The genomic landscape of childhood acute lymphoblastic leukaemia with intrachromosomal amplification of chromosome 21 (iAMP21-ALL)
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PROVIDER: EGAS00001004998 | EGA |
REPOSITORIES: EGA
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Project description:Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) shown to have a dismal outcome on standard therapy. For improved diagnosis and prognosis of these patients, the initiating genetic events need to be elucidated. To investigate the genetic basis, the genomes of 94 iAMP21 patients were interrogated by genomic arrays, FISH and MLPA. Detailed mapping of chromosome 21 refined the common region of amplification (CRA) to 5.1 Mb; including the RUNX1 gene, miR-802 and genes mapping to the Down Syndrome Critical Region. Over a quarter of copy number alterations targeted chromosome 21, including telomeric deletions in 88% of patients. Global analysis by genomic arrays identified recurrent abnormalities affecting genes in key pathways. The frequency of these abnormalities were determined by FISH and/or MLPA; IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%) and RB1 (37%). Study of the clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 instability. This study provides convincing evidence that chromosome 21 instability is the only abnormality common to all iAMP21 patients and the initiating event is likely hidden within the complex structural rearrangements of this abnormal chromosome. DNA copy number analysis of 17 diagnostic and 1 relapse acute lymphoblastic leukaemia samples was performed using agilent 185K microarrays. These samples were hybridised against gender matched reference DNA.
2012-03-02 | E-GEOD-26192 | biostudies-arrayexpress
Project description:Intrachromosomal amplification of chromosome 21 (iAMP21) defines a distinct subgroup of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) shown to have a dismal outcome on standard therapy. For improved diagnosis and prognosis of these patients, the initiating genetic events need to be elucidated. To investigate the genetic basis, the genomes of 94 iAMP21 patients were interrogated by genomic arrays, FISH and MLPA. Detailed mapping of chromosome 21 refined the common region of amplification (CRA) to 5.1 Mb; including the RUNX1 gene, miR-802 and genes mapping to the Down Syndrome Critical Region. Over a quarter of copy number alterations targeted chromosome 21, including telomeric deletions in 88% of patients. Global analysis by genomic arrays identified recurrent abnormalities affecting genes in key pathways. The frequency of these abnormalities were determined by FISH and/or MLPA; IKZF1 (22%), CDKN2A/B (17%), PAX5 (8%), ETV6 (19%) and RB1 (37%). Study of the clonal architecture provided evidence that these abnormalities, and P2RY8-CRLF2, were secondary to chromosome 21 instability. This study provides convincing evidence that chromosome 21 instability is the only abnormality common to all iAMP21 patients and the initiating event is likely hidden within the complex structural rearrangements of this abnormal chromosome.
2012-03-02 | GSE26192 | GEO
Project description:<p>DNA Inverted Repeats as an At-risk Motif for Palindromic Gene Amplificatio defines oncogene amplification that is configured as a series of inverted duplications (palindromic gene amplification). There are several, recurrently amplified oncogenes throughout the human genome. However, it remains unclear whether this recurrent amplification is solely a manifestation of increased fitness resulting from random amplification mechanisms, or if genomic locus-specific amplification mechanism plays a role. </p> <p>In this study, we show that the ERBB2 oncogene at 17q12 is susceptible to palindromic gene amplification in HER2-positive breast tumors. We investigated eight tumors in this study, of which five tumors were HER2-positive, and three tumors were HER2-negative. HER2-status was determined by clinical FISH tests. We applied three genomic approaches to investigate the amplification mechanism: (1) copy number analysis by array-CGH on the Affymetrix SNP6.0 platform (8 files), (2) sequencing of DNA libraries enriched with tumor-derived palindromic DNA (Genome-wide Analysis of Palindrome Formation, GAPF-seq) (8 files) and (3) unbiased whole genome sequencing (WGS) (1 file). These molecular data is made available in the dbGaP. </p> <p>Genomic studies using tumor DNA was approved under the Internal Institutional Review Board at the Cleveland Clinic (IRB07-136: EXEMPT: Chromosome Breakage and DNA Palindrome Formation). Specimens were obtained and methods were carried out under the auspices of IRB 7881 (Evaluation of Genetic and Molecular Markers in Patients with Breast Cancer). All patients consented to allow their cancer specimens to be used by researchers in an anonymized fashion. The consent form indicates that publication will take place without identifiers to protect the identity of any specific individual.</p> <p>We observed significant and enrichment of palindromic DNA within amplified ERBB2 genomic segments in four out of five HER2-positive tumors. None of three HER2-negative tumors showed such enrichment. Palindromic DNA was particularly enriched at amplification peaks and boundaries between amplified and normal copy-number regions. Thus, palindromic gene amplification shaped the amplified ERBB2 locus. The moderate enrichment of palindromic DNA throughout the amplified segments leads us to propose that the ERBB2 locus is amplified through a mechanism that repeatedly generates palindromic DNA, such as Breakage-Fusion-Bridge cycles. Our results reveal a potential interaction between local genomic environments and gene amplification mechanisms. </p> <p>This study is published under the title "Palindromic amplification of the ERBB2 oncogene in primary HER2-positive breast tumors" <a href="https://www.ncbi.nlm.nih.gov/pubmed/?term=28211519" target="_blank">(PMID:28211519)</a>. </p>
| phs001261 | dbGaP
Project description:Use scRNA-seq data from 4 iAMP21 patients to study the clonal evolution of iAMP21.
| EGAS00001006577 | EGA
Project description:Use single cell whole genome sequencing data from one iAMP21 patient SJBALL021901 to study the clonal evolution of iAMP21.
| EGAS00001006796 | EGA
Project description:End-to-end chromosome fusions that occur in the context of telomerase deficiency can trigger genomic duplications. These duplications are suggested to arise via Breakage-Fusion-Bridge cycles. To test this hypothesis, we examined end-to-end fusions isolated from C. elegans telomere replication mutants. Genome level rearrangements revealed fused chromosome ends possessing interrupted terminal duplications accompanied by template switching events. These features are very similar to disease-associated duplications of interstitial segments of the human genome. A model termed Fork Stalling and Template Switching has been proposed previously to explain such duplications, where promiscuous replication of large, non-contiguous segments of the genome occurs. Thus, a DNA synthesis-based process can create duplications that seal end-to-end fusions, in the absence of Breakage-Fusion-Bridge cycles. Numerous C. elegans mutant samples were studied with comparative genomic hybridization. There were no replicates or dye-swap hybridizations.
2011-01-21 | E-GEOD-26691 | biostudies-arrayexpress
Project description:Nijmegen breakage syndrome (NBS) is a rare genetic disorder inherited in an autosomal recessive pattern associated with an increased risk of developing lymphoproliferative disorders, mainly non-Hodgkin lymphoma (NHL) and acute lymphoblastic leukemia (ALL). This work presents a patient previously diagnosed with Nijmegen breakage syndrome who rapidly developed T-NHL despite of constant medical supervision. Cytogenetic karyotype and microarray tests revealed complex aberrations, indicating enhanced chromosomal instability.
2020-04-07 | GSE148229 | GEO
Project description:End-to-end chromosome fusions that occur in the context of telomerase deficiency can trigger genomic duplications. These duplications are suggested to arise via Breakage-Fusion-Bridge cycles. To test this hypothesis, we examined end-to-end fusions isolated from C. elegans telomere replication mutants. Genome level rearrangements revealed fused chromosome ends possessing interrupted terminal duplications accompanied by template switching events. These features are very similar to disease-associated duplications of interstitial segments of the human genome. A model termed Fork Stalling and Template Switching has been proposed previously to explain such duplications, where promiscuous replication of large, non-contiguous segments of the genome occurs. Thus, a DNA synthesis-based process can create duplications that seal end-to-end fusions, in the absence of Breakage-Fusion-Bridge cycles.
2011-01-21 | GSE26691 | GEO
Project description:Purpose: The purpose of this study was to evaluate SNP genotyping methodology as a means to detect chromosomal abnormalities previously diagnosed by G-band karyotype or fluorescence in situ hybridization (FISH) analysis and to determine the frequency of sub-microscopic (cryptic) chromosomal alterations in these subjects. Methods: We used the Illumina HumanHap Beadchip platform to genotype 40 individuals having previously detected chromosomal anomalies (by G-banded and/or FISH analysis). The resulting data were analyzed for signal intensity (log R ratio) and allelic composition (B allele frequency). Results: SNP array analysis detected 100% of previously identified cytogenetic abnormalities. Changes or clarifications of the ISCN karyotype designation assigned by conventional cytogenetic and/or FISH analysis were made in 82 % of the cases (32 of 39). Nine of the 39 cases (23%) involved a reassignment of an abnormal band while an additional 9 of the 39 (23%) resulted in a clarification of a sub-band assignment. In 8 more of the 39 cases (21%) the previously reported alterations were confirmed, however the SNP analysis also identified related cryptic alterations. SNP analysis not only confirmed FISH-detected abnormalities but also more precisely mapped the breakpoints of 6/6 patients. Investigations into the origin of de novo abnormalities in 15 trio families established that 12 /15 occurred on the paternal chromosome. Conclusions: SNP genotyping array analysis, confirmed all previously detected structural chromosomal abnormalities and provided additional, clinically-relevant genomic information in 82% of these alterations.
2011-02-22 | GSE20623 | GEO
Project description:Purpose: The purpose of this study was to evaluate SNP genotyping methodology as a means to detect chromosomal abnormalities previously diagnosed by G-band karyotype or fluorescence in situ hybridization (FISH) analysis and to determine the frequency of sub-microscopic (cryptic) chromosomal alterations in these subjects. Methods: We used the Illumina HumanHap Beadchip platform to genotype 40 individuals having previously detected chromosomal anomalies (by G-banded and/or FISH analysis). The resulting data were analyzed for signal intensity (log R ratio) and allelic composition (B allele frequency). Results: SNP array analysis detected 100% of previously identified cytogenetic abnormalities. Changes or clarifications of the ISCN karyotype designation assigned by conventional cytogenetic and/or FISH analysis were made in 82 % of the cases (32 of 39). Nine of the 39 cases (23%) involved a reassignment of an abnormal band while an additional 9 of the 39 (23%) resulted in a clarification of a sub-band assignment. In 8 more of the 39 cases (21%) the previously reported alterations were confirmed, however the SNP analysis also identified related cryptic alterations. SNP analysis not only confirmed FISH-detected abnormalities but also more precisely mapped the breakpoints of 6/6 patients. Investigations into the origin of de novo abnormalities in 15 trio families established that 12 /15 occurred on the paternal chromosome. Conclusions: SNP genotyping array analysis, confirmed all previously detected structural chromosomal abnormalities and provided additional, clinically-relevant genomic information in 82% of these alterations. To evaluate potential chromosomal abnormalities in patients, we measured SNPs using Illumina 550K and 300K arrays. In some cases we also measured SNPs in parents to determine whether deletions or duplications occurred de novo or were inherited.
2011-02-22 | E-GEOD-20623 | biostudies-arrayexpress