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704805ad-817b-42c8-81db-8d5e10061223 - samples

ABSTRACT: RNA-sequencing (RNA-seq) efforts in acute lymphoblastic leukaemia (ALL) have identified numerous prognostically significant genomic alterations which can guide diagnostic risk stratification and treatment choices when detected early. However, a full RNA-seq Bioinformatics workflow is time-consuming and costly in a clinical setting where rapid detection and accurate reporting of clinically relevant alterations are essential. To accelerate the identification of ALL-specific alterations (including gene fusions, single nucleotide variants and focal gene deletions), we developed the rapid screening tool RaScALL, capable of identifying more than 100 prognostically significant lesions directly from raw sequencing reads. RaScALL uses the k-mer based targeted detection tool km and known ALL variant information to achieve a high degree of accuracy for reporting subtype defining genomic alterations compared to standard alignment-based pipelines. Gene fusions, including difficult to detect fusions involving EPOR and DUX4, were accurately identified in 98% (164 samples) of reported cases in a 180-patient Australian study cohort and 95% (n=63) of samples in a North American validation cohort. Pathogenic sequence variants were correctly identified in 75% of tested samples, including all cases involving subtype defining variants PAX5 p.P80R (n=12) and IKZF1 p.N159Y (n=4). Accurate detection of intragenic IKZF1 deletions resulting in aberrant transcript isoforms was also detectable with 98% accuracy. Importantly, the median analysis time for detection of all targeted alterations averaged 22 minutes per sample, significantly shorter than standard alignment-based approaches, ensuring accelerated risk-stratification and therapeutic triage.

PROVIDER: EGAD00001009087 | EGA |

REPOSITORIES: EGA

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Project description:We studied a cohort of 221 high-risk pediatric B-progenitor ALL patients that excluded known high risk ALL subtypes (BCR-ABL1 and infant ALL), using Affymetrix single nucleotide polymorphism microarrays, gene expression profiling and candidate gene resequencing. A CNA poor outcome predictor was identified using a semi-supervised principal components approach, and tested in an independent validation cohort of 258 pediatric B-progenitor ALL cases. Over 50 regions of recurring somatically acquired CNA, with the most frequently targeted genes encoding regulators of B-lymphoid development (66.8% of cases; with PAX5 targeted in 31.7% and IKZF1 in 28.6%). A CNA classifier identified a very poor outcome subgroup in the high-risk cohort (P=4.2x10-5) and was strongly associated with the presence of deletions involving IKZF1, which encodes the early lymphoid transcription factor IKAROS. This classifier, and IKZF1 deletions, also predicted poor outcome and elevated minimal residual disease at the end of induction therapy in the validation cohort. The gene expression signature of the poor outcome group was characterized by reduced expression of B lineage specific genes, and was highly related to the expressing signature of BCR-ABL1 ALL, a known high-risk ALL subtype also characterized by a high frequency of IKZF1 deletion.Somatically acquired deletions involving IKZF1 identify a very poor outcome subgroup of pediatric ALL patients. Incorporation of molecular tests to identify IKZF1 deletion in diagnostic leukemic blasts should improve the ability to accurately risk stratify patients for appropriate therapy. Affymetrix U133A arrays were performed according to the maufacturers directions on RNA extracted from cryopreserved diagnostic bone marrow or peripheral blood samples. Samples with less than 80% blasts were flow sorted prior to RNA extraction Experiment Overall Design: One hundred seventy five pediatric B-progenitor ALL samples were studied using either Affymetrix U133A

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704805ad-817b-42c8-81db-8d5e10061223 - samples

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