Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia
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ABSTRACT:
PROVIDER: PRJNA686976 | ENA |
REPOSITORIES: ENA
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Project description:Despite high survival rates in pediatric acute lymphoblastic leukemia (ALL), relapse remains a leading cause of cancer-related death in children. Many patients suffer from adverse drug effects during treatment and other complications later in life, and would benefit from improved relapse prediction at diagnosis. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients with pediatric ALL. Somatic mutations were called using individually matched remission samples as controls, and allelic expression of the mutations in the ALL cells was assessed using RNA-sequencing. These analyses identified 29 previously known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, and 20 mutated driver genes occurred in individual samples. We detected putative non-coding mutations in regulatory regions of seven additional genes that have not been described previously in ALL. We observed an increased burden of somatic mutations at relapse. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression. In an “ancestral clone trajectory”, the major cell clone at relapse originated from a founder clone that was not detectable at diagnosis. In a “rising diagnostic clone trajectory”, a minor cell clone at diagnosis expanded to form the major cell clone at relapse. In a “persistent diagnostic clone trajectory”, the major cell clone at diagnosis persisted during treatment until relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.
2021-08-11 | GSE163634 | GEO
Project description:There is a distinct signature of differentially expressed probes from diagnosis to relapse Gene expression profiles of pediatric patients with B-precursor ALL were compared to at 2 time points, diagnosis and relapse. The overall design was a comparison of gene expression at diagnosis and relapse within individual patients. A subset analysis (comparing diagnosis to relapse expression within individuals), was done for early relapse (less than 36 months) cases only and late relapse (greater than 36 months) cases only.
2011-09-23 | E-GEOD-28460 | biostudies-arrayexpress
Project description:There is a distinct signature of differentially expressed probes from diagnosis to relapse
2011-09-23 | GSE28460 | GEO
Project description:Relapse samples have high methylation level than dianosis samples Promoter mehtylation level was measured and compared between relapse and diagnosis samples
2011-09-22 | E-GEOD-28461 | biostudies-arrayexpress
Project description:The mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.
| S-EPMC8346595 | biostudies-literature
Project description:Acute myeloid leukemia (AML) is a hematological malignancy, associated with unfavorable patient outcome primarily due to disease relapse. Since specific early leukemic hematopoietic stem and progenitor cells (HSPCs) are suggested to be responsible for AML propagation, the present study used single cell analysis (SCA) to detect and explore rare relapse-initiating HSPC clones, appearing already at diagnosis. To address inherent SCA limitations, we developed a unique high-resolution technique capable to follow single cell-derived subclones of heterogeneous HSPC subpopulations during AML evolution. Each of these subclones was evaluated for chemo-resistance, in-vivo leukemogenic potential, mutational profile, and the subclone cell of origin identified using reconstruction of phylogenetic trees. This study, employing combined functional and genomic analyses, unraveled the patient-specific HSPC subpopulations involved in chemo-resistance and determined, at time of diagnosis, the phenotype of the relapse-initiating clone, allowing early prediction of AML recurrence and suggesting novel precise therapeutic targets for relapse prevention.
2022-11-12 | E-MTAB-12238 | biostudies-arrayexpress
Project description:Background: The clonal basis of relapse in acute lymphoblastic leukemia (ALL) is complex and not fully understood. Methods: Next-generation sequencing (NGS), array comparative genomic hybridization (aCGH), and multiplex-ligation-dependent probe amplification (MLPA) were carried out in matched diagnosis-relapse samples from 13 B-cell precursor acute lymphoblastic leukemia (BCP-ALL) patients to identify patterns of genetic evolution that could account for the phenotypic changes associated with disease relapse. Findings: The integrative genomic analysis of aCGH, MLPA and NGS revealed that 100% of BCP-ALL patients showed at least one genetic alteration at diagnosis and relapse. In addition, there was a significant increase in the frequency of chromosomal lesions at the time of relapse (median, 6 alterations per sample) relative to that at diagnosis (median, 47 alterations) (p = 0.019). The combination of MLPA and aCGH techniques showed that IKZF1 was the most frequently deleted gene. Notably, TP53 was the most frequently mutated gene at relapse (31%). Two TP53 mutations were detected only at relapse, whereas the three others showed an increase of their mutational burden at relapse. Interpretation: Clonal evolution patterns were heterogeneous, involving acquisition, loss and maintenance of lesions at relapse. Therefore, this study confirmed that BCP-ALL is a genetically dynamic disease with distinct genetic profiles at diagnosis and relapse. The combination of the NGS, aCGH, and MLPA approaches enables better molecular characterization of the genetic profile in ALL patients during the evolution from diagnosis to relapse.
2020-08-12 | GSE128031 | GEO
Project description:35 paired samples from initial diagnosis and first marrow relapse. Genes and pathways differentiating diagnosis and relapse were identified. Potential therapeutic targets were also identified. Keywords: paired
2006-03-20 | GSE3910 | GEO
Project description:Single cell lineage analysis was used to assess clonal genetic heterogeneity and functional aspects of AML HSPCs derived at diagnosis and relapse. To address inherent limitations of single cell analysis, we developed a unique high-resolution technique capable of following single cell-derived subclones of different HSPC subpopulations during the AML course. Each of these subclones was evaluated for chemo-resistance, in-vivo leukemogenic potential in Nod Scid Gamma (NSG) mice, mutational profile, and the subclone cell of origin identified using retrospective cell lineage reconstruction.
2022-08-12 | E-MTAB-11884 | biostudies-arrayexpress
Project description:Almost a quarter of pediatric patients with Acute Lymphoblastic Leukemia (ALL) suffer from relapses. The biological mechanisms underlying therapy response and development of relapses have remained unclear. In an attempt to better understand this phenomenon, we have analyzed 41 matched diagnosis relapse pairs of ALL patients using genomeâ??wide expression arrays (82 arrays) on purified leukemic cells. In roughly half of the patients very few differences between diagnosis and relapse samples were found (â??stable groupâ??), suggesting that mostly extra-leukemic factors (e.g., drug distribution, drug metabolism, compliance) contributed to the relapse. Therefore, we focused our further analysis on 20 samples with clear differences in gene expression (â??skewed groupâ??), reasoning that these would allow us to better study the biological mechanisms underlying relapsed ALL. After finding the differences between diagnosis and relapse pairs in this group, we identified four major gene clusters corresponding to several pathways associated with changes in cell cycle, DNA replication, recombination and repair, as well as B cell developmental genes. We also identified cancer genes commonly associated with colon carcinomas and ubiquitination to be upregulated in relapsed ALL. Thus, about half of relapses are due to selection or emergence of a clone with deregulated expression of a genes involved in pathways that regulate B cell signaling, development, cell cycle, cellular division and replication. The study contains 41 pairs of samples taken from patients at diagnosis and relapse (a total of 82 arrays).
2010-03-23 | E-GEOD-18497 | biostudies-arrayexpress