Comprehensive profiling of disease-relevant copy number aberrations for advanced clinical diagnostics of pediatric acute lymphoblastic leukemia

Kiss, Richárd; Gángó, Ambrus; Benard-Slagter, Anne; Egyed, Bálint; Haltrich, Irén; Hegyi, Lajos; Groot, Karel de; Király, Péter Attila; Krizsán, Szilvia; Kajtár, Béla; Pikó, Henriett; Pajor, László; Vojcek, Ágnes; Matolcsy, András; Kovàcs, Gabór; Szuhai, Károly; Savola, Suvi; Bödör, Csaba; Alpár, Donát

doi:10.1038/s41379-019-0423-5

Cited by 10 publications

(16 citation statements)

References 37 publications

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Section: Introductionmentioning

confidence: 99%

“…Triggered by these clinical needs, ALL blast genomic analyses aim to identify novel prognostic markers related to patient outcome [13,[15][16][17][18][19][20][21][22][23][24][25][26][27]. Within this frame, individual copy number alterations (CNAs) involving deletions, duplications or amplifications of genes implicated in B-cell differentiation, cell cycle regulation, proliferation and transcription are constantly gaining relevance as potential risk stratification markers [15][16][17][18][19][20][21][22][23][24][25][26][27]. Additionally, the identification of commonly affected genes in childhood ALL has inspired the development of combined risk classifiers based on copy number status, such as the IKZF1 plus entity [14] and the United Kingdom (UK) ALL-CNA classifiers [25,26], in an effort to further improve patient outcome prediction.…”

Section: Introductionmentioning

confidence: 99%

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Copy Number Alteration Profile Provides Additional Prognostic Value for Acute Lymphoblastic Leukemia Patients Treated on BFM Protocols

Ampatzidou

Florentin

Papadakis

et al. 2021

Cancers

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We present our data of a novel proposed CNA-profile risk-index, applied on a Greek ALLIC-BFM-treated cohort, aiming at further refining genomic risk-stratification. Eighty-five of 227 consecutively treated ALL patients were analyzed for the copy-number-status of eight genes (IKZF1/CDKN2A/2B/PAR1/BTG1/EBF1/PAX5/ETV6/RB1). Using the MLPA-assay, patients were stratified as: (1) Good-risk(GR)-CNA-profile (n = 51), with no deletion of IKZF1/CDKN2A/B/PAR1/BTG1/EBF1/PAX5/ETV6/RB1 or isolated deletions of ETV6/PAX5/BTG1 or ETV6 deletions with a single additional deletion of BTG1/PAX5/CDKN2A/B. (2) Poor-risk(PR)-CNA-profile (n = 34), with any deletion of ΙΚΖF1/PAR1/EBF1/RB1 or any other CΝΑ. With a median follow-up time of 49.9 months, EFS for GR-CNA-profile and PR-CNA-profile patients was 96.0% vs. 57.6% (p < 0.001). For IR-group and HR-group patients, EFS for the GR-CNA/PR-CNA subgroups was 100.0% vs. 60.0% (p < 0.001) and 88.2% vs. 55.6% (p = 0.047), respectively. Among FC-MRDd15 + patients (MRDd15 ≥ 10−4), EFS rates were 95.3% vs. 51.7% for GR-CNA/PR-CNA subjects (p < 0.001). Similarly, among FC-MRDd33 + patients (MRDd33 ≥ 10−4), EFS was 92.9% vs. 27.3% (p < 0.001) and for patients FC-MRDd33 − (MRDd33 < 10−4), EFS was 97.2% vs. 72.7% (p = 0.004), for GR-CNA/PR-CNA patients, respectively. In a multivariate analysis, the CNA-profile was the most important outcome predictor. In conclusion, the CNA-profile can establish a new genomic risk-index, identifying a distinct subgroup with increased relapse risk among the IR-group, as well as a subgroup of patients with superior prognosis among HR-patients. The CNA-profile is feasible in BFM-based protocols, further refining MRD-based risk-stratification.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Copy Number Alteration Profile Provides Additional Prognostic Value for Acute Lymphoblastic Leukemia Patients Treated on BFM Protocols

Ampatzidou

Florentin

Papadakis

et al. 2021

Cancers

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“…Design of multiplexed primers and probes to highly diverse DNA data is a problem commonly encountered in various screening applications [ 2 – 5 ]. For instance, in pathogenicity detection, clinical virology and antimicrobial resistance surveillance one needs to account for the extremely high diversity of relevant genes [ 16 – 18 ].…”

Section: Discussionmentioning

confidence: 99%

“…Here we present an R package Prider, which computes a near-optimal primer coverage for input FASTA file and scales linearly to increasing sequence data. Prider is a flexible tool which permits designing primers and probes for highly scalable molecular screening and quantification applications [ 2 – 5 ]. The key features of Prider are its suitability for scripting, capability of approximating near-optimal set coverage with minimal user intervention, linear scalability to increasing data, and inbuilt capability to visualise the estimated coverage.…”

Section: Introductionmentioning

confidence: 99%

Prider: multiplexed primer design using linearly scaling approximation of set coverage

2022

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Background Designing oligonucleotide primers and probes is one of the key steps of various laboratory experiments such as multiplexed PCR or digital multiplexed ligation assays. When designing multiplexed primers and probes to complex, heterogeneous DNA data sets, an optimization problem can arise where the smallest number of oligonucleotides covering the largest diversity of the input dataset needs to be identified. Tools that provide this optimization in an efficient manner for large input data are currently lacking. Results Here we present Prider, an R package for designing primers and probes with a nearly optimal coverage for complex and large sequence sets. Prider initially prepares a full primer coverage of the input sequences, the complexity of which is subsequently reduced by removing components of high redundancy or narrow coverage. The primers from the resulting near-optimal coverage are easily accessible as data frames and their coverage across the input sequences can be visualised as heatmaps using Prider’s plotting function. Prider permits efficient design of primers to large DNA datasets by scaling linearly to increasing sequence data, regardless of the diversity of the dataset. Conclusions Prider solves a recalcitrant problem in molecular diagnostics: how to cover a maximal sequence diversity with a minimal number of oligonucleotide primers or probes. The combination of Prider with highly scalable molecular quantification techniques will permit an unprecedented molecular screening capability with immediate applicability in fields such as clinical microbiology, epidemic virus surveillance or antimicrobial resistance surveillance.

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“…Secondary aberrations required for the clinically manifest leukemia likely emerge postnatally and generate a branching subclonal architecture in the malignant cell population [ 80 , 81 , 82 ]. During the clinical disease course, leukemic cells with treatment-resistant potential gain selective advantage, and on average, a higher number of genetic alterations can be observed at the time of relapse as compared with diagnosis [ 83 , 84 ]. Recent studies reported distinct signatures of known or therapy-induced novel mutational processes leading to hypermutation and to the acquisition of relapse-driving, drug resistance-associated genomic aberrations [ 85 , 86 , 87 , 88 ].…”

Section: Genomic Epigenomic and Transcriptomic Background Of Pediatric Leukemiamentioning

confidence: 99%

Single-Cell Sequencing: Biological Insight and Potential Clinical Implications in Pediatric Leukemia

Alpár

Egyed

Bödör

et al. 2021

Cancers

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Single-cell sequencing (SCS) provides high-resolution insight into the genomic, epigenomic, and transcriptomic landscape of oncohematological malignancies including pediatric leukemia, the most common type of childhood cancer. Besides broadening our biological understanding of cellular heterogeneity, sub-clonal architecture, and regulatory network of tumor cell populations, SCS can offer clinically relevant, detailed characterization of distinct compartments affected by leukemia and identify therapeutically exploitable vulnerabilities. In this review, we provide an overview of SCS studies focused on the high-resolution genomic and transcriptomic scrutiny of pediatric leukemia. Our aim is to investigate and summarize how different layers of single-cell omics approaches can expectedly support clinical decision making in the future. Although the clinical management of pediatric leukemia underwent a spectacular improvement during the past decades, resistant disease is a major cause of therapy failure. Currently, only a small proportion of childhood leukemia patients benefit from genomics-driven therapy, as 15–20% of them meet the indication criteria of on-label targeted agents, and their overall response rate falls in a relatively wide range (40–85%). The in-depth scrutiny of various cell populations influencing the development, progression, and treatment resistance of different disease subtypes can potentially uncover a wider range of driver mechanisms for innovative therapeutic interventions.

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Comprehensive profiling of disease-relevant copy number aberrations for advanced clinical diagnostics of pediatric acute lymphoblastic leukemia

Cited by 10 publications

References 37 publications

Copy Number Alteration Profile Provides Additional Prognostic Value for Acute Lymphoblastic Leukemia Patients Treated on BFM Protocols

Copy Number Alteration Profile Provides Additional Prognostic Value for Acute Lymphoblastic Leukemia Patients Treated on BFM Protocols

Prider: multiplexed primer design using linearly scaling approximation of set coverage

Single-Cell Sequencing: Biological Insight and Potential Clinical Implications in Pediatric Leukemia

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