Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

A compendium of myeloma associated chromosomal copy number abnormalities and their prognostic value

ABSTRACT: To obtain a comprehensive genomic profile of presenting multiple myeloma cases we performed high resolution single nucleotide polymorphism (SNP) mapping array analysis in 114 samples alongside 258 samples analysed by U133 Plus 2.0 expression array (Affymetrix). We examined DNA copy number alterations and loss of heterozygosity (LOH) in order to define the spectrum of minimally deleted regions in which relevant genes of interest can be found. The most frequent deletions are located at 1p (30%), 6q (33%), 8q (25%), 12 (22%), 13q (59%), 14q (39%), 16q (35%), 17p (7%), 20 (12%) and 22 (18%). In addition, copy number-neutral LOH, or uniparental disomy, was also prevalent on 1q (8%), 16q (9%), and X (20%), and was associated with regions of gain and loss. Based on fluorescent in situ hybridisation (FISH) and expression quartile analysis, genes of prognostic importance were found to be located at 1p (FAF1, CDKN2C), 1q (ANP32E), and 17p (TP53). In addition, we identified common homozygously deleted genes which have functions relevant to myeloma biology. Taken together, the dysregulated genes from the myeloma genome indicate that the crucial pathways in myeloma pathogenesis include the NF-?B pathway, apoptosis, cell-cycle regulation and Wnt signalling. SNP data: 114 tumour samples (MM) analyzed by Affymetrix 500K array set (Nsp+Sty), of which 80 samples have matched peripheral blood (PB) (non-tumour) DNA performed on the same array types. Matched tumour and non-tumour samples have the same ID number, e.g. MM400 and PB400 Expression data: 258 expression samples from CD138+ cell selection

ORGANISM(S): Homo sapiens

SUBMITTER: Brian Walker

PROVIDER: E-GEOD-21349 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value.

Walker Brian A BA Leone Paola E PE Chiecchio Laura L Dickens Nicholas J NJ Jenner Matthew W MW Boyd Kevin D KD Johnson David C DC Gonzalez David D Dagrada Gian Paolo GP Protheroe Rebecca K M RK Konn Zoe J ZJ Stockley David M DM Gregory Walter M WM Davies Faith E FE Ross Fiona M FM Morgan Gareth J GJ

Blood 20100708 15

To obtain a comprehensive genomic profile of presenting multiple myeloma cases we performed high-resolution single nucleotide polymorphism mapping array analysis in 114 samples alongside 258 samples analyzed by U133 Plus 2.0 expression array (Affymetrix). We examined DNA copy number alterations and loss of heterozygosity (LOH) to define the spectrum of minimally deleted regions in which relevant genes of interest can be found. The most frequent deletions are located at 1p (30%), 6q (33%), 8p (25 ...[more]

PMID: 20616218

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Project description:Background: The high incidence of recurrence and unpredictable clinical outcome for paediatric ependymoma reflect the imprecision of current therapeutic staging and need for novel risk stratification markers. Gain of chromosome 1q has been reported as a frequent aberration and correlate of adverse outcome in ependymoma. We therefore evaluated a prognostic role for 1q25 gain across three age-defined European clinical trial cohorts of paediatric intracranial ependymoma. Methods: The frequency of 1q gain in paediatric ependymoma was assessed across 51 tumours (42 primary, 9 recurrent) using Affymetrix® 500K SNP arrays. Gain of 1q25 was evaluated by interphase FISH (iFISH) across 189 primary intracranial ependymomas from children treated on the CCLG/SIOP CNS9204 (n = 60) and BBSFOP (n = 65) adjuvant chemotherapy trials, or with primary post-operative radiotherapy (SIOP CNS9904/RT group, n = 64). Results were correlated with clinical, histological and survival data. Findings: Gain of 1q was the most frequent imbalance in primary (7/42, 17 %) and recurrent ependymomas (3/9, 33 %). Gain of 1q25 was the strongest independent predictor of tumour progression in both CNS9204 (HR 3·36, p = 0·0009) and BBSFOP (HR 4·10, p = 0·0009) trial cohorts. In contrast, 1q25 gain was not prognostic for the older CNS9904/RT only group (PFS: p = 0·37, OS: p = 0·95). Clinical variables implicated in adverse outcome amongst cohorts included incomplete tumour resection and posterior fossa location. Interpretation: This is the first study to prospectively identify then validate a prognostic genomic marker for childhood ependymoma across independent prospective trial groups. 1q25 gain predicts progression in primary chemotherapy cohorts but not those treated by post-operative radiotherapy. We propose 1q25 gain is incorporated as an adverse marker into future European chemotherapeutic clinical trial design. Affymetrix SNP arrays were performed according to the manufacturer's directions on DNA extracted from flash frozen tumour specimens and patient-matched peripheral blood Copy number analysis of Affymetrix 500K SNP arrays was performed for DNA from 51 ependymomas and 40 constitutional DNA samples. Analysing broad genomic aberrations in 51 paediatric ependymomas, looking particularly at 1q gain.

Project description:A SNP microarray and FISH-based procedure to detect allelic imbalances in multiple myeloma: an integrated genomics approach reveals a wide dosage effect on gene and microRNA expression Multiple myeloma (MM) is characterized by marked genomic instability. Beyond structural rearrangements, a relevant role in its biology is represented by allelic imbalances leading to significant variations in ploidy status. To better elucidate the genomic complexity of MM, we analyzed a panel of 45 patients using combined FISH and microarray approaches. Using a self-developed procedure to infer exact local copy numbers for each sample, we identified a significant fraction of patients showing marked aneuploidy. A conventional clustering analysis showed that aneuploidy, chromosome 1 alterations, hyperdiploidy and recursive deletions at 1p and chromosomes 13, 14 and 22 were the main aberrations driving samples grouping. Then, we integrated mapping information with gene and microRNAs expression profiles: a multiclass analysis of the identified clusters showed a marked gene-dosage effect, particularly concerning 1q transcripts, also confirmed by correlating gene expression levels and local copy number alterations. A wide dosage effect affected also microRNAs, indicating that structural abnormalities in MM closely reflect in their expression imbalances. Finally, we identified several loci in which genes and microRNAs expression correlated with loss-of-heterozygosity occurrence. Our results provide insights into the composite network linking genome structure and gene/microRNA transcriptional features in MM. Keywords: Integrated genomics approach based on SNP microarray and FISH procedures to detect allelic imbalances in multiple myeloma. Pathological bone marrow specimens from 41 MM and four plasma cell leukemia (PCL) patients at diagnosis. 250 nanograms of genomic DNA was processed and, in accordance with the manufacturer's protocols, 40 micrograms of fragmented biotin-labelled DNA were hybridized on GeneChip Human Mapping 50K XbaI Arrays (Affymetrix Inc.). The arrays were scanned using the GeneChip Scanner 3000 7G. The images were acquired using Affymetrix GeneChip® Operating Software (GCOS version 1.4). Copy number values for individual SNPs were extracted and converted from CEL files into signal intensities using GTYPE 4.1 and Affymetrix Copy Number Analysis Tool (CNAT 4.0.1) softwares. Genomic Smoothing analysis was performed by using the smoothing window of 0 Mb, and inferred copy number states were derived from a Hidden Markov Model (HMM) based algorithm implemented in CNAT 4.0.1. Circular Binary Segmentation (Ohlsen et al., 2004) was applied using DNAcopy package for R Bioconductor on raw data. FBN procedure was finally applied to infer exact local copy number as described in the mentioned Reference.

Dataset Information

A compendium of myeloma associated chromosomal copy number abnormalities and their prognostic value

Publications

A compendium of myeloma-associated chromosomal copy number abnormalities and their prognostic value.

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