scholarly journals Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Shumaila Sayyab ◽  
Anders Lundmark ◽  
Malin Larsson ◽  
Markus Ringnér ◽  
Sara Nystedt ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Large Scale ◽  
Somatic Mutations ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Point Mutations ◽  
Driver Genes ◽  
Protein Coding ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Evolutionary Trajectories

AbstractThe 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.

scholarly journals Unravelling the Sequential Interplay of Mutational Mechanisms during Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia

Genes ◽  
2021 ◽  
Vol 12 (2) ◽  
pp. 214
Author(s):  
Željko Antić ◽  
Stefan H. Lelieveld ◽  
Cédric G. van der Ham ◽  
Edwin Sonneveld ◽  
Peter M. Hoogerbrugge ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
De Novo ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Leukemic Cells ◽  
Proliferative Potential ◽  
Disease Evolution ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
First Relapse ◽  
Mutational Processes

Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and is characterized by clonal heterogeneity. Genomic mutations can increase proliferative potential of leukemic cells and cause treatment resistance. However, mechanisms driving mutagenesis and clonal diversification in ALL are not fully understood. In this proof of principle study, we performed whole genome sequencing of two cases with multiple relapses in order to investigate whether groups of mutations separated in time show distinct mutational signatures. Based on mutation allele frequencies at diagnosis and subsequent relapses, we clustered mutations into groups and performed cluster-specific mutational profile analysis and de novo signature extraction. In patient 1, who experienced two relapses, the analysis unraveled a continuous interplay of aberrant activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity. The associated signatures SBS2 and SBS13 were present already at diagnosis, and although emerging mutations were lost in later relapses, the process remained active throughout disease evolution. Patient 2 had three relapses. We identified episodic mutational processes at diagnosis and first relapse leading to mutations resembling ultraviolet light-driven DNA damage, and thiopurine-associated damage at first relapse. In conclusion, our data shows that investigation of mutational processes in clusters separated in time may aid in understanding the mutational mechanisms and discovery of underlying causes.

scholarly journals Methionine synthase A2756G polymorphism influences pediatric acute lymphoblastic leukemia risk: a meta-analysis

2019 ◽  
Vol 39 (1) ◽  
Author(s):  
Li-Min Ma ◽  
Hai-Ping Yang ◽  
Xue-Wen Yang ◽  
Lin-Hai Ruan
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Large Scale ◽  
Lymphoblastic Leukemia ◽  
Meta Analysis ◽  
Population Based ◽  
Methionine Synthase ◽  
China National Knowledge Infrastructure ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Pediatric All ◽  
And Control

Abstract Plenty of studies have investigated the effect of methionine synthase (MTR) A2756G polymorphism on risk of developing pediatric acute lymphoblastic leukemia (ALL), but the available results were inconsistent. Therefore, a meta-analysis was conducted to derive a more precise estimation of the association between MTR A2756G polymorphism and genetic susceptibility to pediatric ALL. The PubMed, Embase, Google Scholar, Web of Science, ScienceDirect, Wanfang Databases and China National Knowledge Infrastructure were systematically searched to identify all the previous published studies exploring the relationship between MTR A2756G polymorphism and pediatric ALL risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the strength of association. Sensitivity analysis and publication bias were also systematically assessed. This meta-analysis finally included ten available studies with 3224 ALL cases and 4077 matched controls. The results showed that there was significant association between MTR A2756G polymorphism and risk of pediatric ALL in overall population (AG vs. AA: OR = 1.13, 95%CI = 1.02–1.26, P = 0.02; AG+GG vs. AA: OR = 1.13, 95%CI = 1.02–1.25, P = 0.01; G allele vs. A allele: OR = 1.10, 95%CI = 1.01–1.20, P = 0.03). In the stratification analyses by ethnicity, quality score and control source, significant association was found in Caucasians, population-based designed studies and studies assigned as high quality. In conclusion, this meta-analysis suggests that MTR A2756G polymorphism may influence the development risk of pediatric ALL in Caucasians. Future large scale and well-designed studies are required to validate our findings.

scholarly journals Refined detection and phasing of structural aberrations in pediatric acute lymphoblastic leukemia by linked-read whole-genome sequencing

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jessica Nordlund ◽  
Yanara Marincevic-Zuniga ◽  
Lucia Cavelier ◽  
Amanda Raine ◽  
Tom Martin ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Large Scale ◽  
Fusion Gene ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Rearrangements ◽  
Block Size ◽  
Compound Heterozygous ◽  
Structural Variants ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Wide Range

AbstractStructural chromosomal rearrangements that can lead to in-frame gene-fusions are a leading source of information for diagnosis, risk stratification, and prognosis in pediatric acute lymphoblastic leukemia (ALL). Traditional methods such as karyotyping and FISH struggle to accurately identify and phase such large-scale chromosomal aberrations in ALL genomes. We therefore evaluated linked-read WGS for detecting chromosomal rearrangements in primary samples of from 12 patients diagnosed with ALL. We assessed the effect of input DNA quality on phased haplotype block size and the detectability of copy number aberrations and structural variants in the ALL genomes. We found that biobanked DNA isolated by standard column-based extraction methods was sufficient to detect chromosomal rearrangements even at low 10x sequencing coverage. Linked-read WGS enabled precise, allele-specific, digital karyotyping at a base-pair resolution for a wide range of structural variants including complex rearrangements and aneuploidy assessment. With use of haplotype information from the linked-reads, we also identified previously unknown structural variants, such as a compound heterozygous deletion of ERG in a patient with the DUX4-IGH fusion gene. We conclude that linked-read WGS allows detection of important pathogenic variants in ALL genomes at a resolution beyond that of traditional karyotyping and FISH.

Ikaros Is a Frequently Affected Hematopoietic Differentiation Factor in Pediatric Relapse-Prone Precursor B-Cell Acute Lymphoblastic Leukemia

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4144-4144 ◽  
Author(s):  
Roland P. Kuiper ◽  
Frank N. van Leeuwen ◽  
Vincent van der Velden ◽  
Simon V. van Reijmersdal ◽  
Jeltje de Vries ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Copy Number ◽  
Lymphoblastic Leukemia ◽  
Point Mutations ◽  
Hematopoietic Differentiation ◽  
Gene Encoding ◽  
Protein Coding ◽  
Differentiation Factor ◽  
Two Samples

Abstract Relapse is the most common cause of treatment failure in childhood acute lymphoblastic leukemia (ALL), and is difficult to predict in the majority of cases. Here, we performed genome-wide copy number profiling of 34 paired diagnosis-relapse samples from children diagnosed with precursor-B cell ALL. The majority of the copy number abnormalities were preserved between matched diagnosis and relapse samples, but lesions unique in either of the two samples were observed in 82% of the cases. In 68% of the cases lesions present at diagnosis were no longer detected in relapse samples (including recurrent lesions affecting the PAX5, CDKN2A, and EBF genes), indicating that these lesions were secondary events, absent in the original therapy-resistant progenitor clone. Deletions in the IKZF1 gene encoding the hematopoietic differentiation factor Ikaros were observed in 38% of the diagnosis samples, which is >6-fold the amount detected in an unselected group of pediatric ALLs. Tiling-resolution oligo arrays were used to map the breakpoints, which demonstrated that the protein-coding exons 3–6, encoding the DNA-binding Zn-finger domains, were most commonly deleted. Sequence analysis revealed that point mutations in IKZF1 do occur but are less frequent. Furthermore, IKZF1 deletions were always preserved in relapse. Together, we conclude that IKZF1 deletions are frequent events in therapy-resistant clones of relapse-prone pediatric precursor B-ALL.

scholarly journals Mutational Landscape and Patterns of Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia

2020 ◽  
Vol 1 (1) ◽  
pp. 96-111 ◽  
Author(s):  
Esmé Waanders ◽  
Zhaohui Gu ◽  
Stephanie M. Dobson ◽  
Željko Antić ◽  
Jeremy Chase Crawford ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Mutational Landscape

scholarly journals Mutational Landscape and Patterns of Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia

2020 ◽  
Vol 1 (1) ◽  
pp. 96-111 ◽  
Author(s):  
Esmé Waanders ◽  
Zhaohui Gu ◽  
Stephanie M. Dobson ◽  
Željko Antić ◽  
Jeremy Chase Crawford ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Mutational Landscape

scholarly journals Advances in the Diagnosis and Treatment of Pediatric Acute Lymphoblastic Leukemia

2021 ◽  
Vol 10 (9) ◽  
pp. 1926
Author(s):  
Hiroto Inaba ◽  
Ching-Hon Pui
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Detailed Analysis ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Survival Rates ◽  
Treatment Strategies ◽  
Chemotherapeutic Agents ◽  
Response To Treatment ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Therapeutic Implications

The outcomes of pediatric acute lymphoblastic leukemia (ALL) have improved remarkably during the last five decades. Such improvements were made possible by the incorporation of new diagnostic technologies, the effective administration of conventional chemotherapeutic agents, and the provision of better supportive care. With the 5-year survival rates now exceeding 90% in high-income countries, the goal for the next decade is to improve survival further toward 100% and to minimize treatment-related adverse effects. Based on genome-wide analyses, especially RNA-sequencing analyses, ALL can be classified into more than 20 B-lineage subtypes and more than 10 T-lineage subtypes with prognostic and therapeutic implications. Response to treatment is another critical prognostic factor, and detailed analysis of minimal residual disease can detect levels as low as one ALL cell among 1 million total cells. Such detailed analysis can facilitate the rational use of molecular targeted therapy and immunotherapy, which have emerged as new treatment strategies that can replace or reduce the use of conventional chemotherapy.

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