The genomic landscape of pediatric acute lymphoblastic leukemia and precision medicine opportunities

Tran, Thai Hoa; Hunger, Stephen P.

doi:10.1016/j.semcancer.2020.10.013

Cited by 61 publications

(61 citation statements)

References 127 publications

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“…Consistent with previous reports 1,44 , the most frequently altered genes included CDKN2A/B, PAX5, ETV6, ERG, RUNX1, NRAS, KRAS and IKZF1 (Fig. 2).…”

Section: Identi Cation Of Driver Genessupporting

confidence: 92%

Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes

Studd¹,

Cornish²,

Hoang

et al. 2021

Preprint

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To obtain a comprehensive picture of composite genetic drivers events and clonal dynamics in subtypes of paediatric acute lymphoblastic leukaemia (ALL) we analysed tumour-normal whole genome sequencing and expression data from 361 newly diagnosed patients. We report the identification of both novel coding and structural drivers as well as recurrent non-coding variation in promoters and cis-regulatory regions. The transcriptional profile of histone gene cluster 1 and CTCF altered tumours shared hallmarks of hyperdiploid ALL suggesting a ‘hyperdiploid like’ subtype. ALL subtypes are driven by distinct mutational processes with AID mutagenesis being confined to ETV6-RUNX1 tumours. Subclonality is a ubiquitous feature of ALL, consistent with Darwinian evolution driving selection and expansion of tumours. Driver mutations in B-cell developmental genes (IKZF1, PAX5, ZEB2) tend to be clonal and RAS/RTK mutations subclonal. In addition to identifying new avenues for therapeutic exploitation this analysis highlights that targeted therapies should take into account composite mutational profile and clonality.

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“…Consistent with previous reports 1,44 , the most frequently altered genes included CDKN2A/B, PAX5, ETV6, ERG, RUNX1, NRAS, KRAS and IKZF1 (Fig. 2).…”

Section: Identi Cation Of Driver Genessupporting

confidence: 92%

Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes

Studd¹,

Cornish²,

Hoang

et al. 2021

Preprint

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“…However, many standard risk cancers do not respond or recur following treatment with current best available therapies. Indeed, such is the case for 15 -20% of acute lymphoblastic leukemia (ALL) (10) or Wilms tumor (11) cases and over 30% of rhabdomyosarcomas (12) or other non-CNS solid tumors. To improve upon these outcomes, it is essential that we comprehensively examine and elucidate the molecular underpinnings of childhood cancer across the full spectrum of presentations.…”

Section: Introductionmentioning

confidence: 99%

Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing

et al. 2021

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Genomic studies of pediatric cancer have primarily focused on specific tumor types or high-risk disease. Here, we used a three-platform sequencing approach, including whole genome (WGS), exome, and RNA sequencing, to examine tumor and germline genomes from 309 prospectively identified children with newly diagnosed (85%) or relapsed/refractory (15%) cancers, unselected for tumor type. Eighty-six percent of patients harbored diagnostic (53%), prognostic (57%), therapeutically-relevant (25%), and/or cancer predisposing (18%) variants. Inclusion of WGS enabled detection of activating gene fusions and enhancer hijacks (36% and 8% of tumors, respectively), small intragenic deletions (15% of tumors) and mutational signatures revealing of pathogenic variant effects. Evaluation of paired tumor-normal data revealed relevance to tumor development for 55% of pathogenic germline variants. This study demonstrates the power of a three-platform approach that incorporates WGS to interrogate and interpret the full range of genomic variants across newly diagnosed as well as relapsed/refractory pediatric cancers. STATEMENT OF SIGNIFICANCEPediatric cancers are driven by diverse genomic lesions and sequencing has proven useful in evaluating high risk and relapsed/refractory cases. We show that combined whole genome, exome, and RNA-sequencing of tumor and paired normal tissues enables identification and characterization of genetic drivers across the full spectrum of pediatric cancers.Research.

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“…Acute lymphoblastic leukemia (ALL) is the most frequent childhood tumor and despite cure rates now exceeding 90% in children, outcomes for older children and adults remain poor with cure rates below 40% in those over the age of 40 [1][2][3], despite pediatricinspired chemotherapy regimens [4]. This discrepancy is in part attributable to the different prevalence of genetic alterations across age.…”

Section: Introductionmentioning

confidence: 99%

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

Iacobucci

Kimura

Mullighan

2021

JCM

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Acute lymphoblastic leukemia (ALL) is the most successful paradigm of how risk-adapted therapy and detailed understanding of the genetic alterations driving leukemogenesis and therapeutic response may dramatically improve treatment outcomes, with cure rates now exceeding 90% in children. However, ALL still represents a leading cause of cancer-related death in the young, and the outcome for older adolescents and young adults with ALL remains poor. In the past decade, next generation sequencing has enabled critical advances in our understanding of leukemogenesis. These include the identification of risk-associated ALL subtypes (e.g., those with rearrangements of MEF2D, DUX4, NUTM1, ZNF384 and BCL11B; the PAX5 P80R and IKZF1 N159Y mutations; and genomic phenocopies such as Ph-like ALL) and the genomic basis of disease evolution. These advances have been complemented by the development of novel therapeutic approaches, including those that are of mutation-specific, such as tyrosine kinase inhibitors, and those that are mutation-agnostic, including antibody and cellular immunotherapies, and protein degradation strategies such as proteolysis-targeting chimeras. Herein, we review the genetic taxonomy of ALL with a focus on clinical implications and the implementation of genomic diagnostic approaches.

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The genomic landscape of pediatric acute lymphoblastic leukemia and precision medicine opportunities

Cited by 61 publications

References 127 publications

Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes

Cancer drivers and clonal dynamics in acute lymphoblastic leukaemia subtypes

Genomes for Kids: The Scope of Pathogenic Mutations in Pediatric Cancer Revealed by Comprehensive DNA and RNA Sequencing

Biologic and Therapeutic Implications of Genomic Alterations in Acute Lymphoblastic Leukemia

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