Early Response and Outcome in High-Risk Childhood Acute Lymphoblastic Leukemia: A Children’s Oncology Group Study
Ontology highlight
ABSTRACT: The cure rate for childhood ALL has improved considerably in part because therapy is routinely tailored to the predicted risk of relapse. Various clinical and laboratory variables are used in current risk-stratification schemes, but many children who fail therapy lack adverse prognostic factors at initial diagnosis. Using gene expression analysis, we have identified genes and pathways in a NCI high-risk childhood B-precursor ALL cohort at diagnosis that may play a role in early blast regression as correlated with the Day 7 marrow status. We have also identified a 47-probeset signature (representing 41 unique genes) that was predictive of long term outcome in our dataset as well as three large independent datasets of childhood ALL treated on different protocols. Keywords: ordered, case-control
Project description:The cure rate for childhood ALL has improved considerably in part because therapy is routinely tailored to the predicted risk of relapse. Various clinical and laboratory variables are used in current risk-stratification schemes, but many children who fail therapy lack adverse prognostic factors at initial diagnosis. Using gene expression analysis, we have identified genes and pathways in a NCI high-risk childhood B-precursor ALL cohort at diagnosis that may play a role in early blast regression as correlated with the Day 7 marrow status. We have also identified a 47-probeset signature (representing 41 unique genes) that was predictive of long term outcome in our dataset as well as three large independent datasets of childhood ALL treated on different protocols. Experiment Overall Design: Diagnostic marrow samples from 99 children with NCI high risk B-precursor ALL treated on the protocol COG 1961 were analyzed. To study genetic profiles associated with early response to therapy, 82 of the total 99 patients were analyzed: 42 patients with a M1 marrow at day 7 of therapy were compared to 40 patients with a M3 marrow at day 7. To study the genes associated with long-term outcome, expression profiles of 59 (of the total 99) patients were analyzed: 28 patients who remained in complete continuous remission (CCR) for at least 4 years and 31 patients who suffered a bone marrow relapse within the first 3 years of initial diagnosis. Forty-two patients were common in both the early response and outcome analyses.
Project description:ALL is the most common form of childhood cancer with >80% cured with contemporary treatment protocols. Accurate risk stratification in childhood ALL is essential to avoid under- and over-treatment. Currently, we use presenting clinical, biological features, and minimal residual disease (MRD) quantitation to risk stratify patients. Although whole genome gene expression profiling (GEP) can accurately classify patients with ALL into various WHO 2008 defined subgroups, its value in predicting relapse remained to be defined. We hypothesized that global time-series GEPs of bone marrow (BM) samples at diagnosis and specific points during initial remission-induction therapy can measure the success of cytoreduction and be used for relapse prediction. We generated time-series GEPs from 210 children with de novo ALL at diagnosis, and Day 8 of remission-induction therapy. We computed the time-series changes from diagnosis to follow-up time point of remission-induction, termed Effective Response Metric (ERM), that measures both the magnitude and direction of time-series change in multi-dimensional gene space towards the normal centroid, and we compared its ability to predict relapse against contemporary risk assignment methods including NCI criteria, cytogenetics and MRD.
Project description:Childhood acute lymphoblastic leukemia (ALL) comprises a large group of genetic subtypes with a favorable prognosis characterized by a TEL-AML1-fusion, hyperdiploidy (>50 chromosomes) or E2A-PBX1 fusion and a smaller group with unfavorable outcome characterized by either a BCR-ABL-fusion, MLL-rearrangement or T-ALL. About 25% of precursor B-ALL are currently genetically unclassified and have an intermediate prognosis. The present study used genome-wide strategies to reveal new biological insights and advance the prognostic classification of childhood ALL. A double-loop cross validation was used to construct a classifier based on gene expression in ALL cells from 190 newly diagnosed cases (COALL cohort, GEO GSE13425) with a prediction accuracy of 90%. T-ALL, TEL-AML1-positive, hyperdiploid and E2A-rearranged cases were identified with 100% sensitivity and â?¥94% specificity. The classifier accuracy was confirmed in an independent cohort of 107 cases (87.9%, DCOG cohort, GEO GSE13351). Experiment Overall Design: Bone marrow and peripheral blood samples were collected at diagnosis and frozen. After thawing, RNA was extracted, labelled and hybridized to Affymetrix U133 Plus 2.0 arrays.
Project description:The PI3K pathway is frequently hyperactivated in primary T-cell acute lymphoblastic leukemia (T-ALL) cells. Activation of the PI3K pathway has been suggested as one mechanism of glucocorticoid resistance in T-ALL, and patients harboring mutations in the PI3K negative regulator PTEN may be at increased risk of induction failure and relapse. In this study, we identified Myc as an important downstream integrator of PI3K pathway activity in T-ALL and we provide data supportive of an association of higher PI3K activity with glucocorticoid resistance and worse clinical outcome. The PI3K inhibitor AS605240 showed anti-leukemic activity and strong synergism with glucocorticoids both in vitro and in a NOD/SCID xenograft model of T-ALL. In contrast, PI3K inhibition showed antagonism with methotrexate and daunorubicin, drugs that preferentially target dividing cells. This antagonistic interaction, however, could be circumvented by the use of correct drug scheduling schemes. Our data indicate the potential benefits and difficulties for the incorporation of PI3K inhibitors in T-ALL therapy. Global gene expression data of diagnostic T-ALL samples were used to analyse whether a gene expression signature of higher PI3K pathway activity is associated with worse prognosis. Patients entered treatment from 2000 to 2007 at Centro Infantil Boldrini. Risk classification and treatment was performed according to the Brazilian Childhood Cooperative Group-Protocol ALL-99.
Project description:Tumor touch imprints (TTIs) are routinely used for the molecular diagnosis of neuroblastomas by interphase fluorescence in-situ hybridization (I-FISH). However, to enable an up-to-date molecular diagnosis of neuroblastomas and to identify new markers to refine risk and therapy stratification methods, whole genome approaches are demanded. We tested whether an ultra-high density SNP array platform identifying copy number changes of varying sizes down to few exons can be applied to detect genomic changes on DNA extracted from TTIs.
Project description:Childhood acute lymphoblastic leukemia (ALL) comprises a large group of genetic subtypes with a favorable prognosis characterized by a TEL-AML1-fusion, hyperdiploidy (>50 chromosomes) or E2A-PBX1 fusion and a smaller group with unfavorable outcome characterized by either a BCR-ABL-fusion, MLL-rearrangement or T-ALL. About 25% of precursor B-ALL are currently genetically unclassified and have an intermediate prognosis. The present study used genome-wide strategies to reveal new biological insights and advance the prognostic classification of childhood ALL. A double-loop cross validation was used to construct a classifier based on gene expression in ALL cells from 190 newly diagnosed cases (COALL cohort, GEO GSE13425) with a prediction accuracy of 90%. T-ALL, TEL-AML1-positive, hyperdiploid and E2A-rearranged cases were identified with 100% sensitivity and ≥94% specificity. The classifier accuracy was confirmed in an independent cohort of 107 cases (87.9%, DCOG cohort, GEO GSE13351). Keywords: gene expression study for classification of ALL subtypes
Project description:Genome wide DNA methylation profiling of samples from adult survivors of childhood and young adult cancer, using the Illumina Infinium Human MethylationEPIC Beadchip arrays. Samples included 32 samples, all sampled at least 10 years after diagnosis . Specific therapies and duration between sampling and diagnosis varied.
Project description:Gene Expression Classifiers for Minimal Residual Disease and Relapse Free Survival Improve Outcome Prediction and Risk Classification in Children with High Risk Acute Lymphoblastic Leukemia: A Children's Oncology Group Study willm-00140 Assay Type: Gene Expression Provider: Affymetrix Array Designs: HG-U133_Plus_2 Organism: Homo sapiens (ncbitax) Tissue Sites: Blood, Bone marrow Material Types: Peripheral Blood, Bone Marrow Disease States: Childhood Precursor B-Lymphoblastic Leukemia