mellitus, hypertension, renal failure, or endocrine disorders). Subjects were recruited from the outpatient clinic of the National Center of Neurology and Psychiatry Hospital, Tokyo, Japan, through advertisements in free local information magazines or through our website announcement. All the subjects were biologically unrelated Japanese individuals who resided in the same geographical area (western Tokyo). The study protocol was approved by the ethics committee at the National Center of Neurology and Psychiatry, Japan. Written informed consent was obtained from every subject after the study was explained to them. Venous blood was collected between 1100 and 1200 h in PAXgene tubes (Qiagen, Valencia) from each subject and was incubated at room temperature for 24 h for RNA stabilization. RNA was extracted from whole blood according to the manufacturer’s guidelines by using the PAXgene Blood RNA System Kit (PreAnalytix GmbH, Hombrechtikon, Switzerland). The RNA was quantified by optical density readings at A260nm by using the NanoDrop ND-1000 (Thermo Scientific, Rockford). Gene expression analysis was performed using Agilent Human Genome 4 × 44 K arrays (Agilent Technologies, Santa Clara). Raw signal data for each of the 3 independent samples were analyzed separately by the GeneSpring GX software (Agilent Technologies). Data were filtered according to the expression level for quality control to eliminate genes that were below the 20th percentile threshold. The expression value of each gene was normalized to the median expression value of all genes in each chip. A total of 30,465 probes were included in the analysis. Genomic DNA was obtained from venous blood samples. Genotyping was performed by Riken Genesis (Yokohama, Japan) using the Illumina HumanOmni1-Quad BeadChip (Illumina, Inc., San Diego). A total of 713,495 autosomal SNPs were assessed for quality using the PLINK v1.07 software. All SNPs with a call rate below 95%, a deviation from Hardy-Weinberg equilibrium at an error level of P < 0.001, or a minor allele frequency of less than 10% were excluded. The remaining 534,404 SNPs were used for further analysis.
2012-11-27 | E-GEOD-42487 | biostudies-arrayexpress
Project description:Background: Moyamoya is a cerebrovascular condition of unknown mechanism characterized by a progressive stenosis of the terminal part of the internal carotid arteries (ICA) and the compensatory development of abnormal “moyamoya” vessels. It leads to ischemic and hemorrhagic stroke. We describe a novel autosomal recessive disease leading to severe moyamoya and early onset achalasia and report its cause in 3 unrelated families. Methods: We used a combination of genetic linkage and exome sequencing in 2 consanguineous to identify rare shared variants. Sanger sequencing of GUCY1A3, the sole gene mutated in both families, was then conducted in the third family. Platelets from one of the patients and controls were used to carry out functional studies. Results: Homozygous mutations of GUCY1A3 gene encoding the alpha1 subunit of soluble guanylate cyclase (sGC), the major receptor for Nitric Oxide (NO), were identified in all 3 families. Platelet analysis showed a complete loss of the mutated protein and showed an unexpected stimulatory role of sGC within platelets. Conclusion: The NO/sGC/cGMP pathway is a major pathway controlling vascular smooth muscle (VSMC) relaxation, vascular tone and vascular remodeling. Our data suggest that alterations of this pathway may lead to an abnormal vascular remodeling process in sensitive vascular areas with low blood A total of 17 samples (8 affected and 9 unaffected) were used for this study. Linkage analysis was performed in a single informative consanguine family composed of 2 unaffected parents, 4 affected siblings and 3 unaffected siblings. Two affected samples in two different families were used for the exome sequencing analysis and results were compared to 20 control exomes (in-house exomes from IntegraGen, Evry, France) and 8 HapMap exomes. All samples were used for Sanger Sequencing confirmation.
2014-06-19 | E-GEOD-48099 | biostudies-arrayexpress
Project description:INTEGRATIVE ONCOGENOMIC AND HIGH-THROUGHPUT SEQUENCING ANALYSES OF THE COMMONLY DELETED REGION IN CHROMOSOME 7q32 IN SPLENIC MARGINAL ZONE LYMPHOMA (SNP data)
| PRJNA156077 | ENA