Homo sapiens
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ABSTRACT:
PROVIDER: PRJNA149299 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Discovery of novel recurrent mutations and rearrangements in early T-cell precursor acute lymphoblastic leukemia by whole genome sequencing
| PRJNA138921 | ENA
Project description:Acute lymphoblastic leukaemia with early T-cell precursor immunophenotype (ETP ALL) is a highly aggressive subtype of ALL of unknown aetiology. To gain insights into the genetic basis of this disease, we performed whole genome sequencing of tumour and normal DNA of 12 children with ETP ALL. Analysis of structural and sequence variants in this discovery cohort, and mutation recurrence screening in a panel of 51 ETP and 43 non ETP ALL samples identified a high frequency of activating mutations in genes regulating cytokine receptor and Ras signalling, including IL7R, NRAS, KRAS, FLT3, BRAF, JAK1 and JAK3 in ETP ALL. Moreover, we identified multiple new targets of mutation in including GATA3, EP300, RUNX1, DNM2, ECT2L, HNRNPA1 and HNRNPR, as well as genes known to be mutated in T-ALL, including NOTCH1, PHF6, and WT1.. Five of 12 ETP ALL cases harboured novel chromosomal translocations, several of which accompanied complex multichromosomal rearrangements and resulted in the expression of chimeric in-frame fusion genes disrupting hematopoietic regulators, including ETV6-INO80D, NAP1L1-MLLT10 and RUNX1-EVX1. These results indicate that although ETP ALL is genetically heterogeneous, activation of Ras and cytokine receptor signalling distinguishes this disease from non-ETP ALL. These findings suggest that targeting this pathway may improve the currently dismal outcome of this disease. Gene expression profiling of an extended panel of childhood B-lineage and T-lineage acute lymphoblastic leukemia samples was performed using Affymetrix U133A arrays.
2011-04-20 | E-GEOD-28497 | biostudies-arrayexpress
Project description:Acute lymphoblastic leukaemia with early T-cell precursor immunophenotype (ETP ALL) is a highly aggressive subtype of ALL of unknown aetiology. To gain insights into the genetic basis of this disease, we performed whole genome sequencing of tumour and normal DNA of 12 children with ETP ALL. Analysis of structural and sequence variants in this discovery cohort, and mutation recurrence screening in a panel of 51 ETP and 43 non ETP ALL samples identified a high frequency of activating mutations in genes regulating cytokine receptor and Ras signalling, including IL7R, NRAS, KRAS, FLT3, BRAF, JAK1 and JAK3 in ETP ALL. Moreover, we identified multiple new targets of mutation in including GATA3, EP300, RUNX1, DNM2, ECT2L, HNRNPA1 and HNRNPR, as well as genes known to be mutated in T-ALL, including NOTCH1, PHF6, and WT1.. Five of 12 ETP ALL cases harboured novel chromosomal translocations, several of which accompanied complex multichromosomal rearrangements and resulted in the expression of chimeric in-frame fusion genes disrupting hematopoietic regulators, including ETV6-INO80D, NAP1L1-MLLT10 and RUNX1-EVX1. These results indicate that although ETP ALL is genetically heterogeneous, activation of Ras and cytokine receptor signalling distinguishes this disease from non-ETP ALL. These findings suggest that targeting this pathway may improve the currently dismal outcome of this disease. Gene expression profiling of an extended panel of childhood B-lineage and T-lineage acute lymphoblastic leukemia samples was performed using Affymetrix U133A arrays.
2012-01-10 | E-GEOD-33315 | biostudies-arrayexpress
Project description:Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole genome sequencing of tumour and normal DNA from 12 children with ETP ALL and assessed the frequency of somatic alterations in 52 ETP and 42 non-ETP T-ALL samples by sequencing and DNA copy number analysis. ETP ALL was characterised by a high frequency of activating mutations in genes regulating cytokine receptor and Ras signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF); alterations disrupting haemopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1, EP300); and inactivating mutations in histone modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of mutation including DNM2, ECT2L and RELN. Ten of 12 ETP ALL cases harboured chromosomal rearrangements, several of which complex and resulted in the expression of novel chimeric in-frame fusion genes disrupting haemopoietic regulators. Thus, similar to myeloid malignancies, mutations that drive proliferation, impair differentiation and disrupt histone modification are hallmarks of ETP ALL. Moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haemopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL. Gene expression profiling was performed on 52 single diagnosis tumor samples. No control or reference samples were included.
2011-11-23 | E-GEOD-28703 | biostudies-arrayexpress
Project description:<p><b>CREST</b></p> <p>The accurate identification of structural variations using whole-genome DNA sequencing data generated by next-generation sequencing technology is extremely difficult. To address this challenge, we have developed CREST, an algorithm that uses sequencing reads with partial alignments to the reference human genome (so-called soft-clipped reads) to directly map the breakpoints of somatic structural variations. We applied CREST to paired tumor/normal whole genome sequencing data from five cases of T-lineage acute lymphoblastic leukemia (T-ALL). A total of 110 somatic structural variants were identified, >80% of which were validated by genomic PCR and Sanger sequencing. The validated structural variants included 31 inter-chromosomal translocations, 19 intra-chromosomal translocations, one inversion, 22 deletions and 16 insertions. A comparison of the results generated with CREST to those obtained using the traditional paired-end discordant mapping methods demonstrate CREST to have a much higher sensitivity and specificity. In addition, application of CREST to publicly available whole-genome sequencing data from the human melanoma cancer cell line COLO-829 demonstrated the identification of 50 novel structural variations not detected using the standard methods, 20 of which were selected for validation with a 90% success rate. These data demonstrate that direct mapping of soft-clipped reads offers an improved method for detecting structural variants at the nucleotide level of resolution.</p> <p><b>T-ALL</b></p> <p>Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole-genome sequencing of 12 ETP ALL cases and assessed the frequency of the identified somatic mutations in 94 T-cell acute lymphoblastic leukaemia cases. ETP ALL was characterized by activating mutations in genes regulating cytokine receptor and RAS signalling (67% of cases; <i>NRAS</i>, <i>KRAS</i>, <i>FLT3</i>, <i>IL7R</i>, <i>JAK3</i>, <i>JAK1</i>, <i>SH2B3</i> and <i>BRAF</i>), inactivating lesions disrupting haematopoietic development (58%; <i>GATA3</i>, <i>ETV6</i>, <i>RUNX1</i>, <i>IKZF1</i> and <i>EP300</i>) and histone-modifying genes (48%; <i>EZH2</i>, <i>EED</i>, <i>SUZ12</i>, <i>SETD2</i> and <i>EP300</i>). We also identified new targets of recurrent mutation including <i>DNM2</i>, <i>ECT2L</i> and <i>RELN</i>. The mutational spectrum is similar to myeloid tumours, and moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haematopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.</p>
| phs000340 | dbGaP
Project description:Early T-cell precursor acute lymphoblastic leukaemia (ETP ALL) is an aggressive malignancy of unknown genetic basis. We performed whole genome sequencing of tumour and normal DNA from 12 children with ETP ALL and assessed the frequency of somatic alterations in 52 ETP and 42 non-ETP T-ALL samples by sequencing and DNA copy number analysis. ETP ALL was characterised by a high frequency of activating mutations in genes regulating cytokine receptor and Ras signalling (67% of cases; NRAS, KRAS, FLT3, IL7R, JAK3, JAK1, SH2B3 and BRAF); alterations disrupting haemopoietic development (58%; GATA3, ETV6, RUNX1, IKZF1, EP300); and inactivating mutations in histone modifying genes (48%; EZH2, EED, SUZ12, SETD2 and EP300). We also identified new targets of mutation including DNM2, ECT2L and RELN. Ten of 12 ETP ALL cases harboured chromosomal rearrangements, several of which complex and resulted in the expression of novel chimeric in-frame fusion genes disrupting haemopoietic regulators. Thus, similar to myeloid malignancies, mutations that drive proliferation, impair differentiation and disrupt histone modification are hallmarks of ETP ALL. Moreover, the global transcriptional profile of ETP ALL was similar to that of normal and myeloid leukaemia haemopoietic stem cells. These findings suggest that addition of myeloid-directed therapies might improve the poor outcome of ETP ALL.
2011-11-23 | GSE28703 | GEO
Project description:PAX5, a transcription factor essential for B-cell development, has been found as a frequent target of abnormalities in B-Cell Precursor Acute Lymphoblastic Leukemia (BCP-ALL) cases, showing point mutations, deletions, as well as translocations with several partner genes. We identified four novel PAX5 fusion partner genes by performing a screening on BCP-ALL cases with 9p rearrangements. Copy Number Variation analysis of translocated samples showed that few significant cooperative genetic lesions are present in addition to the translocation event, suggesting that it might have a primary role in leukemogenesis.
2015-03-02 | E-MTAB-2416 | biostudies-arrayexpress
Project description:Acute lymphoblastic leukaemia with early T-cell precursor immunophenotype (ETP ALL) is a highly aggressive subtype of ALL of unknown aetiology. To gain insights into the genetic basis of this disease, we performed whole genome sequencing of tumour and normal DNA of 12 children with ETP ALL. Analysis of structural and sequence variants in this discovery cohort, and mutation recurrence screening in a panel of 51 ETP and 43 non ETP ALL samples identified a high frequency of activating mutations in genes regulating cytokine receptor and Ras signalling, including IL7R, NRAS, KRAS, FLT3, BRAF, JAK1 and JAK3 in ETP ALL. Moreover, we identified multiple new targets of mutation in including GATA3, EP300, RUNX1, DNM2, ECT2L, HNRNPA1 and HNRNPR, as well as genes known to be mutated in T-ALL, including NOTCH1, PHF6, and WT1.. Five of 12 ETP ALL cases harboured novel chromosomal translocations, several of which accompanied complex multichromosomal rearrangements and resulted in the expression of chimeric in-frame fusion genes disrupting hematopoietic regulators, including ETV6-INO80D, NAP1L1-MLLT10 and RUNX1-EVX1. These results indicate that although ETP ALL is genetically heterogeneous, activation of Ras and cytokine receptor signalling distinguishes this disease from non-ETP ALL. These findings suggest that targeting this pathway may improve the currently dismal outcome of this disease.
2012-01-10 | GSE33315 | GEO
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:Deregulated expression of cytokine receptor gene, CRLF2, is involved in lymphoid transformation in B-cell precursor acute lymphoblastic leukemia We report two novel, cryptic chromosomal abnormalities in precursor B-cell acute lymphoblastic leukemia (BCP-ALL): a translocation, either t(X;14)(p22;q32) or t(Y;14)(p11;q32), in 33 patients and an interstitial deletion, either del(X)(p22.33p22.33) or del(Y)(p11.32p11.32), in 64 patients, involving the pseudoautosomal region (PAR1) of the sex chromosomes. The incidence of these abnormalities was 5% in childhood ALL (0.8% with the translocation, 4.2% with the deletion). Patients with the translocation were older (median age 16 years), whilst the patients with the deletion were younger (median age 4 years). The two abnormalities result in deregulated expression of the cytokine receptor, cytokine receptor-like factor 2, CRLF2 (also known as thymic stromal-derived lymphopoietin receptor, TSLPR). Over-expression of CRLF2 was associated with activation of the JAK-STAT pathway in cell lines and transduced primary B-cell progenitors, sustaining their proliferation and indicating a causal role of CRLF2 over-expression in lymphoid transformation. In Down Syndrome (DS) ALL and two non DS BCP-ALL cell lines, CRLF2 deregulation was associated with mutations of the JAK2 pseudokinase domain suggesting oncogenic cooperation, as well as highlighting a link between non DS ALL and JAK2 mutations. Keyword(s): Global copy number analysis using Agilent oligonucleotide arrays DNA copy number analysis of 16 acute lymphoblastic leukaemia samples (13 diagnostic, 1 diagnostic and relapse pair and 2 cell-lines) was performed using Agilent 244K and 105K custom microarrays. These samples were hybridised against gender matched reference DNA.
2010-05-16 | E-GEOD-17165 | biostudies-arrayexpress